WO2014118418A1 - Novel inhibitors of the enzyme isoprenylcysteine carboxyl methyltransferase (icmt) - Google Patents

Novel inhibitors of the enzyme isoprenylcysteine carboxyl methyltransferase (icmt) Download PDF

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WO2014118418A1
WO2014118418A1 PCT/ES2014/070071 ES2014070071W WO2014118418A1 WO 2014118418 A1 WO2014118418 A1 WO 2014118418A1 ES 2014070071 W ES2014070071 W ES 2014070071W WO 2014118418 A1 WO2014118418 A1 WO 2014118418A1
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phenyl
octyl
alaninamide
alkyl
furoyl
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PCT/ES2014/070071
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Spanish (es)
French (fr)
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María Luz LÓPEZ RODRÍGUEZ
Sílvia ORTEGA GUTIÉRREZ
María Del Mar MARTÍN-FONTECHA CORRALES
Moisés BALABASQUER PEÑA
Francisco Jesús ORTEGA NOGALES
Nagore Isabel MARÍN RAMOS
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Universidad Complutense De Madrid
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Publication of WO2014118418A1 publication Critical patent/WO2014118418A1/en

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Definitions

  • New inhibitors of the enzyme isoprenylcysteine carboxymethyltransferase The present invention relates to certain compounds that exhibit activity as inhibitors of the enzyme isoprenylcysteine carboxymethyltransferase (ICMT).
  • the compounds of the present invention are therefore useful in the prevention and / or treatment of pathologies mediated by the ICMT enzyme, in particular antitumor processes.
  • Ras is a small GTPase whose C-terminal end contains the CAAX tetrapeptide motif, where C represents the amino acid cysteine, A is an aliphatic amino acid and X can be any amino acid. Ras undergoes three sequential post-translational modifications.
  • farnesyltransferase (FTase) or geranylgeranyltransferase (GGTase) enzymes bind a farnesyl or geranylgeranyl group to the cysteine of the CAAX sequence.
  • the Ras-converting enzyme 1 (Rce1) endoprotease hydrolyzes the AAX moiety and, finally, the resulting protein is a substrate for the enzyme isoprenylcysteine carboxymethyltransferase (ICMT), which catalyzes the methylation of the carboxy terminal group of the prenylcysteine.
  • ICMT isoprenylcysteine carboxymethyltransferase
  • the enzymes involved in Ras post-translational processing are receiving great attention as targets for the development of new antitumor drugs.
  • the FTase protein has been the subject of various medical chemistry programs, the inhibitors of this enzyme have not shown efficacy in clinical trials, which has been attributed to the fact that in the absence of FTase activity is the enzyme GGTase who catalyzes the farnesylation of the substrate. Therefore, the Rce1 and ICMT proteins have emerged as new targets.
  • the genetic inhibition of the ICMT enzyme i) interferes with the correct location and, therefore, with the activity of said enzyme; ii) induces the death of tumor cells and iii) decreases tumor growth in vivo.
  • ICMT could be a better target, at least a priori, than Rce1.
  • some natural products spermatinamine, aplysamine 6, certain ⁇ -hydroxyhalconas preniladas or flavanones such as (S) -glabrol
  • (S) -glabrol) have been described as inhibitors of the ICMT enzyme
  • Buschanan, MS, et al. Spermatinamine, the first natural product inhibitor of isoprenylcysteine carboxyl methyitransferase, a new cancer target. Bioorg. Med. Chem. Lett.
  • the compound cysmethynil a potent inhibitor of the ICMT enzyme that has antitumor effects
  • Winter-Vann, AM, et al. A small-molecule inhibitor of isoprenylcysteine carboxyl methyitransferase with antitumor activity in cancer cells. Proc. Nati. Acad. Sci. USA 2005, 102, 4336-4341; Wang, M. et al., A small molecule inhibitor of isoprenylcysteine carboxymethyltransferase induces autophagic cell death in PC3 prostate cancer cells. J. Biol. Chem. 2008, 283, 18678- 18684; Cushman, I. et al., Role of isoprenylcysteine carboxyl methyltransferase-catalyzed methylation in Rho function and migration. J. Biol. Chem. 2009, 284,
  • European application EP290393 describes the compound A / 1 -ethyl - / ⁇ / 2 - ⁇ 2- [ethyl (2, 2,6,6-tetramethylpiperidin-4-yl) amino] -2-oxoethyl ⁇ - / ⁇ / 2 -octyl - / ⁇ / 1 - (2, 2,6,6-tetramethylpiperidin-4-yl) glycinamide among other compounds. Indicating that It has activity as a stabilizer of light, heat and oxidation.
  • the present invention relates to compounds of formula (I) or a pharmaceutically acceptable salt, solvate, crystalline form, stereoisomer or prodrug thereof.
  • n is an integer selected from 0, 1 and 2;
  • n is an integer selected from 1 to 2;
  • Q is a radical selected from - (CHUCHU, - (CH 2 ) 5CH 3 , -0 (CH 2 ) 3CH 3 ,
  • R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R 6 , -COR 6 , -COCH 2 R 6 ,
  • R 3 and R 5 are independently selected from H or an alkyl (CC 4 ), cycloyl (C 3 -C 6 ), aryl (C 6 -Cio) or heterocyclyl (C 5 -Ci 0 ) group;
  • R 4 and R 6 are independently selected from a cyclyl (C 3 -C 6 ), aryl (C 6 -Cio) or heterocyclyl (C 5 -Ci 0 ) group optionally substituted by at least one group selected from: H, alkyl ( CC 4 ), alkoxy (CC 4 ), halogen, CF 3 , OH, N0 2 , NH 2 , COOH, CN, alkyl (CrC 4 ) aryl (C 6 -C 10 ), alkyl (CC 4 ) carbonyl, alkyl ( CC 4 ) ester, alkyl (CrC 4 ) amide;
  • a second aspect of this invention relates to the pharmaceutical composition
  • the pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, crystalline forms, stereoisomers or prodrugs together with a carrier or adjuvant pharmaceutically acceptable.
  • the pharmaceutical composition is an antitumor pharmaceutical composition.
  • the invention provides a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, crystalline forms, stereoisomers or prodrugs, as defined above, for use as a medicament.
  • the invention provides the use of a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, crystalline forms, stereoisomers or prodrugs, as defined above, in the preparation of a medicament for prevention and / or treatment of pathologies mediated by the ICMT enzyme in mammals, including humans, said pathology being preferably selected from cancer and proliferative cell disorders.
  • this aspect of the invention can be formulated as a method of prevention and / or treatment of a mammal, including humans, suffering or being susceptible to suffering a pathology mediated by the ICMT enzyme, preferably selected from cancer and proliferative cell disorders, which comprises administering to said patient a therapeutically amount effective of a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, crystalline forms, stereoisomers or prodrugs in combination with a pharmaceutically acceptable carrier or adjuvant.
  • the present invention further comprises a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, crystalline form, stereoisomer or prodrug thereof, in combination with known cancer treatments or proliferative cell disorders, such as a radiotherapy or chemotherapy regimen in combination with cytostatic or cytotoxic agents, antibiotic type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon type agents, cyclooxygenase inhibitors (e.g.
  • COX-2 inhibitors inhibitors of matrix metalloproteases, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptors, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents (e.g., angiogenesis inhibitors), farnesyl transferase inhibitors, inhibitors of transducci route n ras-raf signal, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors and the like.
  • telomerase inhibitors e.g., telomerase inhibitors
  • tyrosine kinase inhibitors e.g., anti-growth factor receptors
  • anti-HER agents e.g., anti-EGFR agents
  • anti-angiogenesis agents e.g., angiogenesis inhibitors
  • farnesyl transferase inhibitors inhibitors of transducci route n ras-raf signal
  • the present invention also relates to the use of a compound of formula (I), as defined above, for the preparation of a medicament for use in the treatment or prevention of cancer or proliferative cell disorders in a patient when said The drug is administered in simultaneous, sequential or combined therapy with a radiotherapy or chemotherapy regimen with one or more chemotherapeutic agents.
  • the invention provides a product or kit comprising a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, crystalline forms, stereoisomers or prodrugs, as defined above, or pharmaceutical compositions thereof and one or more chemotherapeutic agents, such as a combined preparation for simultaneous, individual or sequential use against cancer or proliferative cell disorders.
  • these refer to the use or method of treatment of specific types of cancer that include, but are not limited to: carcinoma such as bladder, breast, colon, kidney, liver, lung, including microcytic lung cancer of the esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hair cell lymphoma and Burkett lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma or
  • these refer to the use or method of treatment of specific cell proliferation disorders, such as, for example, benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, psoriasis, associated vascular smooth cell proliferation with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and stenosis and post-surgical restenosis.
  • specific cell proliferation disorders such as, for example, benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, psoriasis, associated vascular smooth cell proliferation with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and stenosis and post-surgical restenosis.
  • a further aspect of this invention relates to the processes of preparation of the compounds of formula (I) described in the present invention.
  • the present invention includes all isomers, tautomers , hydrates, solvates, complexes, metabolites, prodrugs, transporters, / V-oxides and pharmaceutically acceptable salts of the compounds of the present invention.
  • a metabolite of a compound of formula (I) is any compound in which the same compound of formula (I) is converted in vivo, for example after administration to a mammal that needs it.
  • this same derivative upon administration of a compound of formula (I), this same derivative can be converted into a variety of compounds, including, for example, more soluble derivatives of the hydroxylated derivative type, which are excreted easily. Therefore, depending on the metabolic pathway that occurs, any of these hydroxylated derivatives can be considered as a metabolite of the compounds of formula (I).
  • the prodrugs are any covalently bound compound, which releases the active compound in vivo according to formula (I).
  • the / V-oxides are compounds of formula (I), in which nitrogen and oxygen are in contact through a dative bond.
  • a chiral center or other form of an isomeric center is present in a compound of the present invention, all forms of said isomer or isomers, including enantiomers and diastereomers, and mixtures thereof, form part of the present invention.
  • the chiral center-containing compounds can be used as a racemic mixture, an enantiomerically enriched mixture or the racemic mixture can be separated using well known techniques thereby obtaining an individual enantiomer that can be used alone.
  • both cis (Z) and trans (£) isomers are within the scope of the present invention.
  • each tautomeric form is contemplated as included in the present invention, even if they exist in equilibrium, or predominantly in one form.
  • the preparation processes of the present invention can be modified to give enantiomerically pure compounds, as well as mixtures of stereoisomers. It is possible to prepare specific stereoisomers or mixtures specific by different processes including the use of stereospecific reagents or by introduction of chiral centers in the compounds during the preparation process. Additionally, it is possible to prepare stereoisomers once the compound has been obtained by standard resolution techniques known to those skilled in the art.
  • CrC 4 alkyl refers to radicals derived from saturated, linear or branched hydrocarbons, of 1 to 4 carbon atoms, and which are attached to the rest of the molecule by a single bond, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tere-butyl, etc.
  • C 3 -C 6 cyclyl refers to a radical derived from a cyclic hydrocarbon, saturated or unsaturated, of 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • C 6 -Ci 0 aryl refers to a radical derived from a ring system with 1-3 rings, the aromatic rings, are isolated or optionally condensed and have 5-7 carbon atoms each, including by example phenyl, indenyl, naphthyl, etc.
  • C5-C1 0 heterocyclyl refers to a radical derived from a monocyclic or polycyclic hydrocarbon, saturated, unsaturated or aromatic, of 5 to 10 carbon atoms, optionally condensed, in which at least one of the carbon atoms of the cycle is substituted by nitrogen, oxygen or sulfur, for example furyl, imidazolyl, thienyl, thiazolyl, oxazolyl, pyridinyl, piperidinyl, piperazinyl, morphyl, quinolyl, benzofuryl, etc.
  • alkoxyCrC 4 refers to a linear or branched saturated hydrocarbon chain of 1 to 4 carbon atoms, ie alkyl (CC 4 ), attached to an oxygen atom, that is, alkyl (CC 4 ) -0.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • alkylCrC 4 arylC 6 -Cio refers to an alkyl group of 1 to 4 carbon atoms substituted by an aryl group of 6 to 10 carbon atoms as defined above, for example benzyl, phenylethyl, phenylpropyl, naphthylmethyl , etc.
  • alkylCrC 4 ester refers to a linear or branched saturated hydrocarbon chain of 1 to 4 carbon atoms, ie alkyl (CC 4 ), attached to an O-CO group, that is, alkyl (CC 4 ) -0-CO.
  • alkylCrC 4 amide refers to a linear or branched saturated hydrocarbon chain of 1 to 4 carbon atoms, ie alkyl (CC 4 ), attached to a group -NH-CO, that is, alkyl (CC 4 ) -NH-CO.
  • pharmaceutically acceptable salts includes any salt that can be used in pharmaceutical forms and which is capable of providing, in vivo, directly or indirectly, a compound of formula (I).
  • the nature of the salt is not critical as long as it is pharmaceutically acceptable.
  • the salts of the compound of formula (I) can be obtained from acids or bases, organic or inorganic, by conventional methods well known to those skilled in the art, by reacting the appropriate acid or base with the compound of formula (I) .
  • the prodrugs can be obtained, for example, from a free hydroxyl group that is converted into an ester or an amino group that is converted into an amide, by methods well known to those skilled in the art, by reacting the compound of formula (I) with a carboxylic acid, an anhydride or an acid halide in the presence of a base or catalyst.
  • the compounds of the invention can be in crystalline form both as solvation-free compounds or as solvates (including hydrates), thus both forms being object of the present invention. Solvation methods are generally known in the state of the art.
  • terapéuticaally effective amount refers to the amount of a compound that, when administered, is sufficient to prevent the development or alleviate in some way, one or more symptoms of the disease to which it is going. directed.
  • the particular dose of the compound to be administered according to the present invention will be determined according to the particular circumstances of the case, including the compound, the route of administration, the particular conditions of the patient to be treated, and similar considerations.
  • pharmaceutically acceptable excipients or adjuvants refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must be suitable for use in contact with human or animal tissues or organs without causing excessive toxicity, irritation, allergic response, immunogenicity or other commensurable problems or complications with a reasonable benefit / risk ratio.
  • treatment refers to elimination, reduction or improvement of the cause, effects or progression of a condition; and includes the reduction in the rate of progression, a stop in the progression, improvement of the condition and cure of the condition. Treatment as a prophylactic measure is also included.
  • treatment includes combination treatments and therapies, where two or more treatments or therapies are combined, for example sequentially or simultaneously.
  • pathology mediated by the ICMT enzyme refers to a pathology in which the ICMT enzyme and / or the action of the ICMT enzyme is important or necessary, for example, onset, progression, expression, etc. of said condition.
  • the compounds of formula (I), as defined in the first aspect of the present invention are those where:
  • R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R6, -COOR 6 , -S0 2 NR 5 R 6 , -CH 2 NR 5 R 6 and -CH 2 NR 5 COR 6 .
  • the compounds of formula (I) are those where R ⁇ is a radical selected from -CONR 3 R 4 , -COR 4 and -S0 2 NR 3 R 4 ; more preferably between -CONR 3 R 4 and -COR 4 .
  • the compounds of formula (I), as defined in the first aspect of the present invention are those where:
  • R ⁇ is a radical selected from -CONR 3 R 4 and -COR 4 ;
  • R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R 6 , -COOR 6 , -S0 2 NR 5 R 6 , -CH 2 NR 5 R 6 and -CH 2 NR 5 COR 6 ;
  • each of the rings being optionally substituted by at least one group selected from: H, alkyl (CC 4 ), alkoxy (CC 4 ), halogen, CF 3 , OH, N0 2 , NH 2 , COOH, CN, alkyl (CrC 4 ) aryl (C 6 -C 10 ), alkyl (CC 4 ) carbonyl, alkyl (CC 4 ) ester, alkyl (CrC 4 ) amide.
  • the compounds of formula (I), as defined in the first aspect of the present invention are selected from those where:
  • R 3 and R 5 are independently selected from each other from H, -CH 3 , -CH 2 CH 3 , - CH2CH2CH3, -CH (CH 3 ) 2 , or a radical
  • the compounds of formula (I), as defined in the first aspect of the present invention are those where:
  • Q is a radical selected from - (CHUCHU, - (CH 2 ) 5CH 3 , - ⁇ 2 0 ( ⁇ 2 ) 3 ⁇ - ⁇ 3 , -0 (CH2) 20CH 2 CH3 and -CH 2 0 (CH2) 20CH3; being more preferred those compounds where Q is a radical selected from - (CH 2 ) 4CH 3 , - (CH 2 ) 5CH 3 , -CH 2 0 (CH 2 ) 3CH 3 and -CH 2 0 (CH 2 ) 20CH3.
  • the compounds of formula (I) are those where:
  • R 3 and R 5 are independently selected from each other from H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CI-I 3 , -CH (CH 3 ) 2 , 3-furoyl, 2-furoyl, 3-tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 / - / - pyrrole-2-yl , tien-3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2-yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3 -yl, pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl,
  • R 4 and R 6 are independently selected from each other from 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 - -pyrrol-2- yl, tien-3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2 -yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morpholin-4- yl, phenyl, cyclohexyl and cyclopentyl; each of the rings being optionally substituted by at least one group selected from:
  • the compounds of formula (I) are those where: Q is a radical selected from - (CHUCHU, - (CH 2 ) 5CH 3 , -CH 2 0 (CH 2 ) 3 CH 3 , -0 (CH 2 ) 20CH 2 CH3 and -CH 2 0 (CH2) 20CH 3 ;
  • R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R6, -COOR 6 , -S0 2 NR 5 R 6 , -CH 2 NR 5 R 6 and -CH 2 NR 5 COR 6 ;
  • R 3 and R 5 are independently selected from each other from H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 / - / - pyrrole-2-yl, thien -3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2-yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl , pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morph
  • R 4 and R 6 are independently selected from each other from 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 - -pyrrol-2- yl, tien-3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2 -yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morpholin-4- yl, phenyl, cyclohexyl and cyclopentyl; optionally substituted by at least one group selected from: H, alkyl
  • n is an integer selected from 0, 1 and 2; being more preferred when n is selected between 0 and 2;
  • n is an integer selected between 1 and 2.
  • Q is a radical selected from - (CH 2 ) 4 CH 3 , - (CH 2 ) 5 CH 3 , -CH 2 0 (CH 2 ) 3 CH 3 and
  • R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R 6 , -COOR 6 , -CH 2 NR 5 R 6 and -CH 2 NR 5 COR 6 ;
  • R 3 and R 5 are independently selected from each other from H, -CH 3 , -CH 2 CH 3 ,
  • n 0;
  • n is an integer selected between 1 and 2.
  • Q is a radical selected from - (CH 2 ) 5CH 3 and -CH 2 0 (CH 2 ) 3 CI-l3;
  • R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R 6 , -COOR 6 , -S0 2 NR 5 R 6 , -CH 2 NR 5 R 6 and -CH 2 NR 5 COR 6 ;
  • R 3 and R 5 are independently selected from each other from H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 / - / - pyrrole-2-yl, thien -3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2-yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl , pyridin-4-yl, 1 / - / - indole-2-yl,
  • R 4 and R 6 are independently selected from each other from 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 - -pyrrol-2- yl, tien-3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2 -yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morpholin-4- yl, phenyl, cyclohexyl and cyclopentyl; optionally substituted by at least one group selected from: H, alkyl
  • n is selected between 0 and 2;
  • the compounds of general formula (I) can be prepared from the corresponding alkylamines (II), following the reaction schemes detailed below.
  • the successive alkylations of the amines (II) with the bromoalkylamides (III) and (V) allow to obtain the asymmetric diamides (the), in which it is -CONR 3 R 4 , R 2 is -CONR 5 R 6 ynym are same or different, while symmetric diamides (Ib) and (le) are obtained by dialkylation of alkylamines (II) with 2- bromoacetamides (lll-a) or with acrylamides (VI) (Scheme 1).
  • asymmetric diamides (la) in which n is 2 can be obtained by alkylation of intermediate monoamides (IV) with acrylamides (VI).
  • the monoalkylations of primary amines are carried out in the absence of base and the alkylations of secondary amines or the dialkylations of primary amines take place in the presence of A /./ V-diisopropylethylamine (DIPEA) or 1, 8-diazabicycloundec-7-ene (DBU)
  • DIPEA V-diisopropylethylamine
  • DBU 1, 8-diazabicycloundec-7-ene
  • asymmetric sulfonamides where -S0 2 NR 3 R 4 and R 2 is -S0 2 NR 5 R 6 , can be obtained by consecutive aza-Michael reactions of amines (II) with two ethylenesulfonamides different (VII) (Scheme 2). While the symmetric sulfonamides (le) (R ⁇ R ⁇ -S0 2 NR 3 R 4 ), are prepared by treating the amines (II) with the corresponding ethylene sulfonamide (VII) in excess.
  • Bromoesters (IX) and sulfonyl chlorides (XVII) are obtained from commercial sources (Sigma-Aldrich, Acros, AlfaAesar, Fluorochem, ABCR). Alkylamines (II), bromoamides (III) and (V), acrylamides (VI), vinylsulfonamides (VII), carboxylic acids (XI) as well as alcohols and amines (XIV) and (XV), can be obtained in some cases from the commercial sources mentioned above or be prepared following conventional synthetic methods well known to those skilled in the art.
  • V ⁇ phenyl-A ⁇ -octyl-p-alaninamide (IVa). It was obtained from octylamine (8.8 mmol) and 3-bromo- / V-phenylpropanamide (4.4 mmol) in 65% yield. Chromatography: dichloromethane / m ethyl) 0.12.
  • V-3-furoyl-V-octyl-p-methyl alaninate (Xlla). It was obtained from 3-furoic acid (0.50 mmol) and methyl / V-octyl-p-alaninate (0.25 mmol) in 100% yield. Chromatography: hexane / ethyl acetate, 7: 3. R f (hexane / ethyl acetate, 7: 3) 0.27.
  • V -octyl- V- (1,3-oxazol-5-ylcarbonyl) -p-methyl alaninate (Xllb) was obtained from 1,3-oxazol-5-carboxylic acid (2.8 mmol) and de / V- Methyl octyl-p-alaninate (1.4 mmol) with a yield of 95% Chromatography: hexane / ethyl acetate, 1: 1. R f (hexane / ethyl acetate, 1: 1) 0.30.
  • V-3-furoyl-V-octyl-p-alanine (Xllla). It was obtained from methyl / V-3-fu roi l- / V-octi ⁇ - ⁇ -alaninate (0.68 mmol) in 100% yield.
  • R f (hexane / ethyl acetate, 7: 3) 0.21. mp 77-80 ° C.
  • V- (1 H-imidazol-2-ylcarbonyl) - V-octyl-p -alanine (Xllld) was obtained from ⁇ - ⁇ ⁇ - imidazol-2-ylcarbonyl) - / ⁇ / - octyl ⁇ -alaninate methyl (0.59 mmol) with a yield of 96% R f (hexane / ethyl acetate, 1: 1) 0.12, mp 65-68 ° C.
  • carboxylic acids that possess other acidic hydrogens such as, for example, N-octyl- / V- (1 / - / - pyrrol-2-ylcarbonyl) ⁇ -alanine and ⁇ / - (1 H-imidazol-2- ilcarbonyl) - / ⁇ / - octyl ⁇ - alanine
  • the reaction crude is washed with saturated aqueous solutions of NaHC0 3 and NaCI, consecutively.
  • V ⁇ phenyl-A ⁇ - furoyl-A ⁇ -octyl-p-alaninamide (8). It was obtained from / V 1 -phenyl- / V 3 -octyl ⁇ -alaninamide (1.4 mmol) and 2-furoic acid (2.8 mmol) with a yield of 77%. Chromatography: hexane to hexane / ethyl acetate, 1: 1. R f (hexane / ethyl acetate, 1: 1) 0.40. mp 90-93 ° C.
  • carboxylic acids that possess other acidic hydrogens such as, for example, N-octyl- / V- (1 / - / - pyrrol-2-ylcarbonyl) ⁇ -alanine and ⁇ / - (1 H-imidazol-2- ilcarbonyl) - V-octyl- - alanine
  • the reaction crude is washed with saturated aqueous solutions of NaHC0 3 and NaCI, consecutively.
  • the organic extracts are dried on Na 2 S0 4 and the solvent is removed under reduced pressure. The residue is purified by column chromatography, obtaining the corresponding amido esters.
  • V-3-Furoyl-V-heptyl-p-phenyl alaninate (27) It was obtained from A / -3-furoyl- / V-heptyl-p-alanine (0.18 mmol) and phenol (0.27 mmol) with a yield of 32% Chromatography: hexane / acet ethyl acetate, 7: 3) 0.40.
  • V- [3- (3-Furoylamino) propyl] - V-octyl-3-furamide 49. It was obtained from 3- furoic acid (2.1 mmol) and A / -octylpropane-1,3-diamine (1.1 mmol), following the general procedure B described for the synthesis of amides (If) in example 8, with a 79% yield. Chromatography: dichloromethane / methanol, 8: 2. R f (hexane / ethyl acetate / a
  • EXAMPLE 14 Determination of the inhibitory capacity of the enzyme isoprenylcarboxymethyl transferase of the derivatives of general formula (I).
  • the ability of synthesized compounds to inhibit ICMT activity was determined using membranes from Sf9 cells (Spodoptera frugiperda ovary) that overexpress ICMT as a source of enzyme, and as biotinyl-S-farnesylcysteine (BFC) and S- substrates Tritium-labeled adenosylmethionine ([ 3 H] SAM).
  • BFC biotinyl-S-farnesylcysteine
  • S- substrates Tritium-labeled adenosylmethionine
  • the reaction was terminated with the addition of Tween 20 and by subsequent enrichment with streptavidin bound to a solid support, the radioactivity was quantified by means of liquid scintillation spectrometry.
  • a fluorescence based assay can be used in which the ICMT enzyme is incubate under conditions similar to those indicated above using as substrate and cosustrate / V-acetyl-S-geranylgeranylcysteine (AGGC) and SAM, respectively, and in the presence of enzyme S-adenosylhomocysteine hydrolase (SAHH) and the fluorescent substrate ThioGIol Under these conditions, the S-adenosylhomocysteine generated in the reaction catalyzed by the ICMT is hydrolyzed by the enzyme SAHH generating adenosine and homocysteine.
  • AGGC V-acetyl-S-geranylgeranylcysteine
  • SAHH enzyme S-adenosylhomo
  • the compounds tested are considered active against the ICMT enzyme when they have a percentage of enzyme inhibition greater than 50% at a concentration of 50 ⁇ (Table 1).
  • the inhibition values have been determined at a compound concentration of 50 ⁇ and correspond to the average value of two independent experiments performed in triplicate with an associated error of less than 10% in all cases.
  • EXAMPLE 15 Determination of the stability of derivatives of general formula (I) in human and mouse microsomes and serum.
  • the stability of the compounds of general formula (I) having an inhibition of the ICMT enzyme greater than 70% at a concentration of 50 ⁇ 50 has been determined. For this, the amount of the remaining compound was measured after incubation in human or mouse microsomes or serum at different times in order to determine the half-life.
  • ⁇ _ of the filtered supernatant was analyzed by HPLC-MS on an Agilent 1200LC-MSD VL spectrometer, using an Eclipse XDB-C18 column (5 ⁇ ⁇ , 4.6 mm x 150 mm) together with a pre-column (5 ⁇ , 4.6 mm x 12.5 mm).
  • the mobile phase used consisted of a gradient of solutions A (water: methanol 95: 5) and B (water: methanol 5:95) with 0.1% ammonium hydroxide and 0.1% formic acid as additives.
  • ⁇ _ of a suspension of human microsomes (Aldrich, M0567) or mouse (Aldrich, M9441) were added at a concentration of 5 mg / mL and incubated at 37 ° C during the time of interest, the final concentrations being of compound, NADPH and microsomes in the mixture of 10 ⁇ , 1 mM and 0.5 mg / mL, respectively.
  • 250 ⁇ _ of the mixture was added over 250 ⁇ _ of cold acetonitrile, stirred and incubated for 10 min on ice to precipitate the proteins.
  • the supernatant was separated from the precipitate by centrifugation at 10,000g for 5 min and was passed through a 0.22 ⁇ pore size Teflon filter (Albet Labscience). Next, 50 ⁇ _ of the filtered supernatant was analyzed by HPLC-MS in a manner analogous to that described in the case of serum stability tests.
  • MCF-7, MDA-MB-231 and PC3 cells were determined by a standard test based on the use of 3- (4,5-dimethylthiazol-2- bromide dye il) -2,5-diphenyltetrazolium (MTT). Briefly, the day before the experiment, cells were seeded in 96 - well plates at a density of 5 or 10- 10 March / 100 ⁇ / ⁇ . On the day of the experiment, the medium was removed and the cells were incubated for 48 h in a fresh medium which contained different concentrations of the compounds to be tested.
  • MTT 3- (4,5-dimethylthiazol-2- bromide dye il) -2,5-diphenyltetrazolium

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Abstract

The invention relates to novel inhibitors of the enzyme isoprenylcysteine carboxyl methyltransferase, to the synthesis methods thereof, and to the use thereof as antitumour agents. Said inhibitors are derived from aliphatic amines and are used in the prevention and/or treatment of pathologies caused by the enzyme ICMT.

Description

DESCRIPCIÓN  DESCRIPTION
Nuevos inhibidores de la enzima isoprenilcisteína carboximetiltransferasa (ICMT) La presente invención se refiere a determinados compuestos que presentan actividad como inhibidores de la enzima isoprenilcisteína carboximetiltransferasa (ICMT). Los compuestos de la presente invención son por lo tanto útiles en la prevención y/o tratamiento de patologías mediadas por la enzima ICMT, en particular procesos antitumorales. New inhibitors of the enzyme isoprenylcysteine carboxymethyltransferase (ICMT) The present invention relates to certain compounds that exhibit activity as inhibitors of the enzyme isoprenylcysteine carboxymethyltransferase (ICMT). The compounds of the present invention are therefore useful in the prevention and / or treatment of pathologies mediated by the ICMT enzyme, in particular antitumor processes.
ESTADO DE LA TÉCNICA STATE OF THE TECHNIQUE
Aproximadamente un 30% de los tumores presentan mutaciones en las proteínas Ras, incluyendo el 50% de los cánceres de colon, el 30% de los de pulmón y hasta el 90% de los tumores de páncreas. En estos tumores, la sobreactivación de Ras contribuye en gran medida a diversos aspectos del fenotipo oncológico, tales como la desregulación del ciclo de crecimiento celular y de los mecanismos de apoptosis, así como a los procesos de angiogénesis y metástasis. Ras es una GTPasa pequeña cuyo extremo C terminal contiene el motivo tetrapeptídico CAAX, donde C representa el aminoácido cisteína, A es un aminoácido alifático y X puede ser cualquier aminoácido. Ras sufre tres modificaciones post-traduccionales secuenciales. En primer lugar, las enzimas farnesiltransferasa (FTasa) o geranilgeraniltransferasa (GGTasa) unen un grupo farnesilo o geranilgeranilo a la cisteína de la secuencia CAAX. A continuación, la endoproteasa Ras-converting enzyme 1 (Rce1) hidroliza el resto AAX y, por último, la proteína resultante es sustrato de la enzima isoprenilcisteína carboximetiltransferasa (ICMT), quien cataliza la metilación del grupo carboxilo terminal de la prenilcisteína. Se ha demostrado que en ausencia de sus modificaciones post-traduccionales Ras pierde la capacidad de inducir transformación tumoral. Debido a esto, las enzimas implicadas en el procesado post-traduccional de Ras están recibiendo una gran atención como dianas para el desarrollo de nuevos antitumorales. Aunque la proteína FTasa ha sido objeto de diversos programas de química médica, los inhibidores de esta enzima no han mostrado eficacia en ensayos clínicos, hecho que se ha atribuido a que en ausencia de actividad FTasa es la enzima GGTasa quien cataliza la farnesilacion del sustrato. Por tanto, las proteínas Rce1 e ICMT han surgido como nuevas dianas. De hecho, diversos resultados indican que la inhibición genética de la enzima ICMT i) interfiere con la correcta localización y, por tanto, con la actividad de dicha enzima; ii) induce la muerte de células tumorales y iii) disminuye el crecimiento tumoral in vivo. Asimismo, existen evidencias que señalan que ICMT podría ser mejor diana, al menos a priori, que Rce1. En este sentido, algunos productos naturales (spermatinamine, aplysamine 6, ciertas β- hidroxichalconas preniladas o flavanonas como el (S)-glabrol) se han descrito como inhibidores de la enzima ICMT (Buchanan, M. S., et al., Spermatinamine, the first natural product inhibitor of isoprenylcysteine carboxyl methyitransferase, a new cáncer target. Bioorg. Med. Chem. Lett. 2007, 17, 6860-6863; Buchanan, M. S., et al., Aplysamine 6, an alkaloidal inhibitor of isoprenylcysteine carboxyl methyitransferase from the Sponge Pseudoceratina sp. J. Nat. Prod. 2008, 71, 1066-1067; Buchanan, M. S., et al., Small-molecule inhibitors of the cáncer target, isoprenylcysteine carboxyl methyitransferase, from Hovea parvicalyx. Phytochemistry 2008, 69, 1886-1889), pero su potencia es en general limitada y carecen de buenas propiedades (drug-like) como fármacos. Recientemente se ha descrito el compuesto cysmethynil, un potente inhibidor de la enzima ICMT que presenta efectos antitumorales (Winter-Vann, A. M., et al., A small-molecule inhibitor of isoprenylcysteine carboxyl methyitransferase with antitumor activity in cáncer cells. Proc. Nati. Acad. Sci. USA 2005, 102, 4336-4341 ; Wang, M. et al., A small molecule inhibitor of isoprenylcysteine carboxymethyltransferase induces autophagic cell death in PC3 prostate cáncer cells. J. Biol. Chem. 2008, 283, 18678- 18684; Cushman, I. et al., Role of isoprenylcysteine carboxyl methyltransferase- catalyzed methylation in Rho function and migration. J. Biol. Chem. 2009, 284,Approximately 30% of tumors have mutations in Ras proteins, including 50% of colon cancers, 30% of lung cancers and up to 90% of pancreatic tumors. In these tumors, the overactivation of Ras contributes greatly to various aspects of the oncological phenotype, such as the deregulation of the cell growth cycle and the mechanisms of apoptosis, as well as the processes of angiogenesis and metastasis. Ras is a small GTPase whose C-terminal end contains the CAAX tetrapeptide motif, where C represents the amino acid cysteine, A is an aliphatic amino acid and X can be any amino acid. Ras undergoes three sequential post-translational modifications. First, farnesyltransferase (FTase) or geranylgeranyltransferase (GGTase) enzymes bind a farnesyl or geranylgeranyl group to the cysteine of the CAAX sequence. Then, the Ras-converting enzyme 1 (Rce1) endoprotease hydrolyzes the AAX moiety and, finally, the resulting protein is a substrate for the enzyme isoprenylcysteine carboxymethyltransferase (ICMT), which catalyzes the methylation of the carboxy terminal group of the prenylcysteine. It has been shown that in the absence of its post-translational modifications Ras loses the ability to induce tumor transformation. Because of this, the enzymes involved in Ras post-translational processing are receiving great attention as targets for the development of new antitumor drugs. Although the FTase protein has been the subject of various medical chemistry programs, the inhibitors of this enzyme have not shown efficacy in clinical trials, which has been attributed to the fact that in the absence of FTase activity is the enzyme GGTase who catalyzes the farnesylation of the substrate. Therefore, the Rce1 and ICMT proteins have emerged as new targets. In fact, several results indicate that the genetic inhibition of the ICMT enzyme i) interferes with the correct location and, therefore, with the activity of said enzyme; ii) induces the death of tumor cells and iii) decreases tumor growth in vivo. There is also evidence that ICMT could be a better target, at least a priori, than Rce1. In this sense, some natural products (spermatinamine, aplysamine 6, certain β-hydroxyhalconas preniladas or flavanones such as (S) -glabrol) have been described as inhibitors of the ICMT enzyme (Buchanan, MS, et al., Spermatinamine, the first natural product inhibitor of isoprenylcysteine carboxyl methyitransferase, a new cancer target. Bioorg. Med. Chem. Lett. 2007, 17, 6860-6863; Buchanan, MS, et al., Aplysamine 6, an alkaloidal inhibitor of isoprenylcysteine carboxyl methyitransferase from the Sponge Pseudoceratin sp. J. Nat. Prod. 2008, 71, 1066-1067; Buchanan, MS, et al., Small-molecule inhibitors of the cancer target, isoprenylcysteine carboxyl methyitransferase, from Hovea parvicalyx. Phytochemistry 2008, 69, 1886-1889 ), but their potency is generally limited and they lack good drug-like properties as drugs. The compound cysmethynil, a potent inhibitor of the ICMT enzyme that has antitumor effects (Winter-Vann, AM, et al., A small-molecule inhibitor of isoprenylcysteine carboxyl methyitransferase with antitumor activity in cancer cells. Proc. Nati. Acad. Sci. USA 2005, 102, 4336-4341; Wang, M. et al., A small molecule inhibitor of isoprenylcysteine carboxymethyltransferase induces autophagic cell death in PC3 prostate cancer cells. J. Biol. Chem. 2008, 283, 18678- 18684; Cushman, I. et al., Role of isoprenylcysteine carboxyl methyltransferase-catalyzed methylation in Rho function and migration. J. Biol. Chem. 2009, 284,
27964-27973) aunque sus propiedades farmacocinéticas limitan su aplicabilidad como fármaco. Por tanto, es necesaria la identificación de nuevos inhibidores de la enzima ICMT los cuales puedan ser útiles para el tratamiento de procesos tumorales así como de otros desórdenes asociados con la función y la actividad de la enzima ICMT. 27964-27973) although its pharmacokinetic properties limit its applicability as a drug. Therefore, it is necessary to identify new inhibitors of the ICMT enzyme which may be useful for the treatment of tumor processes as well as other disorders associated with the function and activity of the ICMT enzyme.
En la solicitud europea EP290393 se describe el compuesto A/1-etil-/\/2-{2- [etil(2, 2,6, 6-tetrametilpiperidin-4-il)amino]-2-oxoetil}-/\/2-octyl-/\/1-(2, 2,6,6- tetrametilpiperidin-4-il)glicinamida entre otros compuestos. Indicándose que presenta actividad como estabilizador de la luz, calor y oxidación. European application EP290393 describes the compound A / 1 -ethyl - / \ / 2 - {2- [ethyl (2, 2,6,6-tetramethylpiperidin-4-yl) amino] -2-oxoethyl} - / \ / 2 -octyl - / \ / 1 - (2, 2,6,6-tetramethylpiperidin-4-yl) glycinamide among other compounds. Indicating that It has activity as a stabilizer of light, heat and oxidation.
EXPLICACIÓN DE LA INVENCIÓN EXPLANATION OF THE INVENTION
Los autores de la presente invención han descubierto que los compuestos de fórmula (I), descritos a continuación, son inhibidores de la enzima isoprenilcisteína carboximetiltransferasa (ICMT) y son, por tanto, útiles en la terapia como agentes antitumorales. The authors of the present invention have discovered that the compounds of formula (I), described below, are inhibitors of the enzyme isoprenylcysteine carboxymethyltransferase (ICMT) and are therefore useful in therapy as antitumor agents.
Por consiguiente, en un primer aspecto, la presente invención se refiere a compuestos de fórmula (I) o una de sus sales, solvatos, formas cristalinas, estereoisómeros o profármacos farmacéuticamente aceptables Accordingly, in a first aspect, the present invention relates to compounds of formula (I) or a pharmaceutically acceptable salt, solvate, crystalline form, stereoisomer or prodrug thereof.
Figure imgf000004_0001
Figure imgf000004_0001
(I) en donde:  (I) where:
n es un número entero seleccionado entre 0, 1 y 2; n is an integer selected from 0, 1 and 2;
m es un número entero seleccionado entre 1 y 2; m is an integer selected from 1 to 2;
Q es un radical seleccionado entre -(CHUCHU, -(CH2)5CH3, -0(CH2)3CH3,Q is a radical selected from - (CHUCHU, - (CH 2 ) 5CH 3 , -0 (CH 2 ) 3CH 3 ,
-0(CH2)4CH3, -CH20(CH2)2CH3, -CH20(CH2)3CH3, -(CH2)2OCH2CH3,-0 (CH 2 ) 4 CH 3 , -CH 2 0 (CH 2 ) 2CH3, -CH 2 0 (CH 2 ) 3 CH 3 , - (CH 2 ) 2 OCH 2 CH 3 ,
-(CH2)20(CH2)2CH3, -(CH2)3OCH3, -(CH2)3OCH2CH3, -0(CH2)2OCH2CH3,- (CH 2 ) 2 0 (CH 2 ) 2 CH 3 , - (CH 2 ) 3 OCH 3 , - (CH 2 ) 3 OCH 2 CH 3 , -0 (CH 2 ) 2 OCH 2 CH 3 ,
-0(CH2)2OCH3 y -CH20(CH2)2OCH3; -0 (CH 2 ) 2 OCH 3 and -CH 2 0 (CH 2 ) 2 OCH 3 ;
es un radical seleccionado entre -CONR3R4, -COR4, -S02R4 y -S02NR3R4; it is a radical selected from -CONR 3 R 4 , -COR 4 , -S0 2 R 4 and -S0 2 NR 3 R 4 ;
R2 es un radical seleccionado entre -CONR5R6, -CONR5CH2R6, -COR6, -COCH2R6,R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R 6 , -COR 6 , -COCH 2 R 6 ,
-COOR6, -COOCH2R6, -S02R6, -S02CH2R6, -S02NR5R6, -S02NR5CH2R6, -CH2NR5R6,-COOR 6 , -COOCH 2 R 6 , -S0 2 R 6 , -S0 2 CH 2 R 6 , -S0 2 NR 5 R 6 , -S0 2 NR 5 CH 2 R 6 , -CH 2 NR 5 R 6 ,
-CH2NR5CH2R6, -CH2NR5COR6 y -CH2NR5S02R6; -CH 2 NR 5 CH 2 R 6 , -CH 2 NR 5 COR 6 and -CH 2 NR 5 S0 2 R 6 ;
R3 y R5 son independientemente seleccionados entre H o un grupo alquilo(C C4), ciclilo(C3-C6), arilo(C6-Cio) o heterociclilo(C5-Ci0); R4 y R6 son independientemente seleccionados entre un grupo ciclilo(C3-C6), arilo(C6-Cio) o heterociclilo(C5-Ci0) opcionalmente sustituidos por al menos un grupo seleccionado entre: H, alquilo(C C4), alcoxi(C C4), halógeno, CF3, OH, N02, NH2, COOH, CN, alquil(CrC4)arilo(C6-C10), alquil(C C4)carbonilo, alquil(C C4)éster, alquil(CrC4)amida; R 3 and R 5 are independently selected from H or an alkyl (CC 4 ), cycloyl (C 3 -C 6 ), aryl (C 6 -Cio) or heterocyclyl (C 5 -Ci 0 ) group; R 4 and R 6 are independently selected from a cyclyl (C 3 -C 6 ), aryl (C 6 -Cio) or heterocyclyl (C 5 -Ci 0 ) group optionally substituted by at least one group selected from: H, alkyl ( CC 4 ), alkoxy (CC 4 ), halogen, CF 3 , OH, N0 2 , NH 2 , COOH, CN, alkyl (CrC 4 ) aryl (C 6 -C 10 ), alkyl (CC 4 ) carbonyl, alkyl ( CC 4 ) ester, alkyl (CrC 4 ) amide;
con la condición de que el compuesto no es A/1-etil-/\/2-{2-[etil(2,2,6,6- tetrametilpiperidin-4-il)amino]-2-oxoetil}-A/2-octyl-/\/1-(2,2,6,6-tetrametilpiperidin-4- il)glicinamida. Un segundo aspecto de esta invención se refiere a la composición farmacéutica que comprende una cantidad terapéuticamente efectiva de al menos un compuesto de fórmula (I) o una de sus sales, solvatos, formas cristalinas, estereoisómeros o profármacos farmacéuticamente aceptables junto con un vehículo o adyuvante farmacéuticamente aceptable. Preferiblemente, la composición farmacéutica es una composición farmacéutica antitumoral. with the proviso that the compound is not A / 1 -ethyl - / \ / 2 - {2- [ethyl (2,2,6,6-tetramethylpiperidin-4-yl) amino] -2-oxoethyl} -A / 2 -octyl - / \ / 1 - (2,2,6,6-tetramethylpiperidin-4-yl) glycinamide. A second aspect of this invention relates to the pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, crystalline forms, stereoisomers or prodrugs together with a carrier or adjuvant pharmaceutically acceptable. Preferably, the pharmaceutical composition is an antitumor pharmaceutical composition.
En otro aspecto más, la invención proporciona un compuesto de fórmula (I) o una de sus sales, solvatos, formas cristalinas, estereoisómeros o profármacos farmacéuticamente aceptables, como se ha definido anteriormente, para su uso como medicamento. In yet another aspect, the invention provides a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, crystalline forms, stereoisomers or prodrugs, as defined above, for use as a medicament.
Adicionalmente, la invención proporciona el uso de un compuesto de fórmula (I) o una de sus sales, solvatos, formas cristalinas, estereoisómeros o profármacos farmacéuticamente aceptables, como se ha definido anteriormente, en la preparación de un medicamento para la prevención y/o tratamiento de patologías mediadas por la enzima ICMT en mamíferos, incluyendo humanos, siendo dicha patología seleccionada de manera preferente entre cáncer y trastornos celulares proliferativos. Alternativamente, este aspecto de la invención puede ser formulado como un método de prevención y/o tratamiento de un mamífero, incluyendo humanos, sufriendo o siendo susceptible de sufrir una patología mediada por la enzima ICMT, seleccionada preferentemente entre cáncer y trastornos celulares proliferativos, que comprende la administración a dicho paciente de una cantidad terapéuticamente efectiva de un compuesto de fórmula (I) o una de sus sales, solvatos, formas cristalinas, estereoisómeros o profármacos farmacéuticamente aceptables en combinación con un vehículo o adyuvante farmacéuticamente aceptable. La presente invención comprende adicionalmente una composición farmacéutica que comprende un compuesto de fórmula (I) o una de sus sales, solvatos, formas cristalinas, estereoisómeros o profármacos farmacéuticamente aceptables, en combinación con tratamientos contra el cáncer o trastornos celulares proliferativos conocidos, tales como un régimen de radioterapia o quimioterapia en combinación con agentes citostáticos o citotóxicos, agentes de tipo antibióticos, agentes alquilantes, agentes antimetabolito, agentes hormonales, agentes inmunológicos, agentes de tipo interferón, inhibidores de ciclooxigenasa (por ejemplo, inhibidores de COX-2), inhibidores de metaloproteasas matriciales, inhibidores de telomerasa, inhibidores de tirosina quinasa, agentes receptores de factores anticrecimiento, agentes anti-HER, agentes anti-EGFR, agentes anti-angiogenesis (por ejemplo, inhibidores de angiogenesis), inhibidores de farnesil transferasa, inhibidores de la ruta de la transducción de señal ras-raf, inhibidores del ciclo celular, otros inhibidores de cdks, agentes de unión a tubulina, inhibidores de topoisomerasa I, inhibidores de topoisomerasa II y similares. Additionally, the invention provides the use of a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, crystalline forms, stereoisomers or prodrugs, as defined above, in the preparation of a medicament for prevention and / or treatment of pathologies mediated by the ICMT enzyme in mammals, including humans, said pathology being preferably selected from cancer and proliferative cell disorders. Alternatively, this aspect of the invention can be formulated as a method of prevention and / or treatment of a mammal, including humans, suffering or being susceptible to suffering a pathology mediated by the ICMT enzyme, preferably selected from cancer and proliferative cell disorders, which comprises administering to said patient a therapeutically amount effective of a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, crystalline forms, stereoisomers or prodrugs in combination with a pharmaceutically acceptable carrier or adjuvant. The present invention further comprises a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, crystalline form, stereoisomer or prodrug thereof, in combination with known cancer treatments or proliferative cell disorders, such as a radiotherapy or chemotherapy regimen in combination with cytostatic or cytotoxic agents, antibiotic type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon type agents, cyclooxygenase inhibitors (e.g. COX-2 inhibitors), inhibitors of matrix metalloproteases, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptors, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents (e.g., angiogenesis inhibitors), farnesyl transferase inhibitors, inhibitors of transducci route n ras-raf signal, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors and the like.
Así, la presente invención se refiere también al uso de un compuesto de fórmula (I), según se ha definido anteriormente, para la preparación de un medicamento para su uso en el tratamiento o prevención de cáncer o trastornos celulares proliferativos en un paciente cuando dicho medicamento se administra en terapia simultánea, secuencial o combinada con un régimen de radioterapia o quimioterapia con uno o más agentes quimioterapéuticos. Thus, the present invention also relates to the use of a compound of formula (I), as defined above, for the preparation of a medicament for use in the treatment or prevention of cancer or proliferative cell disorders in a patient when said The drug is administered in simultaneous, sequential or combined therapy with a radiotherapy or chemotherapy regimen with one or more chemotherapeutic agents.
Adicionalmente, la invención proporciona un producto o un kit que comprende un compuesto de fórmula (I) o una de sus sales, solvatos, formas cristalinas, estereoisómeros o profármacos farmacéuticamente aceptables, como se define anteriormente, o composiciones farmacéuticas de los mismos y uno o más agentes quimioterapéuticos, como una preparación combinada para el uso simultáneo, individual o secuencial contra el cáncer o trastornos celulares proliferativos. Según realizaciones preferidas de la presente invención, éstas se refieren al uso o método de tratamiento de tipos específicos de cáncer que incluyen, pero sin limitación: carcinoma tal como de vejiga, de mama, colon, riñon, hígado, pulmón, incluyendo cáncer microcítico pulmonar, de esófago, de vesícula biliar, ovario, páncreas, estómago, cuello uterino, tiroide, próstata y piel, incluyendo carcinoma de células escamosas; tumores hematopoyéticos de linaje linfoide incluyendo leucemia, leucemia linfocítica aguda, leucemia linfoblástica aguda, linfoma de células B, linfoma de células T, linfoma de Hodgkin, linfoma no Hodgkin, linfoma de células pilosas y linfoma de Burkett; tumores hematopoyéticos de linaje mieloide, incluyendo leucemias mielógenas agudas y crónicas, síndrome mielodisplásico y leucemia promielocítica; tumores de origen mesenquimal, incluyendo fibrosarcoma o rabdomiosarcoma; tumores del sistema nervioso central y periférico, incluyendo astrocitoma, neuroblastoma, glioma y schwannomas; otros tumores incluyendo melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentoso, queratoxantoma, cáncer tiroideo folicular y sarcoma de Kaposi. Additionally, the invention provides a product or kit comprising a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates, crystalline forms, stereoisomers or prodrugs, as defined above, or pharmaceutical compositions thereof and one or more chemotherapeutic agents, such as a combined preparation for simultaneous, individual or sequential use against cancer or proliferative cell disorders. According to preferred embodiments of the present invention, these refer to the use or method of treatment of specific types of cancer that include, but are not limited to: carcinoma such as bladder, breast, colon, kidney, liver, lung, including microcytic lung cancer of the esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hair cell lymphoma and Burkett lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma or rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; other tumors including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosa, keratoxanthoma, follicular thyroid cancer and Kaposi's sarcoma.
Según otras realizaciones preferidas de la presente invención, éstas se refieren al uso o método de tratamiento de trastornos de proliferación celular específicos, tales como, por ejemplo, hiperplasia de próstata benigna, poliposis adenomatosa familiar, neurofibromatosis, psoriasis, proliferación de células lisas vasculares asociada con aterosclerosis, fibrosis pulmonar, artritis, glomerulonefritis y estenosis y reestenosis post-quirúrgica. According to other preferred embodiments of the present invention, these refer to the use or method of treatment of specific cell proliferation disorders, such as, for example, benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, psoriasis, associated vascular smooth cell proliferation with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and stenosis and post-surgical restenosis.
Un aspecto adicional de esta invención se refiere a los procesos de preparación de los compuestos de fórmula (I) que se describen en la presente invención. A further aspect of this invention relates to the processes of preparation of the compounds of formula (I) described in the present invention.
A menos que se especifique de otra manera, cuando se hace referencia a los compuestos de fórmula (I) en sí, así como a cualquier composición farmacéutica de los mismos o a cualquier tratamiento terapéutico que los comprenda, la presente invención incluye todos los isómeros, tautómeros, hidratos, solvatos, complejos, metabolitos, profármacos, transportadores, /V-óxidos y sales farmacéuticamente aceptables de los compuestos de la presente invención. Unless otherwise specified, when referring to the compounds of formula (I) itself, as well as any pharmaceutical composition thereof or any therapeutic treatment comprising them, the present invention includes all isomers, tautomers , hydrates, solvates, complexes, metabolites, prodrugs, transporters, / V-oxides and pharmaceutically acceptable salts of the compounds of the present invention.
Un metabolito de un compuesto de fórmula (I) es cualquier compuesto en el que el mismo compuesto de fórmula (I) se convierte in vivo, por ejemplo después de la administración a un mamífero que lo necesite. Típicamente, sin representar de ninguna manera un ejemplo limitante, tras la administración de un compuesto de fórmula (I), este mismo derivado puede convertirse en una diversidad de compuestos, incluyendo, por ejemplo, derivados más solubles de tipo derivados hidroxilados, que se excretan fácilmente. Por tanto, dependiendo de la ruta metabólica que ocurra, cualquiera de estos derivados hidroxilados puede considerarse como un metabolito de los compuestos de fórmula (I). A metabolite of a compound of formula (I) is any compound in which the same compound of formula (I) is converted in vivo, for example after administration to a mammal that needs it. Typically, without representing in any way a limiting example, upon administration of a compound of formula (I), this same derivative can be converted into a variety of compounds, including, for example, more soluble derivatives of the hydroxylated derivative type, which are excreted easily. Therefore, depending on the metabolic pathway that occurs, any of these hydroxylated derivatives can be considered as a metabolite of the compounds of formula (I).
En el contexto de la presente invención, los profármacos son cualquier compuesto unido covalentemente, que libera in vivo el compuesto activo de acuerdo con la fórmula (I). In the context of the present invention, the prodrugs are any covalently bound compound, which releases the active compound in vivo according to formula (I).
Los /V-óxidos son compuestos de fórmula (I), en los que el nitrógeno y oxígeno están en contacto a través de un enlace dativo. The / V-oxides are compounds of formula (I), in which nitrogen and oxygen are in contact through a dative bond.
Si en un compuesto de la presente invención está presente un centro quiral u otra forma de un centro isomérico, todas la formas de dicho isómero o isómeros, incluyendo enantiómeros y diastereómeros, y sus mezclas, forman parte de la presente invención. Los compuestos que contienen centro quiral pueden usarse como una mezcla racémica, una mezcla enantioméricamente enriquecida o bien la mezcla racémica puede separarse usando técnicas bien conocidas obteniéndose de este modo un enantiomero individual que puede usarse en solitario. En los casos en los que los compuestos tengan dobles enlaces carbono-carbono no saturados, tanto los isómeros cis (Z) como los trans (£) se encuentran dentro del alcance de la presente invención. If a chiral center or other form of an isomeric center is present in a compound of the present invention, all forms of said isomer or isomers, including enantiomers and diastereomers, and mixtures thereof, form part of the present invention. The chiral center-containing compounds can be used as a racemic mixture, an enantiomerically enriched mixture or the racemic mixture can be separated using well known techniques thereby obtaining an individual enantiomer that can be used alone. In cases where the compounds have unsaturated carbon-carbon double bonds, both cis (Z) and trans (£) isomers are within the scope of the present invention.
En casos en los que puedan existir compuestos en otras formas tautoméricas, tales como tautómeros de ceto-enol, cada forma tautomérica se contempla como incluida en la presente invención, aunque existan en equilibrio, o predominantemente en una forma. In cases where there may be compounds in other tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as included in the present invention, even if they exist in equilibrium, or predominantly in one form.
Los procesos de preparación de la presente invención, pueden ser modificados para dar compuestos enantioméricamente puros, así como mezclas de estereoisómeros. Es posible preparar estereoisómeros específicos o mezclas específicas mediante diferentes procesos incluyendo el uso de reactivos estereoespecíficos o por introducción de centros quirales en los compuestos durante el proceso de preparación. Adicionalmente, es posible preparar estereoisómeros una vez ha sido obtenido el compuesto mediante técnicas estándar de resolución conocidas por el experto en la materia. The preparation processes of the present invention can be modified to give enantiomerically pure compounds, as well as mixtures of stereoisomers. It is possible to prepare specific stereoisomers or mixtures specific by different processes including the use of stereospecific reagents or by introduction of chiral centers in the compounds during the preparation process. Additionally, it is possible to prepare stereoisomers once the compound has been obtained by standard resolution techniques known to those skilled in the art.
En el contexto de la presente invención los siguientes términos tienen el significado que se detalla a continuación. El término "alquilo CrC4" se refiere a radicales derivados de hidrocarburos saturados, lineales o ramificados, de 1 a 4 átomos de carbono, y que se unen al resto de la molécula mediante un enlace sencillo, por ejemplo metilo, etilo, propilo, isopropilo, butilo, sec-butilo, tere-butilo, etc. El término "ciclilo C3-C6" se refiere a un radical derivado de un hidrocarburo cíclico, saturado o insaturado, de 3 a 6 átomos de carbono, por ejemplo ciclopropilo, ciclobutilo, ciclopentilo o ciclohexilo. In the context of the present invention the following terms have the meaning detailed below. The term "CrC 4 alkyl" refers to radicals derived from saturated, linear or branched hydrocarbons, of 1 to 4 carbon atoms, and which are attached to the rest of the molecule by a single bond, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tere-butyl, etc. The term "C 3 -C 6 cyclyl" refers to a radical derived from a cyclic hydrocarbon, saturated or unsaturated, of 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
El término "arilo C6-Ci0" se refiere a un radical derivado de un sistema de anillo con 1-3 anillos, los anillos aromáticos, están aislados u opcionalmente condensados y tienen de 5-7 átomos de carbono cada uno, incluyendo por ejemplo fenilo, indenilo, naftilo, etc. The term "C 6 -Ci 0 aryl" refers to a radical derived from a ring system with 1-3 rings, the aromatic rings, are isolated or optionally condensed and have 5-7 carbon atoms each, including by example phenyl, indenyl, naphthyl, etc.
El término "heterociclilo C5-C10" se refiere a un radical derivado de un hidrocarburo monocíclico o policíclico, saturado, insaturado o aromático, de 5 a 10 átomos de carbono, opcionalmente condensados, en el cual al menos uno de los átomos de carbono del ciclo es sustituido por nitrógeno, oxígeno o azufre, por ejemplo furilo, imidazolilo, tienilo, tiazolilo, oxazolilo, piridinilo, piperidinilo, piperazinilo, morfolilo, quinolilo, benzofurilo, etc. The term "C5-C1 0 heterocyclyl" refers to a radical derived from a monocyclic or polycyclic hydrocarbon, saturated, unsaturated or aromatic, of 5 to 10 carbon atoms, optionally condensed, in which at least one of the carbon atoms of the cycle is substituted by nitrogen, oxygen or sulfur, for example furyl, imidazolyl, thienyl, thiazolyl, oxazolyl, pyridinyl, piperidinyl, piperazinyl, morphyl, quinolyl, benzofuryl, etc.
El término "alcoxiCrC4" se refiere a una cadena hidrocarbonada satura lineal o ramificada de 1 a 4 átomos de carbono, es decir alquil(C C4), unida a un átomo de oxígeno, es decir, alquil(C C4)-0. The term "alkoxyCrC 4 " refers to a linear or branched saturated hydrocarbon chain of 1 to 4 carbon atoms, ie alkyl (CC 4 ), attached to an oxygen atom, that is, alkyl (CC 4 ) -0.
El término "halógeno" incluye flúor, cloro, bromo y yodo. El término "alquilCrC4ariloC6-Cio" se refiere a un grupo alquilo de 1 a 4 átomos de carbono sustituido por un grupo arilo de 6 a 10 átomos de carbono tal como se definió anteriormente, por ejemplo bencilo, feniletilo, fenilpropilo, naftilmetilo, etc. The term "halogen" includes fluorine, chlorine, bromine and iodine. The term "alkylCrC 4 arylC 6 -Cio" refers to an alkyl group of 1 to 4 carbon atoms substituted by an aryl group of 6 to 10 carbon atoms as defined above, for example benzyl, phenylethyl, phenylpropyl, naphthylmethyl , etc.
El término "alquilCrC4carbonilo" se refiere a una cadena hidrocarbonada saturada lineal o ramificada de 1 a 4 átomos de carbono, es decir alquil (C C4), unida a un grupo C=0, es decir, alquil(C C4)-CO. El término "alquilCrC4éster" se refiere a una cadena hidrocarbonada saturada lineal o ramificada de 1 a 4 átomos de carbono, es decir alquil(C C4), unida a un grupo - O-CO, es decir, alquil(C C4)-0-CO. The term "alkylCrC 4 carbonyl" refers to a linear or branched saturated hydrocarbon chain of 1 to 4 carbon atoms, ie alkyl (CC 4 ), attached to a group C = 0, that is, alkyl (CC 4 ) - CO. The term "alkylCrC 4 ester" refers to a linear or branched saturated hydrocarbon chain of 1 to 4 carbon atoms, ie alkyl (CC 4 ), attached to an O-CO group, that is, alkyl (CC 4 ) -0-CO.
El término "alquilCrC4amida" se refiere a una cadena hidrocarbonada saturada lineal o ramificada de 1 a 4 átomos de carbono, es decir alquil(C C4), unida a un grupo -NH-CO, es decir, alquil(C C4)-NH-CO. The term "alkylCrC 4 amide" refers to a linear or branched saturated hydrocarbon chain of 1 to 4 carbon atoms, ie alkyl (CC 4 ), attached to a group -NH-CO, that is, alkyl (CC 4 ) -NH-CO.
El término "sales farmacéuticamente aceptables" tal como se utiliza en la presente invención incluye cualquier sal susceptible de ser utilizada en formas farmacéuticas y que es capaz de proporcionar in vivo, directa o indirectamente, un compuesto de fórmula (I). La naturaleza de la sal no es crítica siempre y cuando sea farmacéuticamente aceptable. The term "pharmaceutically acceptable salts" as used in the present invention includes any salt that can be used in pharmaceutical forms and which is capable of providing, in vivo, directly or indirectly, a compound of formula (I). The nature of the salt is not critical as long as it is pharmaceutically acceptable.
Las sales del compuesto de fórmula (I) pueden obtenerse a partir de ácidos o bases, orgánicos o inorgánicos, por métodos convencionales bien conocidos por los técnicos en la materia, haciendo reaccionar el ácido o la base apropiado con el compuesto de fórmula (I). The salts of the compound of formula (I) can be obtained from acids or bases, organic or inorganic, by conventional methods well known to those skilled in the art, by reacting the appropriate acid or base with the compound of formula (I) .
Los profármacos pueden obtenerse, por ejemplo, a partir de un grupo hidroxilo libre que es convertido en un éster o de un grupo amino que es convertido en una amida, mediante procedimientos bien conocidos por los técnicos en la materia, haciendo reaccionar el compuesto de fórmula (I) con un ácido carboxílico, un anhídrido o un haluro de ácido en presencia de una base o catalizador. Los compuestos de la invención pueden estar en forma cristalina tanto como compuestos libres de solvatación o como solvatos (incluyendo hidratos), siendo por tanto objeto de la presente invención ambas formas. Los métodos de solvatación son generalmente conocidos en el estado de la técnica. The prodrugs can be obtained, for example, from a free hydroxyl group that is converted into an ester or an amino group that is converted into an amide, by methods well known to those skilled in the art, by reacting the compound of formula (I) with a carboxylic acid, an anhydride or an acid halide in the presence of a base or catalyst. The compounds of the invention can be in crystalline form both as solvation-free compounds or as solvates (including hydrates), thus both forms being object of the present invention. Solvation methods are generally known in the state of the art.
La expresión "cantidad terapéuticamente efectiva" tal como se emplea aquí, se refiere a la cantidad de un compuesto que, cuando se administra, es suficiente para prevenir el desarrollo o aliviar de algún modo, uno o más síntomas de la enfermedad a la que va dirigida. La dosis particular del compuesto a administrar de acuerdo con la presente invención será determinada de acuerdo con las circunstancias particulares del caso, incluyendo el compuesto, la ruta de administración, las condiciones particulares del paciente a tratar, y consideraciones similares. La expresión "excipientes o adyuvantes farmacéuticamente aceptables" se refiere a materiales, composiciones o vehículos farmacéuticamente aceptables. Cada componente debe ser farmacéuticamente aceptable en el sentido de ser compatible con los otros ingredientes de la composición farmacéutica. Debe ser adecuado para su uso en contacto con tejidos u órganos de humanos o animales sin provocar excesiva toxicidad, irritación, respuesta alérgica, inmunogenicidad u otros problemas o complicaciones conmensurables con una razonable relación beneficio/riesgo. The term "therapeutically effective amount" as used herein refers to the amount of a compound that, when administered, is sufficient to prevent the development or alleviate in some way, one or more symptoms of the disease to which it is going. directed. The particular dose of the compound to be administered according to the present invention will be determined according to the particular circumstances of the case, including the compound, the route of administration, the particular conditions of the patient to be treated, and similar considerations. The term "pharmaceutically acceptable excipients or adjuvants" refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must be suitable for use in contact with human or animal tissues or organs without causing excessive toxicity, irritation, allergic response, immunogenicity or other commensurable problems or complications with a reasonable benefit / risk ratio.
A lo largo de la presente invención, el término "tratamiento" se refiere a eliminación, reducción o mejora de la causa, los efectos o progresión de una condición; e incluye la reducción en el ratio de progresión, una parada en la progresión, mejora de la condición y cura de la condición. Tratamiento como medida profiláctica está también incluido. El término tratamiento incluye tratamientos y terapias de combinación, en donde dos o más tratamientos o terapias son combinadas, por ejemplo secuencial o simultáneamente. Throughout the present invention, the term "treatment" refers to elimination, reduction or improvement of the cause, effects or progression of a condition; and includes the reduction in the rate of progression, a stop in the progression, improvement of the condition and cure of the condition. Treatment as a prophylactic measure is also included. The term treatment includes combination treatments and therapies, where two or more treatments or therapies are combined, for example sequentially or simultaneously.
El término "patología mediada por la enzima ICMT" se refiere a una patología en la que la enzima ICMT y/o la acción de la enzima ICMT es importante o necesaria, por ejemplo el inicio, progresión, expresión, etc. de dicha condición. Según una realización preferida de la presente invención, los compuestos de fórmula (I), según se definen en el primer aspecto de la presente invención, son aquellos donde: The term "pathology mediated by the ICMT enzyme" refers to a pathology in which the ICMT enzyme and / or the action of the ICMT enzyme is important or necessary, for example, onset, progression, expression, etc. of said condition. According to a preferred embodiment of the present invention, the compounds of formula (I), as defined in the first aspect of the present invention, are those where:
R2 es un radical seleccionado entre -CONR5R6, -CONR5CH2R6, -COOR6, -S02NR5R6, -CH2NR5R6 y -CH2NR5COR6. R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R6, -COOR 6 , -S0 2 NR 5 R 6 , -CH 2 NR 5 R 6 and -CH 2 NR 5 COR 6 .
De acuerdo con algunas realizaciones preferidas, los compuestos de fórmula (I) son aquellos donde R^ es un radical seleccionado entre -CONR3R4, -COR4 y -S02NR3R4 ; más preferiblemente entre -CONR3R4 y -COR4. According to some preferred embodiments, the compounds of formula (I) are those where R ^ is a radical selected from -CONR 3 R 4 , -COR 4 and -S0 2 NR 3 R 4 ; more preferably between -CONR 3 R 4 and -COR 4 .
Según algunas realizaciones preferidas los compuestos de fórmula (I), según se definen en el primer aspecto de la presente invención, son aquellos donde: According to some preferred embodiments the compounds of formula (I), as defined in the first aspect of the present invention, are those where:
es un radical seleccionado entre -CONR3R4, -COR4 y -S02NR3R4; más preferiblemente R^ es un radical seleccionado entre -CONR3R4 y -COR4; it is a radical selected from -CONR 3 R 4 , -COR 4 and -S0 2 NR 3 R 4 ; more preferably R ^ is a radical selected from -CONR 3 R 4 and -COR 4 ;
R2 es un radical seleccionado entre -CONR5R6, -CONR5CH2R6, -COOR6, -S02NR5R6, -CH2NR5R6 y -CH2NR5COR6; R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R 6 , -COOR 6 , -S0 2 NR 5 R 6 , -CH 2 NR 5 R 6 and -CH 2 NR 5 COR 6 ;
Figure imgf000012_0001
estando cada uno de los anillos opcionalmente sustituido por al menos un grupo seleccionado entre: H, alquilo(C C4), alcoxi(C C4), halógeno, CF3, OH, N02, NH2, COOH, CN, alquil(CrC4)arilo(C6-C10), alquil(C C4)carbonilo, alquil(C C4)éster, alquil(CrC4)amida. De acuerdo con algunas realizaciones preferidas, los compuestos de fórmula (I), según se definen en el primer aspecto de la presente invención, se seleccionan entre aquellos donde:
Figure imgf000012_0001
each of the rings being optionally substituted by at least one group selected from: H, alkyl (CC 4 ), alkoxy (CC 4 ), halogen, CF 3 , OH, N0 2 , NH 2 , COOH, CN, alkyl (CrC 4 ) aryl (C 6 -C 10 ), alkyl (CC 4 ) carbonyl, alkyl (CC 4 ) ester, alkyl (CrC 4 ) amide. According to some preferred embodiments, the compounds of formula (I), as defined in the first aspect of the present invention, are selected from those where:
R3 y R5 se seleccionan independientemente uno del otro entre H, -CH3, -CH2CH3, - CH2CH2CH3, -CH (CH3)2, o un radical R 3 and R 5 are independently selected from each other from H, -CH 3 , -CH 2 CH 3 , - CH2CH2CH3, -CH (CH 3 ) 2 , or a radical
Figure imgf000013_0001
Figure imgf000013_0001
Según otra realización preferida, los compuestos de fórmula (I), según se definen en el primer aspecto de la presente invención, son aquellos donde: According to another preferred embodiment, the compounds of formula (I), as defined in the first aspect of the present invention, are those where:
Q es un radical seleccionado entre -(CHUCHU, -(CH2)5CH3, -ΟΗ20(ΟΗ2)3ΟΙ-Ι3, -0(CH2)20CH2CH3 y -CH20(CH2)20CH3; siendo más preferidos aquellos compuestos donde Q es un radical seleccionado entre -(CH2)4CH3, -(CH2)5CH3, -CH20(CH2)3CH3 y -CH20(CH2)20CH3. Q is a radical selected from - (CHUCHU, - (CH 2 ) 5CH 3 , -ΟΗ 2 0 (ΟΗ 2 ) 3 ΟΙ-Ι 3 , -0 (CH2) 20CH 2 CH3 and -CH 2 0 (CH2) 20CH3; being more preferred those compounds where Q is a radical selected from - (CH 2 ) 4CH 3 , - (CH 2 ) 5CH 3 , -CH 2 0 (CH 2 ) 3CH 3 and -CH 2 0 (CH 2 ) 20CH3.
En algunas realizaciones preferidas, los compuestos de fórmula (I) son aquellos donde: In some preferred embodiments, the compounds of formula (I) are those where:
R3 y R5 se seleccionan independientemente uno del otro entre H, -CH3, -CH2CH3, -CH2CH2CI-I3, -CH(CH3)2, 3-furoilo, 2-furoilo, 3-tetrahidrofuranilo, 1 ,3-oxazol-5-ilo, 1 /-/-pirrol-3-ilo, 1 /-/-pirrol-2-ilo, 1-metil-1 /-/-pirrol-2-ilo, tien-3-ilo, 1 /-/-1 ,2,4-triazol-3-ilo, 1 /-/-imidazol-2-ilo, pirrolidin-2-ilo, piridin-2-ilo, piridin-3-ilo, piridin-4-ilo, 1 /-/-indol-2-ilo, 1-benzofuran-3-ilo, morfolin-4-ilo, fenilo, ciclohexilo y ciclopentilo; R 3 and R 5 are independently selected from each other from H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CI-I 3 , -CH (CH 3 ) 2 , 3-furoyl, 2-furoyl, 3-tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 / - / - pyrrole-2-yl , tien-3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2-yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3 -yl, pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morpholin-4-yl, phenyl, cyclohexyl and cyclopentyl;
R4 y R6 se seleccionan independientemente uno del otro entre 3-furoilo, 2-furoilo, 3- tetrahidrofuranilo, 1 ,3-oxazol-5-ilo, 1 /-/-pirrol-3-ilo, 1 /-/-pirrol-2-ilo, 1-metil-1 - -pirrol-2- ilo, tien-3-ilo, 1 /-/-1 ,2,4-triazol-3-ilo, 1 /-/-imidazol-2-ilo, pirrolidin-2-ilo, piridin-2-ilo, piridin-3-ilo, piridin-4-ilo, 1 /-/-indol-2-ilo, 1-benzofuran-3-ilo, morfolin-4-ilo, fenilo, ciclohexilo y ciclopentilo; estando cada uno de los anillos opcionalmente sustituido por al menos un grupo seleccionado entre: H, alquilo(C C4), alcoxi(C C4), halógeno, CF3, OH, N02, NH2, COOH, CN, alquil(CrC4)arilo(C6-C10), alquil(C C4)carbonilo, alquil(CrC4)éster, alquil(C C4)amida; R 4 and R 6 are independently selected from each other from 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 - -pyrrol-2- yl, tien-3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2 -yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morpholin-4- yl, phenyl, cyclohexyl and cyclopentyl; each of the rings being optionally substituted by at least one group selected from: H, alkyl (CC 4 ), alkoxy (CC 4 ), halogen, CF 3 , OH, N0 2 , NH 2 , COOH, CN, alkyl (CrC 4 ) aryl (C 6 -C 10 ), alkyl (CC 4 ) carbonyl, alkyl (CrC 4 ) ester, alkyl (CC 4 ) amide;
Así, según ciertas realizaciones preferidas, los compuestos de fórmula (I) son aquellos donde: Q es un radical seleccionado entre -(CHUCHU, -(CH2)5CH3, -CH20(CH2)3CH3, -0(CH2)20CH2CH3 y -CH20(CH2)20CH3; Thus, according to certain preferred embodiments, the compounds of formula (I) are those where: Q is a radical selected from - (CHUCHU, - (CH 2 ) 5CH 3 , -CH 2 0 (CH 2 ) 3 CH 3 , -0 (CH 2 ) 20CH 2 CH3 and -CH 2 0 (CH2) 20CH 3 ;
es un radical seleccionado entre -CONR3R4 y -COR4, -S02NR3R4; it is a radical selected from -CONR 3 R 4 and -COR 4 , -S0 2 NR 3 R 4 ;
R2 es un radical seleccionado entre -CONR5R6, -CONR5CH2R6, -COOR6, -S02NR5R6, -CH2NR5R6 y -CH2NR5COR6; R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R6, -COOR 6 , -S0 2 NR 5 R 6 , -CH 2 NR 5 R 6 and -CH 2 NR 5 COR 6 ;
R3 y R5 se seleccionan independientemente uno del otro entre H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, 3-furoilo, 2-furoilo, 3-tetrahidrofuranilo, 1 ,3-oxazol-5-ilo, 1 /-/-pirrol-3-ilo, 1 /-/-pirrol-2-ilo, 1-metil-1 /-/-pirrol-2-ilo, tien-3-ilo, 1 /-/-1 ,2,4-triazol-3-ilo, 1 /-/-imidazol-2-ilo, pirrolidin-2-ilo, piridin-2-ilo, piridin-3-ilo, piridin-4-ilo, 1 /-/-indol-2-ilo, 1-benzofuran-3-ilo, morfolin-4-ilo, fenilo, ciclohexilo y ciclopentilo; R 3 and R 5 are independently selected from each other from H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 / - / - pyrrole-2-yl, thien -3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2-yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl , pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morpholin-4-yl, phenyl, cyclohexyl and cyclopentyl;
R4 y R6 se seleccionan independientemente uno del otro entre 3-furoilo, 2-furoilo, 3- tetrahidrofuranilo, 1 ,3-oxazol-5-ilo, 1 /-/-pirrol-3-ilo, 1 /-/-pirrol-2-ilo, 1-metil-1 - -pirrol-2- ilo, tien-3-ilo, 1 /-/-1 ,2,4-triazol-3-ilo, 1 /-/-imidazol-2-ilo, pirrolidin-2-ilo, piridin-2-ilo, piridin-3-ilo, piridin-4-ilo, 1 /-/-indol-2-ilo, 1-benzofuran-3-ilo, morfolin-4-ilo, fenilo, ciclohexilo y ciclopentilo; opcionalmente sustituidos por al menos un grupo seleccionado entre: H, alquilo(C C4), alcoxi(C C4), halógeno, CF3, OH, N02, NH2, COOH, CN, alquil(CrC4)arilo(C6-C10), alquil(C C4)carbonilo, alquil(C C4)éster, alquil(CrC4)amida; R 4 and R 6 are independently selected from each other from 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 - -pyrrol-2- yl, tien-3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2 -yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morpholin-4- yl, phenyl, cyclohexyl and cyclopentyl; optionally substituted by at least one group selected from: H, alkyl (CC 4 ), alkoxy (CC 4 ), halogen, CF 3 , OH, N0 2 , NH 2 , COOH, CN, alkyl (CrC 4 ) aryl (C 6 -C 10 ), alkyl (CC 4 ) carbonyl, alkyl (CC 4 ) ester, alkyl (CrC 4 ) amide;
n es un número entero seleccionado entre 0, 1 y 2; siendo más preferido cuando n se selecciona entre 0 y 2; n is an integer selected from 0, 1 and 2; being more preferred when n is selected between 0 and 2;
m es un número entero seleccionado entre 1 y 2. m is an integer selected between 1 and 2.
Son particularmente preferidos aquellos compuestos de fórmula (I), según se definen en el primer aspecto de la presente invención, donde: Particularly preferred are those compounds of formula (I), as defined in the first aspect of the present invention, where:
Q es un radical seleccionado entre -(CH2)4CH3, -(CH2)5CH3, -CH20(CH2)3CH3 yQ is a radical selected from - (CH 2 ) 4 CH 3 , - (CH 2 ) 5 CH 3 , -CH 2 0 (CH 2 ) 3 CH 3 and
-CH20(CH2)2OCH3; -CH 2 0 (CH 2 ) 2 OCH 3 ;
es un radical seleccionado entre -CONR3R4 y -COR4; it is a radical selected from -CONR 3 R 4 and -COR 4 ;
R2 es un radical seleccionado entre -CONR5R6, -CONR5CH2R6, -COOR6, -CH2NR5R6 y -CH2NR5COR6; R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R 6 , -COOR 6 , -CH 2 NR 5 R 6 and -CH 2 NR 5 COR 6 ;
R3 y R5 se seleccionan independientemente uno del otro entre H, -CH3, -CH2CH3,R 3 and R 5 are independently selected from each other from H, -CH 3 , -CH 2 CH 3 ,
-CH2CH2CH3, -CH(CH3)2, 3-furoilo, 2-furoilo, 3-tetrahidrofuranilo, 1 ,3-oxazol-5-ilo, 1 /-/-pirrol-3-ilo, 1 /-/-pirrol-2-ilo, 1-metil-1 /-/-pirrol-2-ilo, tien-3-ilo, 1 /-/-1 ,2,4-triazol-3-ilo, 1 /-/-imidazol-2-ilo, pirrolidin-2-ilo, piridin-2-ilo, piridin-3-ilo, piridin-4-ilo, 1 /-/-indol-2-ilo, 1-benzofuran-3-ilo, morfolin-4-ilo, fenilo y ciclopentilo; R4 y R6 se seleccionan independientemente uno del otro entre 3-furoilo, 2-furoilo, 3- tetrahidrofuranilo, 1 ,3-oxazol-5-ilo, 1 /-/-pirrol-3-ilo, 1 /-/-pirrol-2-ilo, 1-metil-1 - -pirrol-2- ilo, tien-3-ilo, 1 /-/-1 ,2,4-triazol-3-ilo, 1 /-/-imidazol-2-ilo, pirrolidin-2-ilo, piridin-2-ilo, piridin-3-ilo, piridin-4-ilo, 1 /-/-indol-2-ilo, 1-benzofuran-3-ilo, morfolin-4-ilo, fenilo y ciclopentilo; estando cada uno de los anillos opcionalmente sustituido por al menos un grupo seleccionado entre: H, alquilo(C C4), alcoxi(C C4), halógeno, CF3, OH, N02, NH2, COOH, CN, alquil(CrC4)arilo(C6-C10), alquil(C C4)carbonilo, alquil(C C4)éster, alquil(C C4)amida; -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , 3-furoyl, 2-furoyl, 3-tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrole-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 / - / - pyrrol-2-yl, tien-3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2-yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3- yl, morpholin-4-yl, phenyl and cyclopentyl; R 4 and R 6 are independently selected from each other from 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 - -pyrrol-2- yl, tien-3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2 -yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morpholin-4- yl, phenyl and cyclopentyl; each of the rings being optionally substituted by at least one group selected from: H, alkyl (CC 4 ), alkoxy (CC 4 ), halogen, CF 3 , OH, N0 2 , NH 2 , COOH, CN, alkyl (CrC 4 ) aryl (C 6 -C 10 ), alkyl (CC 4 ) carbonyl, alkyl (CC 4 ) ester, alkyl (CC 4 ) amide;
n es 0; n is 0;
m es un número entero seleccionado entre 1 y 2. m is an integer selected between 1 and 2.
Realizaciones particularmente preferidas son aquellas donde: Particularly preferred embodiments are those where:
Q es un radical seleccionado entre -(CH2)5CH3 y -CH20(CH2)3CI-l3; Q is a radical selected from - (CH 2 ) 5CH 3 and -CH 2 0 (CH 2 ) 3 CI-l3;
es un radical seleccionado entre -CONR3R4, -COR4 y -S02NR3R4; it is a radical selected from -CONR 3 R 4 , -COR 4 and -S0 2 NR 3 R 4 ;
R2 es un radical seleccionado entre -CONR5R6, -CONR5CH2R6, -COOR6, -S02NR5R6, -CH2NR5R6 y -CH2NR5COR6; R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R 6 , -COOR 6 , -S0 2 NR 5 R 6 , -CH 2 NR 5 R 6 and -CH 2 NR 5 COR 6 ;
R3 y R5 se seleccionan independientemente uno del otro entre H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, 3-furoilo, 2-furoilo, 3-tetrahidrofuranilo, 1 ,3-oxazol-5-ilo, 1 /-/-pirrol-3-ilo, 1 /-/-pirrol-2-ilo, 1-metil-1 /-/-pirrol-2-ilo, tien-3-ilo, 1 /-/-1 ,2,4-triazol-3-ilo, 1 /-/-imidazol-2-ilo, pirrolidin-2-ilo, piridin-2-ilo, piridin-3-ilo, piridin-4-ilo, 1 /-/-indol-2-ilo,R 3 and R 5 are independently selected from each other from H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 / - / - pyrrole-2-yl, thien -3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2-yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl , pyridin-4-yl, 1 / - / - indole-2-yl,
1-benzofuran-3-ilo, morfolin-4-ilo, fenilo, ciclohexilo y ciclopentilo; 1-benzofuran-3-yl, morpholin-4-yl, phenyl, cyclohexyl and cyclopentyl;
R4 y R6 se seleccionan independientemente uno del otro entre 3-furoilo, 2-furoilo, 3- tetrahidrofuranilo, 1 ,3-oxazol-5-ilo, 1 /-/-pirrol-3-ilo, 1 /-/-pirrol-2-ilo, 1-metil-1 - -pirrol-2- ilo, tien-3-ilo, 1 /-/-1 ,2,4-triazol-3-ilo, 1 /-/-imidazol-2-ilo, pirrolidin-2-ilo, piridin-2-ilo, piridin-3-ilo, piridin-4-ilo, 1 /-/-indol-2-ilo, 1-benzofuran-3-ilo, morfolin-4-ilo, fenilo, ciclohexilo y ciclopentilo; opcionalmente sustituidos por al menos un grupo seleccionado entre: H, alquilo(C C4), alcoxi(C C4), halógeno, CF3, OH, N02, NH2, COOH, CN, alquil(CrC4)arilo(C6-C10), alquil(C C4)carbonilo, alquil(C C4)éster, alquil(CrC4)amida; R 4 and R 6 are independently selected from each other from 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 - -pyrrol-2- yl, tien-3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2 -yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morpholin-4- yl, phenyl, cyclohexyl and cyclopentyl; optionally substituted by at least one group selected from: H, alkyl (CC 4 ), alkoxy (CC 4 ), halogen, CF 3 , OH, N0 2 , NH 2 , COOH, CN, alkyl (CrC 4 ) aryl (C 6 -C 10 ), alkyl (CC 4 ) carbonyl, alkyl (CC 4 ) ester, alkyl (CrC 4 ) amide;
n se selecciona entre 0 y 2; y n is selected between 0 and 2; Y
m es 2. m is 2.
Particularmente preferidos son: Particularly preferred are:
Λ/3-(2-anilino-2-oxoetil)-Λ/1-fenil-Λ/3-octil-β-alaninamida (1); Λ/1-fenil-Λ/3-(3-morfolin-4-il-3-oxopropil)-Λ/3-octil-β-alaninarτlida (2); Λ / 3 - (2-anilino-2-oxoethyl) -Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide (1); Λ / 1 -phenyl-Λ / 3 - (3-morpholin-4-yl-3-oxopropyl) -Λ / 3 -octyl-β-alaninarτlide (2);
A/2-(2-anilino-2-oxoetil)-/\/1-fenil-/\/2-octilglicinamida (3); A / 2 - (2-anilino-2-oxoethyl) - / \ / 1 -phenyl - / \ / 2 -octylglycinamide (3);
Λ/3-(3-anilino-3-oxopropil)-Λ/1-fenil-Λ/3-octil-β-alaninamida (4); Λ / 3 - (3-anilino-3-oxopropyl) -Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide (4);
Λ/3-(3-anilino-3-oxopropil)-Λ/3-(3-butoxipropil)-Λ/1-fenil-β-alaninamida (5); Λ/3-(3-anilino-3-oxopropil)-Λ/1-fenil-Λ/3-[3-(2-metoxietoxi)propil]-β-alaninarτlidaΛ / 3 - (3-anilino-3-oxopropyl) -Λ / 3 - (3-butoxypropyl) -Λ / 1 -phenyl-β-alaninamide (5); Λ / 3 - (3-anilino-3-oxopropyl) -Λ / 1 -phenyl-Λ / 3 - [3- (2-methoxyethoxy) propyl] -β-alaninarτlide
Λ/1 -feni -Λ/3- ■3-furoil-Λ/3-octil-β-alaninamida (7); Λ / 1 -feni -Λ / 3 - ■ 3-furoyl-Λ / 3 -octyl-β-alaninamide (7);
Λ/1 -feni -Λ/3- ■2-furoil-Λ/3-octil-β-alaninamida (8); Λ / 1 -feni -Λ / 3 - ■ 2-furoyl-Λ / 3 -octyl-β-alaninamide (8);
Λ/1 -feni -Λ/3- ■octil-Λ/3-(tetrahidrofuran-3-ilcarbonil)-β-alaninamida (9); Λ / 1 -feni -Λ / 3 - ■ octyl-Λ / 3 - (tetrahydrofuran-3-ylcarbonyl) -β-alaninamide (9);
Λ/1 -feni -Λ/3- -octil-/\/3-(1 ,3-oxazol-5-ilcarbonil)-β-alaninamida (10); Λ / 1 -feni -Λ / 3 - -octyl - / \ / 3 - (1,3-oxazol-5-ylcarbonyl) -β-alaninamide (10);
Λ/1 -feni -Λ/3- ■octil-Λ/3-(1 /-/-pirrol-3-ilcarbonil)-β-alaninamida (11); Λ / 1 -feni -Λ / 3 - ■ octyl-Λ / 3 - (1 / - / - pyrrol-3-ylcarbonyl) -β-alaninamide (11);
Λ/1 -feni -Λ/3- ■octil-Λ/3-(1 /-/-pirrol-2-ilcarbonil)-β-alaninamida (12); Λ / 1 -feni -Λ / 3 - ■ octyl-Λ / 3 - (1 / - / - pyrrol-2-ylcarbonyl) -β-alaninamide (12);
Λ/1 -feni -Λ/3- ■[(1-metil-1 /-/-pirrol-2-il)carbonil]-Λ/3-octil-β-alaninamida (13);Λ / 1 -feni -Λ / 3 - ■ [(1-methyl-1 / - / - pyrrol-2-yl) carbonyl] -Λ / 3 -octyl-β-alaninamide (13);
Λ/1 -feni -Λ/3- -octil-A/3-(tien-3-ilcarbonil)^-alaninamida (14); Λ / 1 -feni -Λ / 3 - -octyl-A / 3 - (tien-3-ylcarbonyl) ^ - alaninamide (14);
Λ/1 -feni -Λ/3- ■octil-Λ/3-(1 /-/-1 ,2,4-triazol-3-ilcarbonil)-β-alaninamida (15); Λ / 1 -feni -Λ / 3 - ■ octyl-Λ / 3 - (1 / - / - 1, 2,4-triazol-3-ylcarbonyl) -β-alaninamide (15);
Λ/1 -feni -Λ/3- -(1 /-/-imidazol-2-ilcarbonil)-/\/3-octil^-alaninamida (16); Λ / 1 -feni -Λ / 3 - - (1 / - / - imidazol-2-ylcarbonyl) - / \ / 3 -octyl ^ -alaninamide (16);
Λ/1 -feni -Λ/3- ■octil-Λ/3-(pirrolidin-2-ilcarbonil)-β-alaninamida (17); Λ / 1 -feni -Λ / 3 - ■ octyl-Λ / 3 - (pyrrolidin-2-ylcarbonyl) -β-alaninamide (17);
Λ/1 -feni -Λ/3- ■octil-Λ/3-(piridin-2-ilcarbonil)-β-alaninamida (18); Λ / 1 -feni -Λ / 3 - ■ octyl-Λ / 3 - (pyridin-2-ylcarbonyl) -β-alaninamide (18);
Λ/1 -feni -Λ/3- ■octil-Λ/3-(piridin-3-ilcarbonil)-β-alaninamida (19); Λ / 1 -feni -Λ / 3 - ■ octyl-Λ / 3 - (pyridin-3-ylcarbonyl) -β-alaninamide (19);
Λ/1 -feni -Λ/3- ■octil-Λ/3-(piridin-4-ilcarbonil)-β-alaninamida (20); Λ / 1 -feni -Λ / 3 - ■ octyl-Λ / 3 - (pyridin-4-ylcarbonyl) -β-alaninamide (20);
Λ/1 -feni -Λ/3- ■(1 /-/-indol-2-ilcarbonil)-Λ/3-octil-β-alaninamida (21); Λ / 1 -feni -Λ / 3 - ■ (1 / - / - indole-2-ylcarbonyl) -Λ / 3 -octyl-β-alaninamide (21);
Λ/3-(1-benzofuran-3-ilcarbonil)-Λ/1-fenil-Λ/3-octil-β-alaninamida (22); Λ / 3 - (1-benzofuran-3-ylcarbonyl) -Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide (22);
Λ/3-benzoil-Λ/1-fenil-Λ/3-octil-β-alaninamida (23); Λ / 3 -benzoyl-Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide (23);
Λ/3-(ciclopentilcarbonil)-Λ/1-fenil-Λ/3-octil-β-alaninamida (24); Λ / 3 - (cyclopentylcarbonyl) -Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide (24);
A/-(3-anilinopropil)-/\/-octil-3-furamida (25); A / - (3-anilinopropyl) - / \ / - octyl-3-furamide (25);
A/-3-furoil-/V-octil-p-alaninato de fenilo (26); A / -3-Furoyl- / V-octyl-p-phenyl alaninate (26);
A/-3-furoil-/\/-heptil-p-alaninato de fenilo (27);  A / -3-furoyl - / \ / - phenyl-p-alaninate (27);
A/-octil-/\/-(1 /-/-pirrol-2-ilcarbonil)-p-alaninato de fenilo (28); A / -octyl - / \ / - (1 / - / - pyrrol-2-ylcarbonyl) -p-phenyl alaninate (28);
A/-(1 /-/-imidazol-2-ilcarbonil)-/\/-octil- -alaninato de fenilo (29); A / - (1 / - / - imidazol-2-ylcarbonyl) - / \ / - octyl- -alaninate phenyl (29);
A/-octil-/\/-(1 ,3-oxazol-5-ilcarbonil)- -alaninato de fenilo (30); A / -octyl - / \ / - (1,3-oxazol-5-ylcarbonyl) -phenyl alaninate (30);
A/-fenil-/\/-{3-[3-furoil(octil)amino]propil}-3-furamida (31); A / -phenyl - / \ / - {3- [3-furoyl (octyl) amino] propyl} -3-furamide (31);
A/1-fenil-/\/3-[3-(4-metilpiperazin-1-il)-3-oxopropil]-/\/3-octil- -alaninamida (32); A/3-[3-(ciclohexilamino)-3-oxopropil]-/\/1-fenil-/\/3-octil- -alaninamida (33); A/1-fenil-A/3-{3-[(4-fluorofenil)amino]-3-oxopropil}-/\/3-octil- -alaninarTiida (34); /V1-fenil-A/3-{3-[metil(fenil)arriino]-3-oxopropil}-/\/3-octil- -alaninarTiida (35); Λ/1-fenil-Λ/3-octil-Λ/3-[3-oxo-3-(piridin-2-ilamino)propil]-β-alaninarτlida (36); Λ/1-fenil-Λ/3-octil-Λ/3-[3-oxo-3-(piridin-3-ilarτlino)propil]-β-alaninarτlida (37); Λ/1-fenil-Λ/3-[3-(metilarτlino)-3-oxopropil]-Λ/3-octil-β-alaninamida (38); A / 1 -phenyl - / \ / 3 - [3- (4-methylpiperazin-1-yl) -3-oxopropyl] - / \ / 3 -octyl- -alaninamide (32); A / 3 - [3- (cyclohexylamino) -3-oxopropyl] - / \ / 1 -phenyl - / \ / 3 -octyl- -alaninamide (33); A / 1 -phenyl-A / 3 - {3 - [(4-fluorophenyl) amino] -3-oxopropyl} - / \ / 3 -octyl--alanine Thiide (34); / V 1 -phenyl-A / 3 - {3- [methyl (phenyl) arriino] -3-oxopropyl} - / \ / 3 -octyl--alanine Thiide (35); Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - [3-oxo-3- (pyridin-2-ylamino) propyl] -β-alaninarτlide (36); Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - [3-oxo-3- (pyridin-3-ilarτlino) propyl] -β-alaninarτlide (37); Λ / 1 -phenyl-Λ / 3 - [3- (methylar-lino) -3-oxopropyl] -Λ / 3- octyl-β-alaninamide (38);
Λ/3-[3-(etilarτlino)-3-oxopropil]-Λ/1-fenil-Λ/3-octil-β-alaninamida (39); Λ / 3 - [3- (ethyloτlino) -3-oxopropyl] -Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide (39);
Λ/1-fenil-Λ/3-[3-(isopropilarτlino)-3-oxopropil]-Λ/3-octil-β-alaninarτlida (40); Λ / 1 -phenyl-Λ / 3 - [3- (isopropyl-lino) -3-oxopropyl] -Λ / 3- octyl-β-alaninarτlide (40);
Λ/3-(3-anilino-3-oxopropil)-Λ/3-[2-(2-etoxietoxi)etil]-Λ/1-fenil-β-alaninarτlida (41); 2-{[(anilinosulfonil)etil](octil)amino}-/\/-feniletanosulfonamida (42); Λ / 3 - (3-anilino-3-oxopropyl) -Λ / 3 - [2- (2-ethoxyethoxy) ethyl] -Λ / 1 -phenyl-β-alaninarτlide (41); 2 - {[(anilinosulfonyl) ethyl] (octyl) amino} - / \ / - phenylethanesulfonamide (42);
Λ/3-[2-(anilinosulfonil)ethyl]-Λ/1-fenil-Λ/3-octil-β-alaninamida (43); Λ / 3 - [2- (anilinosulfonyl) ethyl] -Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide (43);
Λ/1-fenil-Λ/3-(2-{[metil(fenil)amino]sulfonil}etil)-Λ/3-octil-β-alaninamida (44); Λ/3-[2-(anilinosulfonil)etil]-Λ/3-(3-butoxipropil)-Λ/1-fenil-β-alaninarτlida (45); A/3-(3-butoxipropil)-/\/1-fenil-/\/3-3-furoil^-alaninamida (46); Λ / 1 -phenyl-Λ / 3 - (2 - {[methyl (phenyl) amino] sulfonyl} ethyl) -Λ / 3 -octyl-β-alaninamide (44); Λ / 3 - [2- (anilinosulfonyl) ethyl] -Λ / 3 - (3-butoxypropyl) -Λ / 1 -phenyl-β-alaninarτlide (45); A / 3 - (3-butoxypropyl) - / \ / 1 -phenyl - / \ / 3 -3-furoyl ^ -alaninamide (46);
Λ/1-fenil-Λ/3-3-furoil-Λ/3-[3-(2-metoxietoxi)propil]-β-alaninamida (47); Λ / 1 -phenyl-Λ / 3 -3-furoyl-Λ / 3 - [3- (2-methoxyethoxy) propyl] -β-alaninamide (47);
A/3-[2-(2-etoxietoxi)etil]-/\/1-fenil-/\/3-3-furoil^-alaninamida (48); A / 3 - [2- (2-ethoxyethoxy) ethyl] - / \ / 1 -phenyl - / \ / 3 -3-furoyl ^ -alaninamide (48);
A/-[3-(3-furoilamino)propil]-/\/-octil-3-furamida (49). A / - [3- (3-Furoylamino) propyl] - / \ / - octyl-3-furamide (49).
Aún más particularmente preferidos son: Even more particularly preferred are:
Λ/3-(2-anilino-2-oxoetil)-Λ/1-fenil-Λ/3-octil-β-alaninamida (1); Λ / 3 - (2-anilino-2-oxoethyl) -Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide (1);
A/2-(2-anilino-2-oxoetil)-/\/1-fenil-/\/2-octilglicinamida (3); A / 2 - (2-anilino-2-oxoethyl) - / \ / 1 -phenyl - / \ / 2 -octylglycinamide (3);
Λ/3-(3-anilino-3-oxopropil)-Λ/1-fenil-Λ/3-octil-β-alaninamida (4); Λ / 3 - (3-anilino-3-oxopropyl) -Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide (4);
Λ/1-fenil-Λ/3-3-furoil-Λ/3-octil-β-alaninamida (7); Λ / 1 -phenyl-Λ / 3 -3-furoyl-Λ / 3 -octyl-β-alaninamide (7);
A/1-fenil-/V3-octil-/V3-(1 ,3-oxazol-5-ilcarbonil)-β-alaninamida (10); A / 1 -phenyl- / V 3 -octyl- / V 3 - (1,3-oxazol-5-ylcarbonyl) -β-alaninamide (10);
Λ/1-fenil-Λ/3-octil-Λ/3-(1 /-/-pirrol-3-ilcarbonil)-β-alaninamida (1 1); Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (1 / - / - pyrrol-3-ylcarbonyl) -β-alaninamide (1 1);
Λ/1-fenil-Λ/3-octil-Λ/3-(1 /-/-pirrol-2-ilcarbonil)-β-alaninamida (12); Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (1 / - / - pyrrol-2-ylcarbonyl) -β-alaninamide (12);
Λ/1-fenil-Λ/3-[(1-metil-1 /-/-pirrol-2-il)carbonil]-Λ/3-octil-β-alaninamida (13); Λ / 1 -phenyl-Λ / 3 - [(1-methyl-1 / - / - pyrrol-2-yl) carbonyl] -Λ / 3- octyl-β-alaninamide (13);
Λ/1-fenil-Λ/3-octil-Λ/3-(pirrolidin-2-ilcarbonil)-β-alaninamida (17); Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (pyrrolidin-2-ylcarbonyl) -β-alaninamide (17);
Λ/1-fenil-Λ/3-octil-Λ/3-(piridin-2-ilcarbonil)-β-alaninamida (18); Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (pyridin-2-ylcarbonyl) -β-alaninamide (18);
Λ/3-benzoil-Λ/1-fenil-Λ/3-octil-β-alaninamida (23); Λ / 3 -benzoyl-Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide (23);
Λ/3-(ciclopentilcarbonil)-Λ/1-fenil-Λ/3-octil-β-alaninamida (24); Λ / 3 - (cyclopentylcarbonyl) -Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide (24);
A/-(3-anilinopropil)-A/-octil-3-furamida (25);A / - (3-anilinopropyl) -A / -octyl-3-furamide (25);
V-3-furoil- V-octil-p-alaninato de fenilo (26); V-3-furoyl-V-octyl-p-phenyl alaninate (26);
A/-3-furoil-/\/-heptil-p-alaninato de fenilo (27);  A / -3-furoyl - / \ / - phenyl-p-alaninate (27);
A/-octil-/\/-(1 ,3-oxazol-5-ilcarbonil)-p-alaninato de fenilo (30); A / -octyl - / \ / - (1,3-oxazol-5-ylcarbonyl) -p-phenyl alaninate (30);
A/-fenil-/\/-{3-[3-furoil(octil)amino]propil}-3-furamida (31); A / -phenyl - / \ / - {3- [3-furoyl (octyl) amino] propyl} -3-furamide (31);
A/3-[3-(ciclohexilamino)-3-oxopropil]-/\/1-fenil-/\/3-octil- -alaninamida (33); A/1-fenil-A/3-{3-[(4-fluorofenil)am (34); A / 3 - [3- (cyclohexylamino) -3-oxopropyl] - / \ / 1 -phenyl - / \ / 3 -octyl- -alaninamide (33); A / 1 -phenyl-A / 3 - {3 - [(4-fluorophenyl) am (34);
2-{[(anilinosulfonil)etil](octil)amino}-/\/-feniletanosulfonarTiida (42); 2 - {[(anilinosulfonyl) ethyl] (octyl) amino} - / \ / - phenylethanesulfonar Thiide (42);
Los compuestos de fórmula general (I) pueden prepararse a partir de las alquilaminas correspondientes (II), siguiendo los esquemas de reacción que se detallan a continuación. The compounds of general formula (I) can be prepared from the corresponding alkylamines (II), following the reaction schemes detailed below.
Así, las alquilaciones sucesivas de las aminas (II) con las bromoalquilamidas (III) y (V) permiten obtener las diamidas asimétricas (la), en las que es -CONR3R4, R2 es -CONR5R6 y n y m son iguales o diferentes, mientras que las diamidas simétricas (Ib) y (le) se obtienen por dialquilación de las alquilaminas (II) con las 2- bromoacetamidas (lll-a) o con las acrilamidas (VI) (Esquema 1). Alternativamente, las diamidas asimétricas (la) en las que n es 2 se pueden obtener por alquilación de las monoamidas intermedias (IV) con las acrilamidas (VI). Las monoalquilaciones de aminas primarias se llevan a cabo en ausencia de base y las alquilaciones de aminas secundarias o las dialquilaciones de aminas primarias tienen lugar en presencia de A/./V-diisopropiletilamina (DIPEA) o 1 ,8-diazabicicloundec-7-eno (DBU). Thus, the successive alkylations of the amines (II) with the bromoalkylamides (III) and (V) allow to obtain the asymmetric diamides (the), in which it is -CONR 3 R 4 , R 2 is -CONR 5 R 6 ynym are same or different, while symmetric diamides (Ib) and (le) are obtained by dialkylation of alkylamines (II) with 2- bromoacetamides (lll-a) or with acrylamides (VI) (Scheme 1). Alternatively, asymmetric diamides (la) in which n is 2 can be obtained by alkylation of intermediate monoamides (IV) with acrylamides (VI). The monoalkylations of primary amines are carried out in the absence of base and the alkylations of secondary amines or the dialkylations of primary amines take place in the presence of A /./ V-diisopropylethylamine (DIPEA) or 1, 8-diazabicycloundec-7-ene (DBU)
Figure imgf000018_0001
Esquema 1. Reactivos y condiciones: (a) diclorometano, t.a.; (b) DI PEA, diclorometano, reflujo; (c) DIPEA, acetonitrilo, 60 °C; (d) DBU, acetonitrilo, 60 °C.
Figure imgf000018_0001
Scheme 1. Reagents and conditions: (a) dichloromethane, ta; (b) DI PEA, dichloromethane, reflux; (c) DIPEA, acetonitrile, 60 ° C; (d) DBU, acetonitrile, 60 ° C.
De forma análoga, las sulfonamidas asimétricas (Id), donde es -S02NR3R4 y R2 es -S02NR5R6, se pueden obtener por reacciones aza-Michael consecutivas de las aminas (II) con dos etilensulfonamidas distintas (VII) (Esquema 2). Mientras que las sulfonamidas simétricas (le) (R^R^ -S02NR3R4), se preparan por tratamiento de las aminas (II) con la etilensulfonamida correspondiente (VII) en exceso. Similarly, asymmetric sulfonamides (Id), where -S0 2 NR 3 R 4 and R 2 is -S0 2 NR 5 R 6 , can be obtained by consecutive aza-Michael reactions of amines (II) with two ethylenesulfonamides different (VII) (Scheme 2). While the symmetric sulfonamides (le) (R ^ R ^ -S0 2 NR 3 R 4 ), are prepared by treating the amines (II) with the corresponding ethylene sulfonamide (VII) in excess.
Figure imgf000019_0001
Figure imgf000019_0001
Esquema 2. Reactivos y condiciones: (a) DBU, acetonitrilo, 60 °C. Scheme 2. Reagents and conditions: (a) DBU, acetonitrile, 60 ° C.
Por otra parte, la sustitución nucleófila de los bromoésteres (IX) con las alquilaminas (II), seguida de la condensación de las aminas secundarias obtenidas (X) con los ácidos carboxílicos (XI), en presencia de 1-etil-3-(3- dimetilaminopropil)carbodiimida (EDC) y 1-hidroxibenzotriazol (HOBt) o 1 ,3- diciclohexilcarbodiimida (DCC) y 4-dimetilaminopiridina (DMAP), da lugar a los amidoésteres (XII). La posterior hidrólisis del grupo éster con hidróxido de litio en una mezcla de tetrahidrofurano (THF)/agua y esterificación o amidación de los ácidos intermedios (XIII) con los alcoholes o las aminas (XIV) permiten la preparación de los amidoésteres y diamidas de fórmula (If), donde R^ es un grupo - COR4 y R2 es -COOR6 o -CONR5R6. Alternativamente, el tratamiento de los ácidos (XIII) con los alcoholes o aminas (XV) da lugar a los amidoésteres y diamidas de fórmula (Ig), donde R^ es -COR4 y un R2 es un grupo -COOCH2R6 o -CONR5CH2R6 (Esquema 3).
Figure imgf000020_0001
On the other hand, the nucleophilic substitution of the bromoesters (IX) with the alkylamines (II), followed by the condensation of the secondary amines obtained (X) with the carboxylic acids (XI), in the presence of 1-ethyl-3- ( 3- dimethylaminopropyl) carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) or 1, 3- dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP), gives rise to the amidoesters (XII). The subsequent hydrolysis of the ester group with lithium hydroxide in a mixture of tetrahydrofuran (THF) / water and esterification or amidation of intermediate acids (XIII) with alcohols or amines (XIV) allow the preparation of amidoesters and diamides of formula (If), where R ^ is a group - COR 4 and R 2 is -COOR 6 or -CONR 5 R 6 . Alternatively, the treatment of the acids (XIII) with the alcohols or amines (XV) gives rise to the amidoesters and diamides of formula (Ig), where R ^ is -COR 4 and an R 2 is a group -COOCH 2 R 6 or -CONR 5 CH 2 R 6 (Scheme 3).
Figure imgf000020_0001
(C)  (C)
R4
Figure imgf000020_0002
R4
Figure imgf000020_0002
( (AX\Yf>\ R 66CCHH22NOHHR o5 (d)
Figure imgf000020_0003
( (A X \ Y f> \ R 6 6CCHH 22 NOHHR or 5 (d)
Figure imgf000020_0003
(Ig): X=0, NR5 (Ig): X = 0, NR 5
Esquema 3. Reactivos y condiciones: (a) diclorometano, t.a.; (b) EDC, HOBt o DCC, DMAP, diclorometano, t.a.; (c) LiOH, THF/agua, t.a.; (d) EDC, HOBt, diclorometano, t.a.  Scheme 3. Reagents and conditions: (a) dichloromethane, t.a .; (b) EDC, HOBt or DCC, DMAP, dichloromethane, t.a .; (c) LiOH, THF / water, t.a .; (d) EDC, HOBt, dichloromethane, t.a.
Además, las diamidas de fórmula (If) (R^ -COR4 y R2= -CONR5R6) se pueden preparar por condensación de las aminoamidas (IV) con los ácidos carboxílicos (XI) empleando cualquiera de las dos carbodiimidas anteriormente mencionadas y HOBt o DMAP como agentes de condensación (Esquema 4). Las diaminoamidas (Ig) (R^ -CONR3R4, R2= -CH2NR5R6) se obtienen a partir de las aminoamidas (IV) por reducción con hidruro de litio y aluminio, seguido de alquilación con los derivados halogenados (III). Asimismo, las diaminas intermedias (XVI) permiten acceder a las aminoamidas (Ih) (R^ -COR4 y R2= -CH2NR5R6), por condensación con los ácidos (XI), y a las sulfonamidas (li), donde es -S02R4 y R2 es -CH2NR5R6, por tratamiento con los cloruros de sulfonilo correspondientes (XVII). In addition, the diamides of formula (If) (R ^ -COR 4 and R 2 = -CONR 5 R 6 ) can be prepared by condensation of the aminoamides (IV) with the carboxylic acids (XI) using either of the two carbodiimides above mentioned and HOBt or DMAP as condensing agents (Scheme 4). Diaminoamides (Ig) (R ^ -CONR 3 R 4 , R 2 = -CH 2 NR 5 R 6 ) are obtained from aminoamides (IV) by reduction with lithium aluminum hydride, followed by alkylation with derivatives halogenated (III). Also, intermediate diamines (XVI) allow access to aminoamides (Ih) (R ^ -COR 4 and R 2 = -CH 2 NR 5 R 6 ), by condensation with acids (XI), and sulfonamides (li) , where it is -S0 2 R 4 and R 2 is -CH 2 NR 5 R 6 , by treatment with the corresponding sulfonyl chlorides (XVII).
Figure imgf000021_0001
Figure imgf000021_0001
Esquema 4. Reactivos y condiciones: (a) EDC, HOBt, diclorometano, t.a.; (b) LÍAIH4, THF, reflujo; (c) DIPEA, diclorometano, reflujo; (d) piridina, THF, t.a. Scheme 4. Reagents and conditions: (a) EDC, HOBt, dichloromethane, t.a .; (b) LÍAIH4, THF, reflux; (c) DIPEA, dichloromethane, reflux; (d) pyridine, THF, t.a.
Las diamidas (Ij) (R^ -COR4 y R2= -CH2NR5COR6) pueden prepararse a partir de las diaminas (XVI-a) por acilaciones sucesivas con dos ácidos carboxílicos (XI) distintos o por doble acilación con el mismo ácido en exceso, cuando R4 y R6 sean iguales (Esquema 5). Diamides (Ij) (R ^ -COR 4 and R 2 = -CH 2 NR 5 COR 6 ) can be prepared from diamines (XVI-a) by successive acylations with two different carboxylic acids (XI) or by double acylation with the same excess acid, when R 4 and R 6 are equal (Scheme 5).
Figure imgf000021_0002
Figure imgf000021_0002
Esquema 5. Reactivos y condiciones: (a) EDC, HOBt o DCC, DMAP, diclorometano, r.t. Finalmente, las amidosulfonamidas (Ik) (F = -S02NR3R4 y R2= -CONR5R6) se pueden obtener por /V-alquilación de las aminoamidas IV con las vinilsulfonamidas (VII) (Esquema 6). Scheme 5. Reagents and conditions: (a) EDC, HOBt or DCC, DMAP, dichloromethane, rt Finally, amidosulfonamides (Ik) (F = -S0 2 NR 3 R 4 and R 2 = -CONR 5 R 6 ) can be obtained by / V-alkylation of aminoamides IV with vinylsulfonamides (VII) (Scheme 6).
Figure imgf000022_0001
Figure imgf000022_0001
Esquema 6. Reactivos y condiciones: (a) DBU, acetonitrilo, reflujo. Scheme 6. Reagents and conditions: (a) DBU, acetonitrile, reflux.
Los bromoésteres (IX) y los cloruros de sulfonilo (XVII) se obtienen de fuentes comerciales (Sigma-Aldrich, Acros, AlfaAesar, Fluorochem, ABCR). Las alquilaminas (II), las bromoamidas (III) y (V), las acrilamidas (VI), las vinilsulfonamidas (VII), los ácidos carboxílicos (XI) así como los alcoholes y aminas (XIV) y (XV), pueden obtenerse en algunos casos de las fuentes comerciales anteriormente mencionadas o prepararse siguiendo métodos sintéticos convencionales bien conocidos por los técnicos en la materia. Todos los compuestos sintetizados han sido aislados, purificados y caracterizados por sus datos espectroscópicos de infrarrojo (IR), resonancia magnética nuclear de protón y carbono (1 H y 13C RMN) y espectrometría de masas (MS). Las etapas de purificación se llevan a cabo por métodos convencionales tales como cromatografía o recristalización en el disolvente adecuado. A lo largo de la descripción y las reivindicaciones la palabra "comprende" y sus variantes no pretenden excluir otras características técnicas, aditivos, componentes o pasos. Además, la palabra "comprende" incluye el caso "consiste en". Para los expertos en la materia, otros objetos, ventajas y características de la invención se desprenderán en parte de la descripción y en parte de la práctica de la invención. Los siguientes ejemplos se proporcionan a modo de ilustración, y no se pretende que sean limitativos de la presente invención. Además, la presente invención cubre todas las posibles combinaciones de realizaciones particulares y preferidas aquí indicadas. Bromoesters (IX) and sulfonyl chlorides (XVII) are obtained from commercial sources (Sigma-Aldrich, Acros, AlfaAesar, Fluorochem, ABCR). Alkylamines (II), bromoamides (III) and (V), acrylamides (VI), vinylsulfonamides (VII), carboxylic acids (XI) as well as alcohols and amines (XIV) and (XV), can be obtained in some cases from the commercial sources mentioned above or be prepared following conventional synthetic methods well known to those skilled in the art. All synthesized compounds have been isolated, purified and characterized by their infrared (IR) spectroscopic data, proton and carbon nuclear magnetic resonance ( 1 H and 13 C NMR) and mass spectrometry (MS). The purification steps are carried out by conventional methods such as chromatography or recrystallization in the appropriate solvent. Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. In addition, the word "comprises" includes the case "consists of". For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention. In addition, the present invention covers all possible combinations of particular and preferred embodiments indicated herein.
EJEMPLOS EJEMPLO 1 : Síntesis de las aminoamidas (IV) y los aminoésteres (X). Procedimiento general. EXAMPLES EXAMPLE 1: Synthesis of aminoamides (IV) and amino esters (X). General procedure.
A una disolución de 2 equiv de la alquilamina (II) en diclorometano anhidro (1 mL/mmol), se le añade gota a gota y bajo atmósfera de argón, una disolución de 1 equiv de la bromoamida (III) o el bromoéster (IX) en diclorometano anhidro (1 mL/mmol bromoderivado). La mezcla de reacción se agita a temperatura ambiente durante toda la noche. A continuación, el crudo de reacción se lava sucesivamente con disoluciones acuosas saturadas de NaHC03 y NaCI. Los extractos orgánicos se secan sobre Na2S04 y el disolvente se elimina a presión reducida. El residuo se purifica por cromatografía en columna, obteniéndose los compuestos (IV) y (X). V^fenil-A^-octil-p-alaninamida (IVa). Se obtuvo a partir de octilamina (8.8 mmol) y de 3-bromo-/V-fenilpropanamida (4.4 mmol) con un rendimiento del 65%. Cromatografía: diclorometano/m de etilo) 0.12.
Figure imgf000023_0001
To a solution of 2 equiv of alkylamine (II) in anhydrous dichloromethane (1 mL / mmol), a solution of 1 equiv of bromoamide (III) or bromoester (IX) is added dropwise under argon ) in anhydrous dichloromethane (1 mL / mmol bromoderivative). The reaction mixture is stirred at room temperature overnight. Then, the reaction crude is washed successively with saturated aqueous solutions of NaHC0 3 and NaCl. The organic extracts are dried over Na 2 S0 4 and the solvent is removed under reduced pressure. The residue is purified by column chromatography, obtaining compounds (IV) and (X). V ^ phenyl-A ^ -octyl-p-alaninamide (IVa). It was obtained from octylamine (8.8 mmol) and 3-bromo- / V-phenylpropanamide (4.4 mmol) in 65% yield. Chromatography: dichloromethane / m ethyl) 0.12.
Figure imgf000023_0001
IR (ATR, cm"1) 3297, 1667, 1601 , 1551 , 1497, 1444. 1 H RMN (CDCI3) δ 0.86-0.88 (m, 3H), 1.29 (m, 10H), 1.54-1.58 (m, 2H), 2.48 (t, J = 5.2 Hz, 2H), 2.69 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 5.4 Hz, 2H), 3.48 (s a, 1 H), 7.06 (t, J = 7.3 Hz, 1 H), 7.29 (t, J = 7.7 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.7, 27.5, 29.3, 29.5, 30.1 , 31.8, 36.1 , 45.5, 49.3 (9CH2), 1 19.7 (2CH), 123.6 (CH), 128.9 (2CH), 138.8, 171.1 (2C). MS (ESI): 277.2 [(M+H)+]. V1-fenil- V2-octil-glicinamida (IVb). Se obtuvo a partir de octilamina (20.7 mmol) y de 2-bromo-/V-fenilacetamida (10.4 mmol) con un rendimiento del 40%. Cromatografía: hexano/acetato de etilo, 1 : 1. Rf (acetato de etilo) 0.24.
Figure imgf000023_0002
IR (ATR, cm "1 ) 3297, 1667, 1601, 1551, 1497, 1444. 1 H NMR (CDCI 3 ) δ 0.86-0.88 (m, 3H), 1.29 (m, 10H), 1.54-1.58 (m, 2H), 2.48 (t, J = 5.2 Hz, 2H), 2.69 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 5.4 Hz, 2H), 3.48 (sa, 1 H), 7.06 (t , J = 7.3 Hz, 1 H), 7.29 (t, J = 7.7 Hz, 2H), 7.53 (d, J = 7.8 Hz, 2H) 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.7, 27.5, 29.3, 29.5, 30.1, 31.8, 36.1, 45.5, 49.3 (9CH 2 ), 1 19.7 (2CH), 123.6 (CH), 128.9 (2CH), 138.8, 171.1 (2C). MS (ESI): 277.2 [ (M + H) + ] V 1 -phenyl-V 2 -octyl-glycinamide (IVb) was obtained from octylamine (20.7 mmol) and 2-bromo- / V-phenylacetamide (10.4 mmol) with a yield 40% Chromatography: hexane / ethyl acetate, 1: 1. R f (ethyl acetate) 0.24.
Figure imgf000023_0002
IR (ATR, cm"1) 3349, 1713, 1598, 1444. 1 H RMN (CDCI3) δ 0.88 (t, J = 6.8 Hz, 3H), 1.28-1.38 (m, 10H), 1.51 (qt, J = 6.9 Hz, 2H), 2.66 (t, J = 6.9 Hz, 2H), 3.36 (s, 4H), 7.09 (tt, J = 7.4, 1.1 Hz, 1 H), 7.32 (t ap, J = 7.9 Hz, 2H), 7.58 (dd, J = 8.7, 1.1 Hz, 2H), 9.38 (s a, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.7, 27.2, 29.3, 29.5, 30.1 , 31.8, 50.3, 53.1 (8CH2), 1 19.4 (2CH), 124.1 (CH), 129.0 (2CH), 137.8, 170.0 (2C). MS (ESI) 263.2 [(M+H)+]. IR (ATR, cm "1 ) 3349, 1713, 1598, 1444. 1 H NMR (CDCI 3 ) δ 0.88 (t, J = 6.8 Hz, 3H), 1.28-1.38 (m, 10H), 1.51 (qt, J = 6.9 Hz, 2H), 2.66 (t, J = 6.9 Hz, 2H), 3.36 (s, 4H), 7.09 (tt, J = 7.4, 1.1 Hz, 1 H), 7.32 (t ap, J = 7.9 Hz , 2H), 7.58 (dd, J = 8.7, 1.1 Hz, 2H), 9.38 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.7, 27.2, 29.3, 29.5, 30.1, 31.8, 50.3, 53.1 (8CH 2 ), 1 19.4 (2CH), 124.1 (CH), 129.0 (2CH), 137.8, 170.0 (2C). MS (ESI) 263.2 [(M + H) + ].
^-(S-butoxipropi -A^fenil-p-alaninamida (IVc). Se obtuvo a partir de 3- butoxipropilamina (4.2 mmol) y de 3-bromo-/V-fenilpropanamida (2.1 mmol) con un rendimiento del 68%. Cromatografía: diclorometano/metanol, 97:3. Rf (diclorometano/metanol, 9: 1 ) 0.5 ^ - (S-Butoxypropyl-A ^ phenyl-p-alaninamide (IVc). It was obtained from 3- butoxypropylamine (4.2 mmol) and 3-bromo- / V-phenylpropanamide (2.1 mmol) in 68% yield Chromatography: dichloromethane / methanol, 97: 3 R f (dichloromethane / methanol, 9: 1) 0.5
Figure imgf000024_0001
Figure imgf000024_0001
IR (ATR, cm"1) 3299, 1664, 1599, 1547, 1495, 1441. 1 H RMN (CDCI3) δ 0.90 (t, J = 7.3 Hz, 3H), 1.34 (sx, J = 7.4 Hz, 2H), 1.55 (qt, J = 6.7 Hz, 2H), 1.88 (qt, J = 6.2 Hz, 2H), 2.59 (t, J = 5.7 Hz, 2H), 2.82 (s a, 1 H), 2.85 (t, J = 6.6 Hz, 2H), 3.01 (t, J = 5.8 Hz, 2H), 3.42 (t, J = 6.0 Hz, 2H), 3.54 (t, J = 6.0 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1 H), 7.29 (t, J = 7.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 10.63 (s a, 1 H). 13C RMN (CDCI3) δ 14.0 (CH3), 19.4, 29.5, 31.8, 35.6, 45.4, 47.2, 69.4, 71.1 (8CH2), 1 19.9 (2CH), 123.8 (CH), 129.0 (2CH), 138.7, 171.0 (2C). MS (ESI): 279.0 [(M+H)+]. IR (ATR, cm "1 ) 3299, 1664, 1599, 1547, 1495, 1441. 1 H NMR (CDCI 3 ) δ 0.90 (t, J = 7.3 Hz, 3H), 1.34 (sx, J = 7.4 Hz, 2H ), 1.55 (qt, J = 6.7 Hz, 2H), 1.88 (qt, J = 6.2 Hz, 2H), 2.59 (t, J = 5.7 Hz, 2H), 2.82 (sa, 1 H), 2.85 (t, J = 6.6 Hz, 2H), 3.01 (t, J = 5.8 Hz, 2H), 3.42 (t, J = 6.0 Hz, 2H), 3.54 (t, J = 6.0 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1 H), 7.29 (t, J = 7.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 10.63 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.0 (CH 3 ), 19.4, 29.5, 31.8, 35.6, 45.4, 47.2, 69.4, 71.1 (8CH 2 ), 1 19.9 (2CH), 123.8 (CH), 129.0 (2CH), 138.7, 171.0 (2C). MS (ESI) : 279.0 [(M + H) + ].
AT5-[2-(2-etoxietoxi)etil]- V1-fenil-p-alaninamida (IVd). Se obtuvo a partir de 2-(2- etoxietoxi)etilamina (6.0 mmol) y de 3-bromo-/V-fenilpropanamida (3.0 mmol) con un rendimiento del 65%. Cromatografía: acetato de etilo/metanol, 98:2 a 9: 1. Rf (acetato de etilo/metanol, 9: 1) 0.24. AT 5 - [2- (2-ethoxyethoxy) ethyl] - V 1 -phenyl-p-alaninamide (IVd). It was obtained from 2- (2- ethoxyethoxy) ethylamine (6.0 mmol) and 3-bromo- / V-phenylpropanamide (3.0 mmol) in 65% yield. Chromatography: ethyl acetate / methanol, 98: 2 to 9: 1. R f (ethyl acetate / methanol, 9: 1) 0.24.
Figure imgf000024_0002
Figure imgf000024_0002
IR (ATR, cm"1) 3295, 1662, 1599, 1548, 1499. 1 H RMN (CDCI3) δ 1.20 (t, J = 7.0 Hz, 3H), 1.96 (s a, 1 H), 2.49 (t, J = 5.7 Hz, 2H), 2.88 (t, J = 5.0 Hz, 2H), 2.99 (t, J = 5.7 Hz, 2H), 3.52 (t, J = 7.0 Hz, 2H), 3.56-3.60 (m, 2H), 3.63-3.67 (m, 2H), 7.05 (tt, J = 7.4, 1.1 Hz, 1 H), 7.30 (t, J = 7.2 Hz, 2H), 7.53 (dd, J = 8.6, 1 .1 Hz, 2H), 10.73 (s a, 1 H). 13C RMN (CDC ) δ 15.2 (CH3), 36.1 , 45.3, 48.6, 66.8, 69.9, 70.3, 70.6 (7CH2), 1 19.9 (2CH), 123.8 (CH), 129.0 (2CH), 138.8, 171.2 (2C). MS (ESI): 281.1 [(M+H)+]. V1-fenil-AT5-[3-(2-metoxietoxi)propil]-p-alaninamida (IVe). Se obtuvo a partir de 3- (2-metoxietoxi)propilamina (2.0 mmol) y de 3-bromo-/V-fenilpropanamida (1.0 mmol) con un rendimiento del 60%. Cromatografía: diclorometano/metanol, 97:3 a 8:2. Rf (diclorometano/metanol, 9: 1) 0.4 IR (ATR, cm "1 ) 3295, 1662, 1599, 1548, 1499. 1 H NMR (CDCI 3 ) δ 1.20 (t, J = 7.0 Hz, 3H), 1.96 (sa, 1 H), 2.49 (t, J = 5.7 Hz, 2H), 2.88 (t, J = 5.0 Hz, 2H), 2.99 (t, J = 5.7 Hz, 2H), 3.52 (t, J = 7.0 Hz, 2H), 3.56-3.60 (m, 2H), 3.63-3.67 (m, 2H), 7.05 (tt, J = 7.4, 1.1 Hz, 1 H), 7.30 (t, J = 7.2 Hz, 2H), 7.53 (dd, J = 8.6, 1 .1 Hz, 2H), 10.73 (sa, 1 HOUR). 13 C NMR (CDC) δ 15.2 (CH 3 ), 36.1, 45.3, 48.6, 66.8, 69.9, 70.3, 70.6 (7CH 2 ), 1 19.9 (2CH), 123.8 (CH), 129.0 (2CH), 138.8, 171.2 (2 C). MS (ESI): 281.1 [(M + H) + ]. V 1 -phenyl-AT 5 - [3- (2-methoxyethoxy) propyl] -p-alaninamide (IVe). It was obtained from 3- (2-methoxyethoxy) propylamine (2.0 mmol) and 3-bromo- / V-phenylpropanamide (1.0 mmol) in a yield of 60%. Chromatography: dichloromethane / methanol, 97: 3 to 8: 2. R f (dichloromethane / methanol, 9: 1) 0.4
Figure imgf000025_0001
Figure imgf000025_0001
1 H RMN (CDCI3) δ 1.87 (qt, J = 6.4 Hz, 2H), 1.92 (s a, 1 H), 2.49 (t, J = 5.7 Hz, 2H), 2.81 (t, J = 5.7 Hz, 2H), 2.97 (t, J = 5.7 Hz, 2H), 3.37 (s, 3H), 3.50-3.62 (m, 6H), 7.06 (t, J = 7.4 Hz, 1 H), 7.29 (t, J = 7.9 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 10.75 (s a, 1 H). 1 H NMR (CDCI 3 ) δ 1.87 (qt, J = 6.4 Hz, 2H), 1.92 (sa, 1 H), 2.49 (t, J = 5.7 Hz, 2H), 2.81 (t, J = 5.7 Hz, 2H ), 2.97 (t, J = 5.7 Hz, 2H), 3.37 (s, 3H), 3.50-3.62 (m, 6H), 7.06 (t, J = 7.4 Hz, 1 H), 7.29 (t, J = 7.9 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 10.75 (sa, 1 H).
/V-octil-p-alaninato de metilo (Xa). Se obtuvo a partir de octilamina (10.2 mmol) y de 3-bromopropanoato de metilo (5.1 mmol) con un rendimiento del 59%. Cromatografía: hexano/acetato de etilo, 2:8. Rf (hexano/acetato de etilo, 2:8) 0.37. / V-octyl-p-methyl alaninate (Xa). It was obtained from octylamine (10.2 mmol) and methyl 3-bromopropanoate (5.1 mmol) in 59% yield. Chromatography: hexane / ethyl acetate, 2: 8. R f (hexane / ethyl acetate, 2: 8) 0.37.
/V-heptil-p-alaninato de metilo (Xb). Se obtuvo a partir de heptilamina (8.2 mmol) y de 3-bromopropanoato de metilo (4.1 mmol) con un rendimiento del 50%. Cromatografía: hexano/acetato de etilo, 2:8. / V-heptyl-p-methyl alaninate (Xb). It was obtained from heptylamine (8.2 mmol) and methyl 3-bromopropanoate (4.1 mmol) in 50% yield. Chromatography: hexane / ethyl acetate, 2: 8.
EJEMPLO 2. Síntesis de las amidas (XII). Procedimiento general. EXAMPLE 2. Synthesis of the amides (XII). General procedure.
A una disolución de 2 equiv del ácido carboxílico correspondiente (XI) en diclorometano anhidro (4 mL/mmol), se le añaden bajo atmósfera de argón, 2 equiv de EDC ó 2.2. equiv de DCC y 2 equiv de HOBt ó 0.4 equiv de DMAP, respectivamente. La mezcla de reacción se agita a temperatura ambiente durante 1 h. A continuación, se adiciona una disolución de 1 equiv de la amina correspondiente (X) en diclorometano anhidro (2 mL/mmol). En el caso de los ácidos 1 /-/-pirrol-2-carboxílico y 1 /-/-imidazol-2-carboxílico no se dejan activando con los agentes de condensación durante 1 h, sino que la amina correspondiente se adiciona inmediatamente después de la carbodiimida y el HOBt o la DMAP a la mezcla de reacción. A continuación, la mezcla de reacción se agita a temperatura ambiente durante toda la noche. El crudo de reacción se lava con disoluciones acuosas saturadas de NaHC03 y NaCI, consecutivamente. Los extractos orgánicos se secan sobre Na2S04 y el disolvente se elimina a presión reducida. El residuo se purifica por cromatografía en columna, obteniéndose los compuestos (XII). V-3-furoil- V-octil-p-alaninato de metilo (Xlla). Se obtuvo a partir de ácido 3-furoico (0.50 mmol) y de /V-octil-p-alaninato de metilo (0.25 mmol) con un rendimiento del 100%. Cromatografía: hexano/acetato de etilo, 7:3. Rf (hexano/acetato de etilo, 7:3) 0.27. To a solution of 2 equiv of the corresponding carboxylic acid (XI) in anhydrous dichloromethane (4 mL / mmol), 2 equiv of EDC or 2.2 are added under argon. equiv of DCC and 2 equiv of HOBt or 0.4 equiv of DMAP, respectively. The reaction mixture is stirred at room temperature for 1 h. Next, a solution of 1 equiv of the corresponding amine (X) in anhydrous dichloromethane (2 mL / mmol) is added. In the case of 1 / - / - pyrrol-2-carboxylic and 1 / - / - imidazol-2-carboxylic acids, they are not allowed to activate with the condensing agents for 1 h, but the corresponding amine is added immediately after carbodiimide and HOBt or DMAP at reaction mixture. Then, the reaction mixture is stirred at room temperature overnight. The reaction crude is washed with saturated aqueous solutions of NaHC0 3 and NaCI, consecutively. The organic extracts are dried over Na 2 S0 4 and the solvent is removed under reduced pressure. The residue is purified by column chromatography, obtaining the compounds (XII). V-3-furoyl-V-octyl-p-methyl alaninate (Xlla). It was obtained from 3-furoic acid (0.50 mmol) and methyl / V-octyl-p-alaninate (0.25 mmol) in 100% yield. Chromatography: hexane / ethyl acetate, 7: 3. R f (hexane / ethyl acetate, 7: 3) 0.27.
Figure imgf000026_0001
Figure imgf000026_0001
IR (ATR, cm"1) 1736, 1626, 1507, 1435. 1 H RMN (CDCI3) δ 0.81 (t, J = 6.5 Hz, 3H), 1.19 (m, 10H), 1.53 (m, 2H), 2.63 (m, 2H), 3.35 (t, J = 7.8 Hz, 2H), 3.62 (s, 3H), 3.65 (t, J = 7.3 Hz, 2H), 6.51 (m, 1 H), 7.36 (t, J = 1.7 Hz, 1 H), 7.64 (m, 1 H). 13C RMN (CDCI3) δ 14.0 (CH3), 22.6, 26.6, 29.1 (2C), 29.2, 31.7, 32.4, 42.3, 49.7 (9CH2), 51.8 (CH3), 1 10.2 (CH), 121.5 (C), 142.9, 143.0 (2CH), 164.7, 172.4 (2C). MS (ESI) 310.2 [(M+H)+]. V-octil- V-(1 ,3-oxazol-5-ilcarbonil)-p-alaninato de metilo (Xllb). Se obtuvo a partir de ácido 1 ,3-oxazol-5-carboxílico (2.8 mmol) y de /V-octil-p-alaninato de metilo (1.4 mmol) con un rendimiento del 95%. Cromatografía: hexano/acetato de etilo, 1 : 1. Rf (hexano/acetato de etilo, 1 : 1) 0.30.
Figure imgf000026_0002
IR (ATR, cm "1 ) 1736, 1626, 1507, 1435. 1 H NMR (CDCI 3 ) δ 0.81 (t, J = 6.5 Hz, 3H), 1.19 (m, 10H), 1.53 (m, 2H), 2.63 (m, 2H), 3.35 (t, J = 7.8 Hz, 2H), 3.62 (s, 3H), 3.65 (t, J = 7.3 Hz, 2H), 6.51 (m, 1 H), 7.36 (t, J = 1.7 Hz, 1 H), 7.64 (m, 1 H) 13 C NMR (CDCI 3 ) δ 14.0 (CH 3 ), 22.6, 26.6, 29.1 (2C), 29.2, 31.7, 32.4, 42.3, 49.7 ( 9CH 2 ), 51.8 (CH 3 ), 1 10.2 (CH), 121.5 (C), 142.9, 143.0 (2CH), 164.7, 172.4 (2C). MS (ESI) 310.2 [(M + H) + ]. V -octyl- V- (1,3-oxazol-5-ylcarbonyl) -p-methyl alaninate (Xllb) was obtained from 1,3-oxazol-5-carboxylic acid (2.8 mmol) and de / V- Methyl octyl-p-alaninate (1.4 mmol) with a yield of 95% Chromatography: hexane / ethyl acetate, 1: 1. R f (hexane / ethyl acetate, 1: 1) 0.30.
Figure imgf000026_0002
IR (ATR, cm"1) 1737, 1632, 1433. 1 H RMN (CDCI3) δ 0.87 (t, J = 6.7 Hz, 3H), 1.26- 1.29 (m, 10H), 1.64 (m, 2H), 2.71 (t, J = 7.2 Hz, 2H), 3.51 (m, 2H), 3.69 (s, 3H), 3.75 (m, 2H), 7.60 (m, 1 H), 7.93 (s, 1 H). 13C RMN (CDCI3) δ 14.3 (CH3), 22.8, 27.0, 29.4, 29.5, 29.7, 32.0, 32.6, 43.7, 49.5 (9CH2), 52.0 (CH3), 131.8 (CH), 145.8 (C), 151.8 (CH), 158.4, 172.4 (2C). MS (ESI) 31 1.2 [(M+H)+]. V-octil- V-(1 H-pirrol-2-ilcarbonil)-p-alaninato de metilo (Xllc). Se obtuvo a partir de ácido 1 /-/-pirrol-2-carboxílico (3.0 mmol) y de /V-octil-p-alaninato de metilo (1.5 mmol) con un rendimiento del 76%. Cromatografía: hexano/acetato de etilo, 9: 1. Rf (hexano/acetato de etilo, 7:3) 0.33.
Figure imgf000027_0001
IR (ATR, cm "1 ) 1737, 1632, 1433. 1 H NMR (CDCI 3 ) δ 0.87 (t, J = 6.7 Hz, 3H), 1.26-1.29 (m, 10H), 1.64 (m, 2H), 2.71 (t, J = 7.2 Hz, 2H), 3.51 (m, 2H), 3.69 (s, 3H), 3.75 (m, 2H), 7.60 (m, 1H), 7.93 (s, 1H). 13 NMR C (CDCI 3 ) δ 14.3 (CH 3 ), 22.8, 27.0, 29.4, 29.5, 29.7, 32.0, 32.6, 43.7, 49.5 (9CH 2 ), 52.0 (CH 3 ), 131.8 (CH), 145.8 (C) , 151.8 (CH), 158.4, 172.4 (2C), MS (ESI) 31 1.2 [(M + H) + ]. V-octyl- V- (1 H -pyrrol-2-ylcarbonyl) -p-methyl alaninate (Xllc). It was obtained from 1 / - / - pyrrole-2-carboxylic acid (3.0 mmol) and methyl / V-octyl-p-alaninate (1.5 mmol) in 76% yield. Chromatography: hexane / ethyl acetate, 9: 1. R f (hexane / ethyl acetate, 7: 3) 0.33.
Figure imgf000027_0001
IR (ATR, cm"1) 3263, 1738, 1593, 1438. 1 H RMN (CDCI3) δ 0.88 (t, J = 6.7 Hz, 3H), 1.28-1.33 (m, 10H), 1.69 (m, 2H), 2.73 (t, J = 7.4 Hz, 2H), 3.56 (t, J = 7.5 Hz, 2H), 3.70 (s, 3H), 3.82 (m, 2H), 6.26 (dt, J = 3.7, 2.7 Hz, 1 H), 6.52 (m, 1 H), 6.92 (td, J = 2.7, 1.2 Hz, 1 H), 9.77 (s a, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.9, 28.6, 29.2, 29.4, 31.8, 33.1 , 44.0, 48.9 (9CH2), 51.8 (CH3), 1 10.1 , 1 1 1.6, 120.9 (3CH), 124.8, 161.8, 172.3 (3C). MS (ESI) 309.2 [(M+H)+]. IR (ATR, cm "1 ) 3263, 1738, 1593, 1438. 1 H NMR (CDCI 3 ) δ 0.88 (t, J = 6.7 Hz, 3H), 1.28-1.33 (m, 10H), 1.69 (m, 2H ), 2.73 (t, J = 7.4 Hz, 2H), 3.56 (t, J = 7.5 Hz, 2H), 3.70 (s, 3H), 3.82 (m, 2H), 6.26 (dt, J = 3.7, 2.7 Hz , 1 H), 6.52 (m, 1 H), 6.92 (td, J = 2.7, 1.2 Hz, 1 H), 9.77 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6, 26.9, 28.6, 29.2, 29.4, 31.8, 33.1, 44.0, 48.9 (9CH 2 ), 51.8 (CH 3 ), 1 10.1, 1 1 1.6, 120.9 (3CH), 124.8, 161.8, 172.3 (3C). (ESI) 309.2 [(M + H) + ].
/V-(1 H-imidazol-2-ilcarbonil)-/V-octil-p-alaninato de metilo (Xlld). Se obtuvo a partir de ácido 1 /-/-imidazol-2-carboxílico (0.66 mmol) y de /V-octil-p-alaninato de metilo (0.33 mmol) con un rendimiento del 60%. Cromatografía: hexano/acetato de etilo, 7:3. Rf (hexano/acetato de etilo, 7:3) 0.24. / V- (1 H-imidazol-2-ylcarbonyl) - / V-octyl-p-methyl alaninate (Xlld). It was obtained from 1 / - / - imidazol-2-carboxylic acid (0.66 mmol) and methyl / V-octyl-p-alaninate (0.33 mmol) with a yield of 60%. Chromatography: hexane / ethyl acetate, 7: 3. R f (hexane / ethyl acetate, 7: 3) 0.24.
Figure imgf000027_0002
Figure imgf000027_0002
IR (ATR, cm"1) 3218, 1738, 1605, 1481 , 1440. 1 H RMN (CDCI3) δ Mezcla de rotámeros A:B, 1 : 1 ; 0.86 (t, J = 6.7 Hz, 3H), 1.24-1.30 (m, 10H), 1.66 (m, 2H), 2.73 (t, J = 7.3 Hz, 2H, rotámero A), 2.81 (t, J = 7.3 Hz, 2H, rotámero B), 3.49 (t, J = 7.5 Hz, 2H, rotámero B), 3.66 (s, 3H, rotámero A), 3.68 (s, 3H, rotámero B), 3.78 (t, J = 7.3 Hz, 2H, rotámero A), 4.26 (t, J = 7.5 Hz, 2H, rotámero A), 4.47 (t, J = 7.3 Hz, 2H, rotámero B), 7.12 (s, 2H, 2CH), 12.06 (s a, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.6, 27.1 , 27.6, 29.1 , 29.2 (2C), 29.3, 29.4, 31.8, 32.5, 34.1 , 43.9, 44.6, 48.0, 49.4 (9CH2, rotámeros A y B), 51.7, 51.8 (CH3, rotámeros A y B), 1 18.5, 129.9 (C, rotámeros A y B), 141.3 (2CH), 159.2, 159.5 (C, rotámeros A y B), 172.3 (C). MS (ESI) 310.2 [(M+H)+]. EJEMPLO 3. Síntesis de los ácidos carboxílicos XIII. Procedimiento general.IR (ATR, cm "1 ) 3218, 1738, 1605, 1481, 1440. 1 H NMR (CDCI 3 ) δ Mixture of rotamers A: B, 1: 1; 0.86 (t, J = 6.7 Hz, 3H), 1.24 -1.30 (m, 10H), 1.66 (m, 2H), 2.73 (t, J = 7.3 Hz, 2H, rotamer A), 2.81 (t, J = 7.3 Hz, 2H, rotamer B), 3.49 (t, J = 7.5 Hz, 2H, rotamer B), 3.66 (s, 3H, rotamer A), 3.68 (s, 3H, rotamer B), 3.78 (t, J = 7.3 Hz, 2H, rotamer A), 4.26 (t, J = 7.5 Hz, 2H, rotamer A), 4.47 (t, J = 7.3 Hz, 2H, rotamer B), 7.12 (s, 2H, 2CH), 12.06 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6, 26.6, 27.1, 27.6, 29.1, 29.2 (2C), 29.3, 29.4, 31.8, 32.5, 34.1, 43.9, 44.6, 48.0, 49.4 (9CH 2 , rotamers A and B), 51.7, 51.8 (CH 3 , rotamers A and B), 1 18.5, 129.9 (C, rotamers A and B), 141.3 (2CH), 159.2, 159.5 (C, rotamers A and B), 172.3 (C). MS (ESI) 310.2 [(M + H) + ]. EXAMPLE 3. Synthesis of carboxylic acids XIII. General procedure.
A una disolución de 2 equiv de LiOH H20 en agua (2.5 mL/mmol), se le añade el éster correspondiente (XII) disuelto en THF (2.5 mL/mmol). La mezcla de reacción se agita a temperatura ambiente durante 4 h. A continuación, se elimina el THF a presión reducida, el residuo se acidifica con una disolución acuosa de HCI 2 M y se extrae con acetato de etilo. Los extractos orgánicos se lavan con una disolución acuosa saturada de NaCI, se secan sobre Na2S04 y el disolvente se elimina a presión reducida, obteniéndose los ácidos correspondientes (XIII) que se purifican por recristalización. V-3-furoil- V-octil-p-alanina (Xllla). Se obtuvo a partir de /V-3-f u roi l-/V-octi Ι-β- alaninato de metilo (0.68 mmol) con un rendimiento del 100%. Rf (hexano/acetato de etilo, 7:3) 0.21. p.f. 77-80 °C. To a solution of 2 equiv of LiOH H 2 0 in water (2.5 mL / mmol), the corresponding ester (XII) dissolved in THF (2.5 mL / mmol) is added. The reaction mixture is stirred at room temperature for 4 h. Then, THF is removed under reduced pressure, the residue is acidified with a 2M aqueous HCI solution and extracted with ethyl acetate. The organic extracts are washed with a saturated aqueous solution of NaCl, dried over Na 2 S0 4 and the solvent is removed under reduced pressure, obtaining the corresponding acids (XIII) which are purified by recrystallization. V-3-furoyl-V-octyl-p-alanine (Xllla). It was obtained from methyl / V-3-fu roi l- / V-octi β-β-alaninate (0.68 mmol) in 100% yield. R f (hexane / ethyl acetate, 7: 3) 0.21. mp 77-80 ° C.
Figure imgf000028_0001
Figure imgf000028_0001
IR (ATR, cm"1) 3132, 1727, 1595, 1436. 1 H RMN (CDCI3) δ 0.84 (t, J = 6.7 Hz, 3H), 1.23 (m, 10H), 1.57 (m, 2H), 2.68 (m, 2H), 3.41 (t, J = 7.8 Hz, 2H), 3.70 (t, J = 7.2 Hz, 2H), 6.53 (m, 1 H), 7.38 (t, J = 1.7 Hz, 1 H), 7.70 (m, 1 H), 1 1.31 (s a, 1 H). 13C RMN (CDCIs) δ 14.0 (CH3), 22.6, 26.6, 29.1 (2C), 29.2, 31.7, 32.6, 42.5, 49.9 (9CH2), 1 10.0 (CH), 120.9 (C), 143.0, 143.5 (2CH), 165.6, 175.9 (2C). MS (ESI) 296.2 [(M+H)+]. IR (ATR, cm "1 ) 3132, 1727, 1595, 1436. 1 H NMR (CDCI 3 ) δ 0.84 (t, J = 6.7 Hz, 3H), 1.23 (m, 10H), 1.57 (m, 2H), 2.68 (m, 2H), 3.41 (t, J = 7.8 Hz, 2H), 3.70 (t, J = 7.2 Hz, 2H), 6.53 (m, 1 H), 7.38 (t, J = 1.7 Hz, 1 H ), 7.70 (m, 1 H), 1 1.31 (sa, 1 H) 13 C NMR (CDCIs) δ 14.0 (CH 3 ), 22.6, 26.6, 29.1 (2C), 29.2, 31.7, 32.6, 42.5, 49.9 (9CH 2 ), 1 10.0 (CH), 120.9 (C), 143.0, 143.5 (2CH), 165.6, 175.9 (2C) MS (ESI) 296.2 [(M + H) + ].
/V-octil-/V-(1 ,3-oxazol-5-ilcarbonil)-p-alanina (Xlllb). Se obtuvo a partir de /V-octil-/V- (1 ,3-oxazol-5-ilcarbonil)- -alaninato de metilo (0.55 mmol) con un rendimiento del 87%. Rf (hexano/acetato de etilo, 1 : 1) 0.24. p.f. 78-80 °C.
Figure imgf000028_0002
/ V-octyl- / V- (1,3-oxazol-5-ylcarbonyl) -p-alanine (Xlllb). It was obtained from / V-octyl- / V- (1,3-oxazol-5-ylcarbonyl) - methyl alaninate (0.55 mmol) with a yield of 87%. R f (hexane / ethyl acetate, 1: 1) 0.24. mp 78-80 ° C.
Figure imgf000028_0002
IR (ATR, cm"1) 3126, 1728, 1624, 1435. 1 H RMN (CDCI3) δ 0.88 (t, J = 6.6 Hz, 3H), 1.23-1.30 (m, 10H), 1.65 (m, 2H), 2.77 (t, J = 7.0 Hz, 2H), 3.55 (m, 2H), 3.75 (m, 2H), 7.63 (m, 1 H), 7.97 (s, 1 H). 13C RMN (CDCI3) δ 14.4 (CH3), 22.9, 27.0, 29.5, 29.6, 29.7, 32.0, 32.6, 43.8, 49.8 (9CH2), 131.8 (CH), 145.7 (C), 152.3 (CH), 158.7, 175.3 (2C). MS (ESI): 297.2 [(M+H)+]. V-octil- V-(1 H-pirrol-2-ilcarbonil)-p-alanina (Xlllc). Se obtuvo a partir de Ν-οοΐ\\-Ν- (1 /-/-pirrol-2-ilcarbonil)^-alaninato de metilo (0.65 mmol) con un rendimiento del 100%. Rf (hexano/acetato de etilo, 1 : 1) 0.20. p.f. 72-73 °C.
Figure imgf000029_0001
IR (ATR, cm "1 ) 3126, 1728, 1624, 1435. 1 H NMR (CDCI 3 ) δ 0.88 (t, J = 6.6 Hz, 3H), 1.23-1.30 (m, 10H), 1.65 (m, 2H ), 2.77 (t, J = 7.0 Hz, 2H), 3.55 (m, 2H), 3.75 (m, 2H), 7.63 (m, 1 H), 7.97 (s, 1 H). 13 C NMR (CDCI 3 ) δ 14.4 (CH 3 ), 22.9, 27.0, 29.5, 29.6, 29.7, 32.0, 32.6, 43.8, 49.8 (9CH 2 ), 131.8 (CH), 145.7 (C), 152.3 (CH) , 158.7, 175.3 (2C). MS (ESI): 297.2 [(M + H) + ]. V-octyl- V- (1 H-pyrrol-2-ylcarbonyl) -p-alanine (Xlllc). It was obtained from Ν-οοΐ \\ - Ν- (1 / - / - pyrrol-2-ylcarbonyl) ^ - methyl alaninate (0.65 mmol) in 100% yield. R f (hexane / ethyl acetate, 1: 1) 0.20. mp 72-73 ° C.
Figure imgf000029_0001
IR (ATR, cm"1) 3258, 1710, 1574, 1444. 1 H RMN (CDCI3) δ 0.88 (t, J = 6.7 Hz, 3H), 1.28-1.33 (m, 10H), 1.71 (m, 2H), 2.73 (t, J = 7.1 Hz, 2H), 3.58 (m, 2H), 3.83 (m, 2H), 6.23-6.26 (m, 1 H), 6.55 (m, 1 H), 6.93 (m, 1 H), 10.42 (s a, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.9, 28.5, 29.2, 29.4, 31.8, 33.3, 44.0, 49.1 (9CH2), 1 10.0, 1 12.4, 121.7 (3CH), 124.1 , 162.6, 175.7 (3C). MS (ESI) 295.2 [(M+H)+]. V-(1 H-imidazol-2-ilcarbonil)- V-octil-p-alanina (Xllld). Se obtuvo a partir de Ν-{Λ Η- imidazol-2-ilcarbonil)-/\/-octil^-alaninato de metilo (0.59 mmol) con un rendimiento del 96%. Rf (hexano/acetato de etilo, 1 : 1) 0.12. p.f. 65-68 °C. IR (ATR, cm "1 ) 3258, 1710, 1574, 1444. 1 H NMR (CDCI 3 ) δ 0.88 (t, J = 6.7 Hz, 3H), 1.28-1.33 (m, 10H), 1.71 (m, 2H ), 2.73 (t, J = 7.1 Hz, 2H), 3.58 (m, 2H), 3.83 (m, 2H), 6.23-6.26 (m, 1 H), 6.55 (m, 1 H), 6.93 (m, 1 H), 10.42 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6, 26.9, 28.5, 29.2, 29.4, 31.8, 33.3, 44.0, 49.1 (9CH 2 ), 1 10.0 , 1 12.4, 121.7 (3CH), 124.1, 162.6, 175.7 (3C). MS (ESI) 295.2 [(M + H) + ]. V- (1 H-imidazol-2-ylcarbonyl) - V-octyl-p -alanine (Xllld) was obtained from Ν- {Λ Η- imidazol-2-ylcarbonyl) - / \ / - octyl ^ -alaninate methyl (0.59 mmol) with a yield of 96% R f (hexane / ethyl acetate, 1: 1) 0.12, mp 65-68 ° C.
Figure imgf000029_0002
Figure imgf000029_0002
IR (ATR, cm"1) 3202, 171 1 , 1601 , 1483, 1441. 1 H RMN (CDCI3) (mezla de rotámeros A:B, 2: 1) δ 0.86 (t, J = 6.2 Hz, 3H), 1.25-1.30 (m, 10H), 1.65 (m, 2H), 2.75 (t, J = 6.9 Hz, 2H, rotámero B), 2.87 (t, J = 7.6 Hz, 2H, rotámero A), 3.51 (t, J = 7.5 Hz, 2H, rotámero A), 3.80 (t, J = 6.9 Hz, 2H, rotámero B), 4.24 (t, J = 7.5 Hz, 2H, rotámero B), 4.32 (t, J = 7.2 Hz, 2H, rotámero A), 7.15 (s, 2H, rotámero B), 7.20 (s, 2H, rotámero A), 10.74 (s a, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.6, 27.0, 27.5, 27.6, 29.0, 29.2, 29.3 (2C), 31.8, 32.6, 36.0, 43.8, 45.0, 48.2, 49.5 (9CH2, rotámeros A y B), 124.3 (2CH), 140.3, 140.7, 158.6, 159.7, 173.9, 176.0 (3C, rotámeros A y B). MS (ESI) 296.2 [(M+H)+]. EJEMPLO 4. Síntesis de las aminas (XVI). Procedimiento general. IR (ATR, cm "1 ) 3202, 171 1, 1601, 1483, 1441. 1 H NMR (CDCI 3 ) (mix of rotamers A: B, 2: 1) δ 0.86 (t, J = 6.2 Hz, 3H) , 1.25-1.30 (m, 10H), 1.65 (m, 2H), 2.75 (t, J = 6.9 Hz, 2H, rotamer B), 2.87 (t, J = 7.6 Hz, 2H, rotamer A), 3.51 (t , J = 7.5 Hz, 2H, rotamer A), 3.80 (t, J = 6.9 Hz, 2H, rotamer B), 4.24 (t, J = 7.5 Hz, 2H, rotamer B), 4.32 (t, J = 7.2 Hz , 2H, rotamer A), 7.15 (s, 2H, rotamer B), 7.20 (s, 2H, rotamer A), 10.74 (sa, 1 H) 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6 , 26.6, 27.0, 27.5, 27.6, 29.0, 29.2, 29.3 (2C), 31.8, 32.6, 36.0, 43.8, 45.0, 48.2, 49.5 (9CH 2 , rotamers A and B), 124.3 (2CH), 140.3, 140.7, 158.6, 159.7, 173.9, 176.0 (3C, rotamers A and B) MS (ESI) 296.2 [(M + H) + ]. EXAMPLE 4. Synthesis of amines (XVI). General procedure.
A una suspensión de 2.5 equiv de LiAIH4 en THF anhidro (1.2 mL/mmol), se le añade gota a gota, a temperatura ambiente y bajo atmósfera de argón, una disolución de la amida correspondiente (IV) en THF anhidro (2 mL/mmol). La mezcla de reacción se calienta a reflujo durante toda la noche. A continuación, se añade agua gota a gota y a 0 °C. El crudo de reacción se filtra y se extrae con acetato de etilo. Los extractos orgánicos se secan sobre Na2S04 y el disolvente se elimina a presión reducida. El residuo se purifica por cromatografía en columna, obteniéndose las aminas correspondientes (XVI). To a suspension of 2.5 equiv of LiAIH 4 in anhydrous THF (1.2 mL / mmol), a solution of the corresponding amide (IV) in anhydrous THF (2 mL) is added dropwise at room temperature and under argon atmosphere / mmol). The reaction mixture is heated at reflux overnight. Then, water is added dropwise and at 0 ° C. The reaction crude is filtered and extracted with ethyl acetate. The organic extracts are dried over Na 2 S0 4 and the solvent is removed under reduced pressure. The residue is purified by column chromatography, obtaining the corresponding amines (XVI).
/V-octil-/V-fenilpropano-1,3-diamina (XVIa). Se obtuvo a partir de /V -fenil-/V3-octil- β-alaninamida (1.1 mmol) con un rendimiento del 46%. Cromatografía: acetato de etilo/metanol, 8:2. Rf (acetato de etilo/metanol, 1 : 1) 0.36.
Figure imgf000030_0001
/ V-octyl- / V-phenylpropane-1,3-diamine (XVIa). It was obtained from / V -phenyl- / V 3 -octyl-β-alaninamide (1.1 mmol) in a yield of 46%. Chromatography: ethyl acetate / methanol, 8: 2. R f (ethyl acetate / methanol, 1: 1) 0.36.
Figure imgf000030_0001
IR (ATR, cm"1) 3303, 1603, 1507, 1465. 1 H RMN (CDCI3) δ 0.90 (t, J = 6.7 Hz, 3H), 1.26-1.30 (m, 10H), 1.45-1.52 (m, 2H), 1.81 (qt, J = 6.6 Hz, 2H), 2.60 (t, J = 7.1 Hz, 2H), 2.75 (t, J = 6.7 Hz, 2H), 3.19 (t, J = 6.6 Hz, 2H), 6.61 (d, J = 8.5 Hz, 2H), 6.69 (t, J = 8.3 Hz, 1 H), 7.17 (t ap, J = 10.1 Hz, 2H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.7, 27.4, 29.3, 29.5, 29.6, 30.1 , 31.9, 43.0, 48.4, 50.1 (10CH2), 1 12.8 (2CH), 1 17.1 (CH), 129.2 (2CH), 148.7 (C). MS (ESI) 263.3 [(M+H)+]. IR (ATR, cm "1 ) 3303, 1603, 1507, 1465. 1 H NMR (CDCI 3 ) δ 0.90 (t, J = 6.7 Hz, 3H), 1.26-1.30 (m, 10H), 1.45-1.52 (m , 2H), 1.81 (qt, J = 6.6 Hz, 2H), 2.60 (t, J = 7.1 Hz, 2H), 2.75 (t, J = 6.7 Hz, 2H), 3.19 (t, J = 6.6 Hz, 2H ), 6.61 (d, J = 8.5 Hz, 2H), 6.69 (t, J = 8.3 Hz, 1 H), 7.17 (t ap, J = 10.1 Hz, 2H). 13 C NMR (CDCI 3 ) δ 14.1 ( CH 3 ), 22.7, 27.4, 29.3, 29.5, 29.6, 30.1, 31.9, 43.0, 48.4, 50.1 (10CH 2 ), 1 12.8 (2CH), 1 17.1 (CH), 129.2 (2CH), 148.7 (C). MS (ESI) 263.3 [(M + H) + ].
EJEMPLO 5. Síntesis de los derivados (la). Procedimiento general A. EXAMPLE 5. Synthesis of derivatives (la). General Procedure A.
A una suspensión de 1 equiv de la amina correspondiente (IV) y 2 equiv del derivado halogenado (III) en diclorometano anhidro (1 mL/mmol derivado halogenado), se le añaden 3 equiv de DIPEA bajo atmósfera de argón. La mezcla de reacción se calienta a reflujo durante 20 h. Una vez alcanzada la temperatura ambiente, el crudo de reacción se lava con una disolución acuosa saturada de NaHC03. Los extractos orgánicos se secan sobre Na2S04 y el disolvente se evapora a presión reducida. El residuo se purifica por cromatografía en columna, obteniéndose las diamidas (la). To a suspension of 1 equiv of the corresponding amine (IV) and 2 equiv of the halogenated derivative (III) in anhydrous dichloromethane (1 mL / mmol halogenated derivative), 3 equiv of DIPEA is added under argon atmosphere. The reaction mixture is heated at reflux for 20 h. Once the room temperature is reached, the reaction crude is washed with a saturated aqueous solution of NaHC0 3 . The organic extracts are dried over Na 2 S0 4 and the solvent is evaporate under reduced pressure. The residue is purified by column chromatography, obtaining the diamides (la).
W3-(2-anilino-2-oxoetil)- V1-fenil-AT5-octil-p-alaninamida (1). Se obtuvo a partir de /V1-fenil-/V2-octil-glicinamida (0.74 mmol) y 3-bromo-/V-fenilpropanamida (1.5 mmol) con un rendimiento del 25%. Cromatografía: hexano/acetato de etilo, 1 : 1. Rf (hexano/acetato de etilo, 6
Figure imgf000031_0001
W 3 - (2-anilino-2-oxoethyl) - V 1 -phenyl-AT 5 -octyl-p-alaninamide (1). It was obtained from / V 1 -phenyl- / V 2 -octyl-glycinamide (0.74 mmol) and 3-bromo- / V-phenylpropanamide (1.5 mmol) in 25% yield. Chromatography: hexane / ethyl acetate, 1: 1. R f (hexane / ethyl acetate, 6
Figure imgf000031_0001
IR (ATR, cm"1) 3274, 1664, 1601 , 1540, 1444 cm"1. 1 H RMN (CDCI3) δ 0.83 (t, J = 6.8 Hz, 3H), 1.18-1.23 (m, 10H), 1.40-1.49 (m, 2H), 2.47-2.54 (m, 4H), 2.91 (t, J = 6.3 Hz, 2H), 3.15 (s, 2H), 7.00-7.08 (m, 2H), 7.18 (t, J = 7.8 Hz, 2H), 7.24 (t, J = 7.9 Hz, 2H), 7.48 (d, J = 7.6 Hz, 2H), 7.53 (d, J = 7.6 Hz, 2H), 8.87 (s a, 1 H), 9.44 (s a, 1 H). 13C RMN (CDCIs) δ 14.0 (CH3), 22.6, 27.2, 27.5, 29.3, 29.5, 31.8, 35.0, 51.1 , 55.7, 58.9 (I OCH2), 1 19.7 (2CH), 119.9 (2CH), 124.1 , 124.2 (2CH), 128.8 (2CH), 128.9 (2CH), 137.5, 138.3 (2C), 170.4 (2C). HRMS (ESI) caled para C25H35N302Na [(M+Na)+] 432.2622, encontrado 432.2615. IR (ATR, cm "1 ) 3274, 1664, 1601, 1540, 1444 cm " 1 . 1 H NMR (CDCI 3 ) δ 0.83 (t, J = 6.8 Hz, 3H), 1.18-1.23 (m, 10H), 1.40-1.49 (m, 2H), 2.47-2.54 (m, 4H), 2.91 (t , J = 6.3 Hz, 2H), 3.15 (s, 2H), 7.00-7.08 (m, 2H), 7.18 (t, J = 7.8 Hz, 2H), 7.24 (t, J = 7.9 Hz, 2H), 7.48 (d, J = 7.6 Hz, 2H), 7.53 (d, J = 7.6 Hz, 2H), 8.87 (sa, 1 H), 9.44 (sa, 1 H). 13 C NMR (CDCIs) δ 14.0 (CH 3 ), 22.6, 27.2, 27.5, 29.3, 29.5, 31.8, 35.0, 51.1, 55.7, 58.9 (I OCH 2 ), 1 19.7 (2CH), 119.9 (2CH), 124.1 , 124.2 (2CH), 128.8 (2CH), 128.9 (2CH), 137.5, 138.3 (2C), 170.4 (2C). HRMS (ESI) caled for C 2 5H 3 5N 3 0 2 Na [(M + Na) + ] 432.2622, found 432.2615.
Procedimiento general B. General Procedure B.
A una suspensión de 1 equiv de la amina correspondiente (IV) y 1.5 equiv de la acrilamida (VI) en acetonitrilo seco (0.5 mL/mmol de amina), se le añaden 1.2 equiv de DBU bajo atmósfera de argón. La mezcla de reacción se calienta a 60 °C durante 5 h. Una vez alcanzada la temperatura ambiente, se elimina el disolvente a presión reducida y el residuo se purifica por cromatografía en columna, obteniéndose las diamidas (la).  To a suspension of 1 equiv of the corresponding amine (IV) and 1.5 equiv of the acrylamide (VI) in dry acetonitrile (0.5 mL / mmol of amine), 1.2 equiv of DBU is added under argon atmosphere. The reaction mixture is heated at 60 ° C for 5 h. Once the room temperature is reached, the solvent is removed under reduced pressure and the residue is purified by column chromatography, obtaining the diamides (la).
^-fenil-A^-ÍS-morfolin^-il-S-oxopropi -A^-octil-p-alaninamida (2). Se obtuvo a partir de A/1-fenil-/V3-octil^-alaninamida (0.36 mmol) y 4-acriloilmorfolina (0.54 mmol) con un rendimiento del 60%. Cromatografía: hexano/acetato de etilo, 1 : 1. Rf (hexano/acetato de etilo, 6:4) 0.16.
Figure imgf000031_0002
IR (ATR, cm"1) 3412, 3295, 1709, 1636, 1600, 1547, 1499 cm"1. 1 H RMN (CDCI3) δ 0.87 (t, J = 6.7 Hz, 3H), 1.22-1.28 (m, 10H), 1.54-1.58 (m, 2H), 2.50-2.59 (m, 6H), 2.83 (t ap, J = 5.8 Hz, 2H), 2.96 (t, J = 6.8 Hz, 2H), 3.38 (t ap, 2H, J = 4.8 Hz), 3.55- 3.61 (m, 6H), 7.07 (t, J = 7.4 Hz, 1 H), 7.30 (t, J = 7.2 Hz, 2H), 7.53 (d, J = 7.6 Hz, 2H), 10.21 (s a, 1 H). 13C RMN (CD3OD) δ 14.6 (CH3), 23.8, 27.9, 28.6, 30.5, 30.8, 30.9, 33.1 , 35.0, 43.4, 47.3, 50.6, 51.3, 55.0, 67.7, 67.8 (15CH2), 121.3 (2CH), 125.2 (CH), 129.9 (2CH), 139.9, 172.7, 173.1 (3C). HRMS (ESI) caled para [(M+H)+] C24H40N3O3: 418.3070; encontrado 418.3046. A^fenil-A^-tS-^-metilpiperazin-l -i -S-oxop (32). Se obtuvo a partir de A^-fenil-A^-octil^-alaninamida (0.18 mmol) y 1 -acriloil-4- metilpiperazina (0.27 mmol) con un rendimiento del 51 %. Cromatografía: acetato de etilo a acetato de etilo/metanol, 8:2. Rf acetato de etilo/metanol, 9: 1) 0.42.
Figure imgf000032_0001
^ -phenyl-A ^ -IS-morpholin-^ -yl-S-oxopropi -A ^ -octyl-p-alaninamide (2). It was obtained from A / 1 -phenyl- / V 3 -octyl ^ -alaninamide (0.36 mmol) and 4-acryloylmorpholine (0.54 mmol) in 60% yield. Chromatography: hexane / ethyl acetate, 1: 1. R f (hexane / ethyl acetate, 6: 4) 0.16.
Figure imgf000031_0002
IR (ATR, cm "1 ) 3412, 3295, 1709, 1636, 1600, 1547, 1499 cm " 1 . 1 H NMR (CDCI 3 ) δ 0.87 (t, J = 6.7 Hz, 3H), 1.22-1.28 (m, 10H), 1.54-1.58 (m, 2H), 2.50-2.59 (m, 6H), 2.83 (t ap, J = 5.8 Hz, 2H), 2.96 (t, J = 6.8 Hz, 2H), 3.38 (t ap, 2H, J = 4.8 Hz), 3.55- 3.61 (m, 6H), 7.07 (t, J = 7.4 Hz, 1 H), 7.30 (t, J = 7.2 Hz, 2H), 7.53 (d, J = 7.6 Hz, 2H), 10.21 (sa, 1 H). 13 C NMR (CD 3 OD) δ 14.6 (CH 3 ), 23.8, 27.9, 28.6, 30.5, 30.8, 30.9, 33.1, 35.0, 43.4, 47.3, 50.6, 51.3, 55.0, 67.7, 67.8 (15CH 2 ), 121.3 (2CH), 125.2 (CH), 129.9 (2CH), 139.9, 172.7, 173.1 (3C). HRMS (ESI) caled for [(M + H) + ] C24H4 0 N 3 O 3 : 418.3070; Found 418.3046. A ^ phenyl-A ^ -tS - ^ - methylpiperazin-l -i -S-oxop (32). It was obtained from A ^ -phenyl-A ^ -octyl ^ -alaninamide (0.18 mmol) and 1-acryloyl-4- methylpiperazine (0.27 mmol) in 51% yield. Chromatography: ethyl acetate to ethyl acetate / methanol, 8: 2. R f ethyl acetate / methanol, 9: 1) 0.42.
Figure imgf000032_0001
IR (ATR, cm"1) 3307, 1683, 1634, 1602, 1548, 1497 cm"1. 1 H RMN (CDCI3) δ 0.85 (t, J = 6.8 Hz, 3H), 1.21 -1.28 (m, 10H), 1.52 (m, 2H), 2.29 (t, J = 5.2 Hz, 2H), 2.35 (t, J = 5.3 Hz, 2H), 2.49-2.56 (m, 6H), 2.79 (t, J = 5.9 Hz, 2H), 2.91 (t, J = 6.8 Hz, 2H), 3.41 (t, J = 5.0 Hz, 2H), 3.47 (s, 3H), 3.58 (t, J = 4.9 Hz, 2H), 7.05 (t, J = 7.4 Hz, 1 H), 7.28 (t, J = 7.8 Hz, 2H), 7.53 (dd, J = 8.7, 1.1 Hz, 2H), 10.27 (br s, 1 H). 13C RMN (CDCI3) δ 14.2 (CH3), 22.8, 26.8, 27.8, 29.4, 29.6, 30.2, 31.9, 34.4, 41.6, 45.3 (I OCH2), 45.9 (CH3), 49.0, 50.8, 53.8, 54.5, 55.0 (5CH2), 1 19.8 (2CH), 123.7 (CH), 129.0 (2CH), 138.8, 169.8, 171.1 (3C). HRMS (ESI) caled para C24H33N3O4 [(M+H)+] 431.3380, encontrado 431.3383. IR (ATR, cm "1 ) 3307, 1683, 1634, 1602, 1548, 1497 cm " 1 . 1 H NMR (CDCI 3 ) δ 0.85 (t, J = 6.8 Hz, 3H), 1.21 -1.28 (m, 10H), 1.52 (m, 2H), 2.29 (t, J = 5.2 Hz, 2H), 2.35 ( t, J = 5.3 Hz, 2H), 2.49-2.56 (m, 6H), 2.79 (t, J = 5.9 Hz, 2H), 2.91 (t, J = 6.8 Hz, 2H), 3.41 (t, J = 5.0 Hz, 2H), 3.47 (s, 3H), 3.58 (t, J = 4.9 Hz, 2H), 7.05 (t, J = 7.4 Hz, 1 H), 7.28 (t, J = 7.8 Hz, 2H), 7.53 (dd, J = 8.7, 1.1 Hz, 2H), 10.27 (br s, 1 H). 13 C NMR (CDCI 3 ) δ 14.2 (CH 3 ), 22.8, 26.8, 27.8, 29.4, 29.6, 30.2, 31.9, 34.4, 41.6, 45.3 (I OCH2), 45.9 (CH 3 ), 49.0, 50.8, 53.8, 54.5, 55.0 (5CH 2 ), 1 19.8 (2CH), 123.7 (CH), 129.0 (2CH), 138.8, 169.8, 171.1 (3C). HRMS (ESI) caled for C24H 33 N 3 O4 [(M + H) + ] 431.3380, found 431.3383.
^-[S-ícicIohexilaminoJ-S-oxopropill-^-fenil-A^-octil-p-alaninamida (33). Se obtuvo a partir de A/1-fenil-/\/3-octil^-alaninamida (0.36 mmol) y N- ciclohexilacrilamida (0.54 mmol) con un rendimiento del 34%. Cromatografía: acetatode etilo a acetato de etilo) 0.31.
Figure imgf000032_0002
IR (ATR, cm"1) 3298, 1646, 1601 , 1547, 1499 cm"1. 1 H RMN (CDCI3) δ 0.87 (t, J = 6.7 Hz, 3H), 0.94-1.1 1 (m, 3H), 1.23-1.26 (m, 12H), 1.50-1.66 (m, 5H), 1.76-1.81 (m, 2H), 2.37 (t, J = 6.5 Hz, 2H), 2.48-2.56 (m, 4H), 2.82 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.5 Hz, 2H), 3.61-3.73 (m, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 7.30 (t, J = 8.1 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 9.74 (br s, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6 (CH2), 24.8 (2CH2), 25.4, 26.9, 27.7, 29.3, 29.6, 31.8 (6CH2), 33.1 (2CH2), 33.9, 34.1 (2CH2), 48.2 (CH), 49.4, 50.2, 53.7 (3CH2), 1 19.8 (2CH), 123.8 (CH), 128.8 (2CH), 138.5, 170.6, 170.8 (3C). HRMS (ESI) caled para C24H34N304 [(M+H)+] 430.3428, encontrado 430.3408. ^ - [S-IcicIohexylaminoJ-S-oxopropill - ^ - phenyl-A ^ -octyl-p-alaninamide (33). It was obtained from A / 1 -phenyl - / \ / 3 -octyl ^ -alaninamide (0.36 mmol) and N-cyclohexylacrylamide (0.54 mmol) with a yield of 34%. Chromatography: ethyl acetate to ethyl acetate) 0.31.
Figure imgf000032_0002
IR (ATR, cm "1 ) 3298, 1646, 1601, 1547, 1499 cm " 1 . 1 H NMR (CDCI 3 ) δ 0.87 (t, J = 6.7 Hz, 3H), 0.94-1.1 1 (m, 3H), 1.23-1.26 (m, 12H), 1.50-1.66 (m, 5H), 1.76- 1.81 (m, 2H), 2.37 (t, J = 6.5 Hz, 2H), 2.48-2.56 (m, 4H), 2.82 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.5 Hz, 2H ), 3.61-3.73 (m, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 7.30 (t, J = 8.1 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 9.74 (br s, 1 H). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6 (CH 2 ), 24.8 (2CH 2 ), 25.4, 26.9, 27.7, 29.3, 29.6, 31.8 (6CH 2 ), 33.1 (2CH 2 ), 33.9, 34.1 (2CH 2 ), 48.2 (CH), 49.4, 50.2, 53.7 (3CH 2 ), 1 19.8 (2CH), 123.8 (CH), 128.8 (2CH), 138.5, 170.6, 170.8 (3C). HRMS (ESI) caled for C 24 H 34 N 3 04 [(M + H) + ] 430.3428, found 430.3408.
^-fenil-A^-ÍS-^-fluorofenilJaminol-S-oxopropi^-A^-octil-p-alaninamida (34). Se obtuvo a partir de A/1-fenil-A/3-octil^-alaninamida (0.18 mmol) y Λ/-(4- fluorofenil)acrilamida (0.27 mmol) con un rendimiento del 58%. Cromatografía: acetato de etilo a acetato de etilo/metanol, 8:2. Rf (acetato de etilo) 0.32.
Figure imgf000033_0001
^ -phenyl-A ^ -IS - ^ - fluorophenylJaminol-S-oxopropi ^ -A ^ -octyl-p-alaninamide (34). It was obtained from A / 1 -phenyl-A / 3- octyl ^ -alaninamide (0.18 mmol) and Λ / - (4- fluorophenyl) acrylamide (0.27 mmol) in 58% yield. Chromatography: ethyl acetate to ethyl acetate / methanol, 8: 2. R f (ethyl acetate) 0.32.
Figure imgf000033_0001
IR (ATR, cm"1) 3290, 1659, 1604, 1550, 1508 cm"1. 1 H RMN (CDCI3) δ 0.87 (t, J = 7.0IR (ATR, cm "1 ) 3290, 1659, 1604, 1550, 1508 cm " 1 . 1 H NMR (CDCI 3 ) δ 0.87 (t, J = 7.0
Hz, 3H), 1.08-1.41 (m, 10H), 1.51 (m, 2H), 2.52-2.61 (m, 6H), 2.85-2.90 (m, 4H), 6.90 (t, J = 8.8 Hz, 2H), 7.07 (t, J = 7.4 Hz, 1 H), 7.23 (t, J = 7.9 Hz, 2H), 7.43-7.50 (m, 4H). 13C RMN (CDCI3) δ 14.4 (CH3), 23.7, 28.3, 28.8, 30.5, 30.8, 33.0, 35.4, 51.0, 51.1 (9CH2), 54.7 (2CH2), 1 16.1 (2CH, d, J = 22.4 Hz), 121.4 (2CH), 123.1 (2CH, d, J = 7.8 Hz), 125.1 (CH), 129.7 (2CH), 135.8 (C, d, J = 2.8 Hz), 139.6 (C), 160.1 (C, d, J = 240.0 Hz), 173.2, 173.3 (2C). Análisis elemental caled para C26H36FN302 C, 70.72; H, 8.22; N, 9.52, encontrado C, 70.33; H, 8.23; N, 9.29. ^-fenil-A^-ÍS-Imetilífeni aminol-S-oxopropi^-A^-octil-p-alaninamida (35). Se obtuvo a partir de A/1-fenil-/\/3-octil^-alaninamida (0.36 mmol) y /V-fenil-A- metilacrilamida (0.54 mmol) con un rendimiento del 58%. Cromatografía: acetato de etilo a acetato de etilo/me tanol, 9: 1) 0.31.
Figure imgf000033_0002
IR (ATR, cm"1) 3306, 1658, 1599, 1547, 1497 cm"1. 1 H RMN (CDCI3) δ 0.88 (t, J = 6.8 Hz, 3H), 1.23 (m, 10H), 1.47 (m, 2H), 2.30 (t, J = 6.8 Hz, 2H), 2.39 (t, J = 7.5 Hz, 2H), 2.46 (t ap, J = 5.5 Hz, 2H), 2.63 (t ap, J = 5.5 Hz, 2H), 2.84 (t, J = 6.8 Hz, 2H), 7.07 (t, J = 7.4 Hz, 1 H), 7.10 (d, J = 6.7 Hz, 2H), 7.27-7.42 (m, 5H), 7.50 (d, J = 7.9 Hz, 2H), 10.40 (br s, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.6, 27.6, 29.3, 29.5, 31.5, 31.8, 33.9 (8CH2), 37.3 (CH3), 49.1 , 50.3, 53.4 (3CH2), 1 19.8 (2CH), 123.5 (CH), 127.1 (2CH), 128.0 (CH), 128.8 (2CH), 129.9 (2CH), 138.7, 143.7, 170.9, 171.2 (4C). HRMS (El) caled para C27H39N302 [M +] 437.3037, encontrado 437.3041. Hz, 3H), 1.08-1.41 (m, 10H), 1.51 (m, 2H), 2.52-2.61 (m, 6H), 2.85-2.90 (m, 4H), 6.90 (t, J = 8.8 Hz, 2H) , 7.07 (t, J = 7.4 Hz, 1 H), 7.23 (t, J = 7.9 Hz, 2H), 7.43-7.50 (m, 4H). 13 C NMR (CDCI 3 ) δ 14.4 (CH 3 ), 23.7, 28.3, 28.8, 30.5, 30.8, 33.0, 35.4, 51.0, 51.1 (9CH 2 ), 54.7 (2CH 2 ), 1 16.1 (2CH, d, J = 22.4 Hz), 121.4 (2CH), 123.1 (2CH, d, J = 7.8 Hz), 125.1 (CH), 129.7 (2CH), 135.8 (C, d, J = 2.8 Hz), 139.6 (C), 160.1 (C, d, J = 240.0 Hz), 173.2, 173.3 (2C). Elemental analysis caled for C 26 H 36 FN 3 0 2 C, 70.72; H, 8.22; N, 9.52, found C, 70.33; H, 8.23; N, 9.29. ^ -phenyl-A ^ -IS-Imethylipheni aminol-S-oxopropi ^ -A ^ -octyl-p-alaninamide (35). It was obtained from A / 1 -phenyl - / \ / 3 -octyl ^ -alaninamide (0.36 mmol) and / V-phenyl-A-methylacrylamide (0.54 mmol) in 58% yield. Chromatography: ethyl acetate to ethyl acetate / methanol, 9: 1) 0.31.
Figure imgf000033_0002
IR (ATR, cm "1 ) 3306, 1658, 1599, 1547, 1497 cm " 1 . 1 H NMR (CDCI 3 ) δ 0.88 (t, J = 6.8 Hz, 3H), 1.23 (m, 10H), 1.47 (m, 2H), 2.30 (t, J = 6.8 Hz, 2H), 2.39 (t, J = 7.5 Hz, 2H), 2.46 (t ap, J = 5.5 Hz, 2H), 2.63 (t ap, J = 5.5 Hz, 2H), 2.84 (t, J = 6.8 Hz, 2H), 7.07 (t, J = 7.4 Hz, 1 H), 7.10 (d, J = 6.7 Hz, 2H), 7.27-7.42 (m, 5H), 7.50 (d, J = 7.9 Hz, 2H), 10.40 (br s, 1 H) . 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6, 26.6, 27.6, 29.3, 29.5, 31.5, 31.8, 33.9 (8CH 2 ), 37.3 (CH 3 ), 49.1, 50.3, 53.4 (3CH 2 ), 1 19.8 (2CH), 123.5 (CH), 127.1 (2CH), 128.0 (CH), 128.8 (2CH), 129.9 (2CH), 138.7, 143.7, 170.9, 171.2 (4C). HRMS (El) caled for C 2 7H 39 N 3 02 [M + ] 437.3037, found 437.3041.
^-(S-anilino-S-oxopropi -A^-octil-^-piridin^-il-p-alaninamida (36). Se obtuvo a partir de A/1-fenil-/V3-octil^-alaninamida (0.27 mmol) y A/-piridin-2-ilacrilamida (0.41 mmol) con un rendimiento del 45%. Cromatografía: acetato de etilo. Rf (acetato de etilo/metanol, 98:2) 0.28.
Figure imgf000034_0001
^ - (S-Anilino-S-oxopropi -A ^ -octil - ^ -pyridin ^ -yl-p-alaninamide (36). It was obtained from A / 1 -phenyl- / V 3 -octyl ^ -alaninamide ( 0.27 mmol) and A / -pyridin-2-ylacrylamide (0.41 mmol) with a yield of 45% Chromatography: ethyl acetate R f (ethyl acetate / methanol, 98: 2) 0.28.
Figure imgf000034_0001
IR (ATR, cm"1) 3274, 1665, 1600, 1540, 1435 cm"1. 1 H RMN (CDCI3) δ 0.83 (t, J = 6.9 Hz, 3H), 1.04-1.34 (m, 10H), 1.51 (m, 2H), 2.51-2.60 (m, 6H), 2.90 (t, J = 6.0 Hz, 4H), 6.98-7.01 (m, 2H), 7.20 (t, J = 7.8 Hz, 2H), 7.47 (d, J = 7.8 Hz, 2H), 7.66 (t, J = 7.9 Hz, 1 H), 8.17-8.22 (m, 2H), 9.89 (br s, 1 H), 10.55 (br s, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.7, 27.5, 29.2, 29.5, 31.7, 34.1 , 36.3, 50.0, 51.0, 54.1 (1 1 CH2), 1 14.5, 1 19.7 (2CH), 120.0 (2CH), 123.9 (CH), 128.8 (2CH), 138.5 (C), 138.6, 147.5 (2CH), 151.6, 170.9, 171.0 (3C). HRMS (El) caled para C25H36N402 [M +] 424.2833, encontrado 424.2832. ^-(S-anilino-S-oxopropi -A^-octil-^-piridin-S-il-p-alaninamida (37). Se obtuvo a partir de A/1-fenil-/V3-octil^-alaninamida (0.36 mmol) y A/-piridin-3-ilacrilamida (0.54 mmol) con un rendimiento del 37%. Cromatografía: acetato de etilo a acetato de etilo/metanol, 9: 1. Rf (acetato de etilo/metanol, 9: 1 0.28.
Figure imgf000034_0002
IR (ATR, cm"1) 3265, 1664, 1600, 1546, 1489 cm"1. 1 H RMN (CDCI3) δ 0.84 (t, J = 6.8 Hz, 3H), 1.07-1.34 (m, 10H), 1.51 (m, 2H), 2.50-2.59 (m, 6H), 2.82 (t, J = 6.4 Hz, 2H), 2.84 (t, J = 6.4 Hz, 2H), 6.99 (t, J = 7.4 Hz, 1 H), 7.10 (dd, J = 8.3, 4.8 Hz, 1 H), 7.15 (t, J = 7.8 Hz, 2H), 7.41 (d, J = 7.8 Hz, 2H), 7.99 (d, J = 8.5 Hz, 1 H), 8.21 (d, J = 5.8 Hz, 1 H), 8.54 (d, J = 2.4 Hz, 1 H), 9.52 (s a, 1 H), 9.98 (s a, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.7, 27.7, 29.3, 29.5, 31.8 (6CH2), 34.3 (2CH2), 49.6, 49.8, 53.7 (3CH2), 1 19.9 (2CH), 123.7, 124.1 , 127.1 (3CH), 128.8 (2CH), 135.4, 138.0 (2C), 140.9, 144.4 (2CH), 170.6, 171.2 (2C). HRMS (El) caled para C25H36N4O2 [M +] 424.2833, encontrado 424.2831. IR (ATR, cm "1 ) 3274, 1665, 1600, 1540, 1435 cm " 1 . 1 H NMR (CDCI 3 ) δ 0.83 (t, J = 6.9 Hz, 3H), 1.04-1.34 (m, 10H), 1.51 (m, 2H), 2.51-2.60 (m, 6H), 2.90 (t, J = 6.0 Hz, 4H), 6.98-7.01 (m, 2H), 7.20 (t, J = 7.8 Hz, 2H), 7.47 (d, J = 7.8 Hz, 2H), 7.66 (t, J = 7.9 Hz, 1 H), 8.17-8.22 (m, 2H), 9.89 (br s, 1 H), 10.55 (br s, 1 H). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6, 26.7, 27.5, 29.2, 29.5, 31.7, 34.1, 36.3, 50.0, 51.0, 54.1 (1 1 CH 2 ), 1 14.5, 1 19.7 (2CH) , 120.0 (2CH), 123.9 (CH), 128.8 (2CH), 138.5 (C), 138.6, 147.5 (2CH), 151.6, 170.9, 171.0 (3C). HRMS (El) caled for C 2 5H 36 N 4 02 [M + ] 424.2833, found 424.2832. ^ - (S-anilino-S-oxopropi -A ^ -octil - ^ -pyridin-S-yl-p-alaninamide (37). It was obtained from A / 1 -phenyl- / V 3 -octyl ^ -alaninamide (0.36 mmol) and A / -pyridin-3-ylacrylamide (0.54 mmol) with a yield of 37% Chromatography: ethyl acetate to ethyl acetate / methanol, 9: 1. R f (ethyl acetate / methanol, 9 : 1 0.28.
Figure imgf000034_0002
IR (ATR, cm "1 ) 3265, 1664, 1600, 1546, 1489 cm " 1 . 1 H NMR (CDCI 3 ) δ 0.84 (t, J = 6.8 Hz, 3H), 1.07-1.34 (m, 10H), 1.51 (m, 2H), 2.50-2.59 (m, 6H), 2.82 (t, J = 6.4 Hz, 2H), 2.84 (t, J = 6.4 Hz, 2H), 6.99 (t, J = 7.4 Hz, 1 H), 7.10 (dd, J = 8.3, 4.8 Hz, 1 H), 7.15 (t , J = 7.8 Hz, 2H), 7.41 (d, J = 7.8 Hz, 2H), 7.99 (d, J = 8.5 Hz, 1 H), 8.21 (d, J = 5.8 Hz, 1 H), 8.54 (d , J = 2.4 Hz, 1 H), 9.52 (sa, 1 H), 9.98 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6, 26.7, 27.7, 29.3, 29.5, 31.8 (6CH 2 ), 34.3 (2CH 2 ), 49.6, 49.8, 53.7 (3CH 2 ), 1 19.9 (2CH ), 123.7, 124.1, 127.1 (3CH), 128.8 (2CH), 135.4, 138.0 (2C), 140.9, 144.4 (2CH), 170.6, 171.2 (2C). HRMS (El) caled for C25H36N4O2 [M + ] 424.2833, found 424.2831.
^-fenil-A^-IS-ímetilaminoJ-S-oxopropill-A^-octil-p-alaninamida (38). Se obtuvo a partir de A/1-fenil-A/3-octil^-alaninamida (0.36 mmol) y /V-metilacrilamida (0.54 mmol) con un rendimiento del 54%. Cromatografía: acetato de etilo a acetato de etilo/metanol, 9: 1. Rf (acetato de etilo/metanol, 9: 1 0.31.
Figure imgf000035_0001
^ -phenyl-A ^ -IS-ímethylaminoJ-S-oxopropill-A ^ -octyl-p-alaninamide (38). It was obtained from A / 1 -phenyl-A / 3- octyl ^ -alaninamide (0.36 mmol) and / V-methylacrylamide (0.54 mmol) in 54% yield. Chromatography: ethyl acetate to ethyl acetate / methanol, 9: 1. R f (ethyl acetate / methanol, 9: 1 0.31.
Figure imgf000035_0001
IR (ATR, cm"1) 3298, 1648, 1601 , 1549, 1497 cm"1. 1 H RMN (CDCI3) δ 0.87 (t, J = 6.8 Hz, 3H), 1.23-1.29 (m, 10H), 1.52 (m, 2H), 2.38 (t, J = 6.5 Hz, 2H), 2.49-2.56 (m, 4H), 2.64 (d, J = 4.6 Hz, 3H, CH3), 2.81 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.5 Hz, 2H), 3.12-3.21 (m, 2H), 6.15 (s a, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 7.30 (t, J = 7.7 Hz, 2H), 7.54 (d, J = 7.7 Hz, 2H). 13C RMN (CDCI3) δ 14.2 (CH3), 22.8 (CH2), 26.3 (CH3), 26.9, 27.8, 29.5, 29.7, 32.0, 33.9, 34.6, 49.7, 50.5, 53.8 (10CH2), 1 19.9 (2CH), 123.9 (CH), 129.0 (2CH), 138.6, 170.9, 172.4 (3C). HRMS (ESI) caled para C21 H35N3O2 [M +] 361.2724, encontrado 361.2723. ^-[S-íetilaminoJ-S-oxopropill-^-fenil-A^-octil-p-alaninamida (39). Se obtuvo a partir de A/1-fenil-/V3-octil^-alaninamida (0.36 mmol) y /V-etilacrilamida (0.54 mmol) con un rendimiento del 52%. Cromatografía: acetato de etilo a acetato de etilo/metanol, 7:3. Rf (acetato de etilo 0.19.
Figure imgf000035_0002
IR (ATR, cm"1) 3296, 1645, 1601 , 1549, 1498 cm"1. 1 H RMN (CDCI3) δ 0.86 (t, J = 6.7 Hz, 3H), 1.02 (t, J = 7.3 Hz, 3H), 1.04-1.17 (m, 10H), 1.51 (m, 2H), 2.35 (t, 2H), 2.47-2.53 (m, 4H), 2.78 (t, J = 5.9 Hz, 2H), 2.85 (t, J = 6.6 Hz, 2H), 3.12-3.21 (m, 2H), 5.98 (s a, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 7.30 (t, J = 7.9 Hz, 2H), 7.54 (d, J = 7.9 Hz, 2H), 9.72 (s a, 1 H). 13C RMN (CDCI3) δ 14.2, 14.8 (2CH3), 22.8, 27.0, 27.8, 29.4, 29.7, 32.0, 34.0, 34.5, 49.6, 50.5, 53.8 (12CH2), 1 19.9 (2CH), 123.9 (CH), 129.0 (2CH), 138.6, 170.9, 171.5 (3C). HRMS (ESI) caled para C22H37N3O2 [M +] 375.2880, encontrado 375.2882. ^-fenil-A^-IS-íisopropilaminoJ-S-oxopropill-A^-octil-p-alaninamida (40). Se obtuvo a partir de A/1-fenil-A/3-octil^-alaninamida (0.58 mmol) y /V-isopropilacrilamida (0.87 mmol) con un rendimiento del 29%. Cromatografía: acetato de etilo. Rf (acetato de etilo) 0.17.
Figure imgf000036_0001
IR (ATR, cm "1 ) 3298, 1648, 1601, 1549, 1497 cm " 1 . 1 H NMR (CDCI 3 ) δ 0.87 (t, J = 6.8 Hz, 3H), 1.23-1.29 (m, 10H), 1.52 (m, 2H), 2.38 (t, J = 6.5 Hz, 2H), 2.49- 2.56 (m, 4H), 2.64 (d, J = 4.6 Hz, 3H, CH 3 ), 2.81 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.5 Hz, 2H), 3.12-3.21 ( m, 2H), 6.15 (sa, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 7.30 (t, J = 7.7 Hz, 2H), 7.54 (d, J = 7.7 Hz, 2H). 13 C NMR (CDCI 3 ) δ 14.2 (CH 3 ), 22.8 (CH 2 ), 26.3 (CH 3 ), 26.9, 27.8, 29.5, 29.7, 32.0, 33.9, 34.6, 49.7, 50.5, 53.8 (10CH 2 ), 1 19.9 (2CH), 123.9 (CH), 129.0 (2CH), 138.6, 170.9, 172.4 (3C). HRMS (ESI) caled for C21 H35N3O2 [M + ] 361.2724, found 361.2723. ^ - [S-EthylaminoJ-S-oxopropill - ^ - phenyl-A ^ -octyl-p-alaninamide (39). It was obtained from A / 1 -phenyl- / V 3 -octyl ^ -alaninamide (0.36 mmol) and / V-ethylacrylamide (0.54 mmol) with a yield of 52%. Chromatography: ethyl acetate to ethyl acetate / methanol, 7: 3. R f (ethyl acetate 0.19.
Figure imgf000035_0002
IR (ATR, cm "1 ) 3296, 1645, 1601, 1549, 1498 cm " 1 . 1 H NMR (CDCI 3 ) δ 0.86 (t, J = 6.7 Hz, 3H), 1.02 (t, J = 7.3 Hz, 3H), 1.04-1.17 (m, 10H), 1.51 (m, 2H), 2.35 ( t, 2H), 2.47-2.53 (m, 4H), 2.78 (t, J = 5.9 Hz, 2H), 2.85 (t, J = 6.6 Hz, 2H), 3.12-3.21 (m, 2H), 5.98 (sa , 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 7.30 (t, J = 7.9 Hz, 2H), 7.54 (d, J = 7.9 Hz, 2H), 9.72 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.2, 14.8 (2CH 3 ), 22.8, 27.0, 27.8, 29.4, 29.7, 32.0, 34.0, 34.5, 49.6, 50.5, 53.8 (12CH 2 ), 1 19.9 (2CH), 123.9 ( CH), 129.0 (2CH), 138.6, 170.9, 171.5 (3C). HRMS (ESI) caled for C22H 3 7N 3 O2 [M + ] 375.2880, found 375.2882. ^ -phenyl-A ^ -IS-ÍisopropylaminoJ-S-oxopropill-A ^ -octyl-p-alaninamide (40). It was obtained from A / 1 -phenyl-A / 3- octyl ^ -alaninamide (0.58 mmol) and / V-isopropylacrylamide (0.87 mmol) in a yield of 29%. Chromatography: ethyl acetate. R f (ethyl acetate) 0.17.
Figure imgf000036_0001
IR (ATR, cm"1) 3299, 1643, 1602, 1548, 1499 cm"1. 1 H RMN (CDCI3) δ 0.81 (t, J = 6.7 Hz, 3H), 1.00 (d, J = 6.5 Hz, 6H), 1.13-1.30 (m, 10H), 1.46 (m, 2H), 2.29 (t, J = 6.6 Hz,2H), 2.42-2.49 (m, 4H), 2.74 (t, J = 6.1 Hz, 2H), 2.80 (t, J = 6.7 Hz, 2H), 3.90- 4.01 (m, 1 H), 5.99 (s a, 1 H), 7.01 (t, J = 7.4 Hz, 1 H), 7.24 (t, J = 7.9 Hz, 2H), 7.49 (d, J = 7.6 Hz, 2H), 9.83 (s a, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6 (2CH3, CH2), 26.9, 27.6, 29.3, 29.5, 31.8, 33.8, 34.2 (7CH2), 41.3 (CH), 49.4, 50.2, 53.7 (3CH2), 1 19.8 (2CH), 123.8 (CH), 128.8 (2CH), 138.6, 170.7, 170.8 (3C). HRMS (ESI) caled para C23H39N3O2 [M +] 389.3037, encontrado 389.3039. IR (ATR, cm "1 ) 3299, 1643, 1602, 1548, 1499 cm " 1 . 1 H NMR (CDCI 3 ) δ 0.81 (t, J = 6.7 Hz, 3H), 1.00 (d, J = 6.5 Hz, 6H), 1.13-1.30 (m, 10H), 1.46 (m, 2H), 2.29 ( t, J = 6.6 Hz, 2H), 2.42-2.49 (m, 4H), 2.74 (t, J = 6.1 Hz, 2H), 2.80 (t, J = 6.7 Hz, 2H), 3.90-4.01 (m, 1 H), 5.99 (sa, 1 H), 7.01 (t, J = 7.4 Hz, 1 H), 7.24 (t, J = 7.9 Hz, 2H), 7.49 (d, J = 7.6 Hz, 2H), 9.83 ( sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6 (2CH 3 , CH 2 ), 26.9, 27.6, 29.3, 29.5, 31.8, 33.8, 34.2 (7CH 2 ), 41.3 (CH), 49.4, 50.2, 53.7 (3CH 2 ), 1 19.8 (2CH), 123.8 (CH), 128.8 (2CH), 138.6, 170.7, 170.8 (3C). HRMS (ESI) caled for C23H39N3O2 [M + ] 389.3037, found 389.3039.
EJEMPLO 6. Síntesis de los derivados (Ib). Procedimiento general. EXAMPLE 6. Synthesis of derivatives (Ib). General procedure.
A una suspensión de 2 equiv del derivado halogenado correspondiente (lll-a) y 1 equiv de la amina adecuada (II) en acetonitrilo seco (1 mL/mmol amina), se le añade DI PEA bajo atmósfera de argón. La mezcla de reacción se calienta a 60 °C durante toda la noche. Una vez alcanzada la temperatura ambiente, se elimina el disolvente a presión reducida y el residuo se purifica por cromatografía en columna, obteniéndose las diamidas (Ib). V2-(2-anilino-2-oxoetil)- V1-fenil- V2-octilglicinamida (3). Se obtuvo a partir de 2- bromo-/V-fenilacetamida (2.7 mmol) y octilamina (1.3 mmol) con un rendimiento del 93%. Cromatografía: hexan (acetato de etilo) 0.71.
Figure imgf000037_0001
To a suspension of 2 equiv of the corresponding halogenated derivative (lll-a) and 1 equiv of the appropriate amine (II) in dry acetonitrile (1 mL / mmol amine), DI PEA is added under an argon atmosphere. The reaction mixture is heated at 60 ° C overnight. Once the room temperature is reached, the solvent is removed under reduced pressure and the residue is purified by column chromatography, obtaining the diamides (Ib). V 2 - (2-anilino-2-oxoethyl) - V 1 -phenyl- V 2 -octylglycinamide (3). It was obtained from 2- bromo- / V-phenylacetamide (2.7 mmol) and octylamine (1.3 mmol) in 93% yield. Chromatography: hexane (ethyl acetate) 0.71.
Figure imgf000037_0001
IR (ATR, cm"1) 3274, 1666, 1601 , 1542, 1444. 1 H RMN (CDCI3) δ 0.85 (t, J = 6.7 Hz, 3H), 1.23-1.28 (m, 10H), 1.44-1.51 (m, 2H), 2.66 (t, J = 7.4 Hz, 2H), 3.36 (s, 4H), 7.10 (t, J = 7.4 Hz, 2H), 7.32 (t ap, J = 7.9 Hz, 4H), 7.62 (d, J = 7.7 Hz, 4H), 9.07 (s a, 2H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 27.2, 27.6, 29.3, 29.4, 31.8, 56.4 (7CH2), 59.8 (2CH2), 1 19.9 (4CH), 124.4 (2CH), 129.0 (4CH), 137.7 (2C), 169.4 (2C). HRMS (ESI) caled para C24H33N302Na [(M+Na)+] 418.2465, encontrado 418.2449. IR (ATR, cm "1 ) 3274, 1666, 1601, 1542, 1444. 1 H NMR (CDCI 3 ) δ 0.85 (t, J = 6.7 Hz, 3H), 1.23-1.28 (m, 10H), 1.44-1.51 (m, 2H), 2.66 (t, J = 7.4 Hz, 2H), 3.36 (s, 4H), 7.10 (t, J = 7.4 Hz, 2H), 7.32 (t ap, J = 7.9 Hz, 4H), 7.62 (d, J = 7.7 Hz, 4H), 9.07 (sa, 2H) 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6, 27.2, 27.6, 29.3, 29.4, 31.8, 56.4 (7CH 2 ) , 59.8 (2CH 2 ), 1 19.9 (4CH), 124.4 (2CH), 129.0 (4CH), 137.7 (2C), 169.4 (2C). HRMS (ESI) caled for C 2 4H33N 3 02Na [(M + Na) + ] 418.2465, found 418.2449.
EJEMPLO 7. Síntesis de los derivados (le). Procedimiento general. EXAMPLE 7. Synthesis of derivatives (le). General procedure.
A una suspensión de 3 equiv de la acrilamida correspondiente (VI) y 1 equiv de la amina adecuada (II) en acetonitrilo seco (0.5 mL/mmol amina), se le añade 1 equiv de DBU y la mezcla se calienta a 60 °C durante toda la noche. Una vez alcanzada la temperatura ambiente, se elimina el disolvente a presión reducida y el residuo se purifica por cromatografía en columna, obteniéndose las diamidas (le). A^-ÍS-anilino-S-oxopropi - V^fenil-A^-octil-p-alaninamida (4). Se obtuvo a partir de /V-fenilacrilamida (3.4 mmol) y octilamina (1.1 mmol) con un rendimiento del 83%. Cromatografía: hexano/acetato de etilo, 1 : 1. Rf (hexano/acetato de etilo, 1 : 1) 0.45.
Figure imgf000037_0002
To a suspension of 3 equiv of the corresponding acrylamide (VI) and 1 equiv of the appropriate amine (II) in dry acetonitrile (0.5 mL / mmol amine), 1 equiv of DBU is added and the mixture is heated to 60 ° C All night long. Once the room temperature is reached, the solvent is removed under reduced pressure and the residue is purified by column chromatography, obtaining the diamides (le). A ^ -IS-anilino-S-oxopropi - V ^ phenyl-A ^ -octyl-p-alaninamide (4). It was obtained from / V-phenylacrylamide (3.4 mmol) and octylamine (1.1 mmol) in 83% yield. Chromatography: hexane / ethyl acetate, 1: 1. R f (hexane / ethyl acetate, 1: 1) 0.45.
Figure imgf000037_0002
IR (ATR, cm"1) 3294, 1659, 1601 , 1546, 1498, 1443. 1 H RMN (CDCI3) δ 0.85 (t, J = 6.7 Hz, 3H), 1.08 (m, 2H), 1.19-1 .25 (m, 8H), 1.52 (m, 2H), 2.53 (t, J = 6.3 Hz, 6H), 2.85 (t, J = 6.2 Hz, 4H), 7.02 (t, J = 7.3 Hz, 2H), 7.20 (t, J = 7.8 Hz, 4H), 7.43 (d, J = 7.8 Hz, 4H), 8.90 (s a, 2H). 13C RMN (CDCI3) δ 14.0 (CH3), 22.6, 26.8, 27.7, 29.3, 29.5, 31.8 (6CH2), 34.5 (2CH2), 49.9 (2CH2), 53.7 (CH2), 1 19.9 (4CH), 124.0 (2CH), 128.9 (4CH), 138.1 (2C), 170.4 (2C). HRMS (ESI) caled para C26H38N302 [(M+H)+] 424.2959, encontrado 424.2959. ^-(S-anilino-S-oxopropi -^-fenil-A^-ÍS-butoxipropi -p-alaninamida (5). Se obtuvo a partir de /V-fenilacrilamida (2.3 mmol) y 3-butoxi-1-propanamina (0.76 mmol) con un rendimiento del 35%. Cromatografía: hexano a acetato de etilo. Rf (acetato de etilo) 0.37. IR (ATR, cm "1 ) 3294, 1659, 1601, 1546, 1498, 1443. 1 H NMR (CDCI 3 ) δ 0.85 (t, J = 6.7 Hz, 3H), 1.08 (m, 2H), 1.19-1 .25 (m, 8H), 1.52 (m, 2H), 2.53 (t, J = 6.3 Hz, 6H), 2.85 (t, J = 6.2 Hz, 4H), 7.02 (t, J = 7.3 Hz, 2H) , 7.20 (t, J = 7.8 Hz, 4H), 7.43 (d, J = 7.8 Hz, 4H), 8.90 (sa, 2H) 13 C NMR (CDCI 3 ) δ 14.0 (CH 3 ), 22.6, 26.8, 27.7, 29.3, 29.5, 31.8 (6CH 2 ), 34.5 (2CH 2 ), 49.9 (2CH 2 ), 53.7 (CH 2 ), 1 19.9 (4CH), 124.0 (2CH), 128.9 (4CH), 138.1 (2C) , 170.4 (2C) HRMS (ESI) caled for C 26 H 38 N 3 0 2 [(M + H) + ] 424.2959, found 424.2959. ^ - (S-anilino-S-oxopropi - ^ - phenyl-A ^ -IS-butoxypropyl-p-alaninamide (5). It was obtained from / V-phenylacrylamide (2.3 mmol) and 3-butoxy-1-propanamine (0.76 mmol) with a yield of 35% Chromatography: hexane to ethyl acetate R f (ethyl acetate) 0.37.
Figure imgf000038_0001
Figure imgf000038_0001
IR (ATR, cm"1) 3287, 1661 , 1600, 1547, 1498 cm"1. 1 H RMN (CD3OD) δ 0.76 (t, J = 7.3 Hz, 3H), 1.08 (m, 2H), 1.10-1.37 (m, 4H), 1.64 (qt, J = 6.6 Hz, 2H), 2.44-2.52 (m, 6H), 2.75 (t, J = 6.3 Hz, 4H), 3.13 (t, J = 6.6 Hz, 2H), 3.30 (t, J = 6.6 Hz, 2H), 6.93 (t, J = 7.4 Hz, 2H), 7.10 (t, J = 7.9 Hz, 4H), 7.37 (d, J = 8.8 Hz, 4H). 13C RMN (CD3OD) δ 14.4 (CH3), 20.4, 28.3, 32.9 (3CH2), 35.6 (2CH2), 51.2 (2CH2), 51.4, 69.8, 71.7 (3CH2), 121.3 (4CH), 125.1 (2CH), 129.8 (4CH), 139.8 (2C), 173.4 (2C). HRMS (ESI) caled para C^HssNsOsNa [(M+Na)+] 448.2576, encontrado 448.2564. IR (ATR, cm "1 ) 3287, 1661, 1600, 1547, 1498 cm " 1 . 1 H NMR (CD 3 OD) δ 0.76 (t, J = 7.3 Hz, 3H), 1.08 (m, 2H), 1.10-1.37 (m, 4H), 1.64 (qt, J = 6.6 Hz, 2H), 2.44 -2.52 (m, 6H), 2.75 (t, J = 6.3 Hz, 4H), 3.13 (t, J = 6.6 Hz, 2H), 3.30 (t, J = 6.6 Hz, 2H), 6.93 (t, J = 7.4 Hz, 2H), 7.10 (t, J = 7.9 Hz, 4H), 7.37 (d, J = 8.8 Hz, 4H). 13 C NMR (CD 3 OD) δ 14.4 (CH 3 ), 20.4, 28.3, 32.9 (3CH 2 ), 35.6 (2CH 2 ), 51.2 (2CH 2 ), 51.4, 69.8, 71.7 (3CH 2 ), 121.3 (4CH ), 125.1 (2CH), 129.8 (4CH), 139.8 (2C), 173.4 (2C). HRMS (ESI) caled for C ^ HssNsOsNa [(M + Na) + ] 448.2576, found 448.2564.
W3-(3-anilino-3-oxopropil)-W1-fenil-W3-[3-(2-metoxietoxi)propil)]-p-alaninamid (6). Se obtuvo a partir de /V-fenilacrilamida (2.2 mmol) y 3-(2-metoxietoxi)-1- propanamina (0.75 mmol) con un rendimiento del 30%. Cromatografía: hexano a acetato de etilo. Rf (aceta W 3 - (3-anilino-3-oxopropyl) -W 1 -phenyl-W 3 - [3- (2-methoxyethoxy) propyl)] - p-alaninamid (6). It was obtained from / V-phenylacrylamide (2.2 mmol) and 3- (2-methoxyethoxy) -1-propanamine (0.75 mmol) in 30% yield. Chromatography: hexane to ethyl acetate. R f (aceta
Figure imgf000038_0002
Figure imgf000038_0002
IR (ATR, cm"1) 3305, 1662, 1600, 1545, 1497 cm"1. 1 H RMN (CDCI3) δ 1.59 (qt, J = 5.6 Hz, 2H), 2.50-2.58 (m, 6H), 2.77 (t ap, J = 5.4 Hz, 4H), 3.28 (t, J = 5.5 Hz, 2H), 3.40-3.43 (m, 2H), 3.47 (m, 3H), 3.62-3.65 (m, 2H), 6.98 (t, J = 7.4 Hz, 2H), 7.10 (t, J = 7.7 Hz, 4H), 7.38 (d, J = 7.7 Hz, 4H). 13C RMN (CDCI3) δ 27.1 (CH2), 35.5 (2CH2), 49.3 (CH2), 50.6 (2CH2), 58.9 (CH30), 67.2, 69.4, 72.5 (3CH2), 1 19.8 (4CH), 123.6 (2CH), 128.7 (4CH), 138.4 (2C), 171.9 (2C). HRMS (ESI) caled para C24H33N304Na [(M+Na)+] 450.2369, encontrado 450.2365. W3-(3-anilino-3-oxopropil)-W3-[2-(2-etoxietoxi)etil)-W1-fenil-p-alaninamid (41 ). Se obtuvo a partir de /V-fenilacrilamida (2.2 mmol) y 2-(2-etoxietoxi)etanamina (0.75 mmol) con un rendimiento del 53%. Cromatografía: acetato de etilo a acetato de etilo/metanol, 8:2. Rf (acet IR (ATR, cm "1 ) 3305, 1662, 1600, 1545, 1497 cm " 1 . 1 H NMR (CDCI 3 ) δ 1.59 (qt, J = 5.6 Hz, 2H), 2.50-2.58 (m, 6H), 2.77 (t ap, J = 5.4 Hz, 4H), 3.28 (t, J = 5.5 Hz , 2H), 3.40-3.43 (m, 2H), 3.47 (m, 3H), 3.62-3.65 (m, 2H), 6.98 (t, J = 7.4 Hz, 2H), 7.10 (t, J = 7.7 Hz, 4H), 7.38 (d, J = 7.7 Hz, 4H). 13 C NMR (CDCI 3 ) δ 27.1 (CH 2 ), 35.5 (2CH 2 ), 49.3 (CH 2 ), 50.6 (2CH 2 ), 58.9 (CH 3 0), 67.2, 69.4, 72.5 (3CH 2 ), 1 19.8 (4CH), 123.6 (2CH), 128.7 (4CH), 138.4 (2C), 171.9 (2C). HRMS (ESI) caled for C 24 H 33 N 3 0 4 Na [(M + Na) + ] 450.2369, found 450.2365. W 3 - (3-anilino-3-oxopropyl) -W 3 - [2- (2-ethoxyethoxy) ethyl) -W 1 -phenyl-p-alaninamid (41). It was obtained from / V-phenylacrylamide (2.2 mmol) and 2- (2-ethoxyethoxy) ethanamine (0.75 mmol) in 53% yield. Chromatography: ethyl acetate to ethyl acetate / methanol, 8: 2. R f (acet
Figure imgf000039_0001
Figure imgf000039_0001
IR (ATR, cm"1) 3303, 1660, 1601 , 1547, 1496, 1443 cm"1. 1 H RMN (CDCI3) δ 1.14 (t, J = 7.0 Hz, 3H), 2.53 (t, J = 6.0 Hz, 4H), 2.74 (t, J = 4.9 Hz, 2H), 2.87 (t, J = 6.0 Hz, 4H), 3.44-3.49 (m, 4H), 3.54-3.59 (m, 4H), 6.98 (t, J = 7.4 Hz, 2H), 7.13 (t, J = 7.8 Hz, 4H), 7.43 (d, J = 7.7 Hz, 4H), 9.24 (br s, 2H). 13C RMN (CDCI3) δ 15.0 (CH3), 35.2 (2CH2), 51.4 (2CH2), 54.7, 66.6, 69.3, 69.6, 70.3 (5CH2), 120.0 (4CH), 123.8 (2CH), 128.7 (4CH), 138.3 (2C), 171.0 (2C). HRMS (ESI) caled para C24H33N304Na [(M+Na)+] 450.2369, encontrado 450.2366 [(M+Na)+]. IR (ATR, cm "1 ) 3303, 1660, 1601, 1547, 1496, 1443 cm " 1 . 1 H NMR (CDCI 3 ) δ 1.14 (t, J = 7.0 Hz, 3H), 2.53 (t, J = 6.0 Hz, 4H), 2.74 (t, J = 4.9 Hz, 2H), 2.87 (t, J = 6.0 Hz, 4H), 3.44-3.49 (m, 4H), 3.54-3.59 (m, 4H), 6.98 (t, J = 7.4 Hz, 2H), 7.13 (t, J = 7.8 Hz, 4H), 7.43 ( d, J = 7.7 Hz, 4H), 9.24 (br s, 2H). 13 C NMR (CDCI 3 ) δ 15.0 (CH 3 ), 35.2 (2CH 2 ), 51.4 (2CH 2 ), 54.7, 66.6, 69.3, 69.6, 70.3 (5CH 2 ), 120.0 (4CH), 123.8 (2CH), 128.7 (4CH), 138.3 (2C), 171.0 (2C). HRMS (ESI) caled for C 24 H 33 N 3 0 4 Na [(M + Na) + ] 450.2369, found 450.2366 [(M + Na) + ].
EJEMPLO 8. Síntesis de las amidas (If) y (Ig). Procedimiento general A. EXAMPLE 8. Synthesis of the amides (If) and (Ig). General Procedure A.
A una disolución de 1 equiv del ácido carboxílico correspondiente (XIII) en diclorometano anhidro (4 mL/mmol), se le añaden, bajo atmósfera de argón, 1 equiv de EDC y 1 equiv de HOBt. La mezcla de reacción se agita a temperatura ambiente durante 1 h. A continuación, se adiciona una disolución de 1.5 equiv de la amina correspondiente (XIV) o (XV) en diclorometano anhidro (2 mL/mmol). En el caso de los ácidos carboxílicos que poseen otros hidrógenos ácidos, como por ejemplo N- octil-/V-(1 /-/-pirrol-2-ilcarbonil)^-alanina y Λ/-(1 H-imidazol-2-ilcarbonil)-/\/-octil^- alanina, no se dejan activando con los agentes de condensación durante 1 h, sino que la amina correspondiente se adicionan inmediatamente después de la EDC y el HOBt a la mezcla de reacción. A continuación, la mezcla de reacción se agita a temperatura ambiente durante toda la noche. El crudo de reacción se lava con disoluciones acuosas saturadas de NaHC03 y NaCI, consecutivamente. Los extractos orgánicos se secan sobre Na2S04 y el disolvente se elimina a presión reducida. El residuo se purifica por cromatografía en columna, obteniéndose las diamidas correspondientes (If) y (Ig). V^fenil-A^-S-furoil-A^-octil-p-alaninamida (7). Se obtuvo a partir de A/-3-furoil-/V- octil-p-alanina (0.16 mmol) y anilina (0.24 mmol) con un rendimiento del 61%. Cromatografía: hexano/acetato de etilo, 7:3. Rf (hexano/acetato de etilo, 7:3) 0.14. p.f.68-69 °C.
Figure imgf000040_0001
To a solution of 1 equiv of the corresponding carboxylic acid (XIII) in anhydrous dichloromethane (4 mL / mmol), 1 equiv of EDC and 1 equiv of HOBt are added under argon. The reaction mixture is stirred at room temperature for 1 h. Then, a solution of 1.5 equiv of the corresponding amine (XIV) or (XV) in anhydrous dichloromethane (2 mL / mmol) is added. In the case of carboxylic acids that possess other acidic hydrogens, such as, for example, N-octyl- / V- (1 / - / - pyrrol-2-ylcarbonyl) ^-alanine and Λ / - (1 H-imidazol-2- ilcarbonyl) - / \ / - octyl ^ - alanine, they are not allowed to activate with the condensing agents for 1 h, but the corresponding amine is added immediately after EDC and HOBt to the reaction mixture. Then, the reaction mixture is stirred at room temperature overnight. The reaction crude is washed with saturated aqueous solutions of NaHC0 3 and NaCI, consecutively. The organic extracts are dried over Na 2 S0 4 and the solvent is removed under reduced pressure. The residue is purified by column chromatography, obtaining the corresponding diamides (If) and (Ig). V ^ phenyl-A ^ -S-furoyl-A ^ -octyl-p-alaninamide (7). It was obtained from A / -3-furoyl- / V-octyl-p-alanine (0.16 mmol) and aniline (0.24 mmol) with a yield of 61%. Chromatography: hexane / ethyl acetate, 7: 3. R f (hexane / ethyl acetate, 7: 3) 0.14. mp68-69 ° C.
Figure imgf000040_0001
IR (ATR, cm"1) 3281, 1685, 1605, 1547, 1501, 1441. 1H RMN (CDCI3) δ 0.88 (t, J = 6.7 Hz, 3H), 1.25 (m, 10H), 1.61 (m, 2H), 2.76 (m, 2H), 3.44 (t, J= 7.9 Hz, 2H), 3.82 (t, J = 6.6 Hz, 2H), 6.55 (m, 1H), 7.08 (t, J = 7.4 Hz, 1H), 7.29 (t, J = 8.3 Hz, 2H), 7.41 (t, J = 1.7 Hz, 1H), 7.55 (d, J = 7.8 Hz, 2H), 7.68 (m, 1H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.6, 29.2 (3C), 31.7, 36.5, 43.2, 50.1 (9CH2), 110.1 (CH), 119.8 (2CH), 121.3 (C), 124.1 (CH), 128.9 (2CH), 138.3 (C), 143.1, 143.2 (2CH), 165.6, 169.4 (2C). MS(ESI) 371.2 [(M+H)+]. Análisis caled para C22H30N2O3 C, 71.32; H, 8.16; N, 7.56; Encontrado C, 71.15; H, 7.91; N, 7.61. IR (ATR, cm "1 ) 3281, 1685, 1605, 1547, 1501, 1441. 1 H NMR (CDCI 3 ) δ 0.88 (t, J = 6.7 Hz, 3H), 1.25 (m, 10H), 1.61 (m , 2H), 2.76 (m, 2H), 3.44 (t, J = 7.9 Hz, 2H), 3.82 (t, J = 6.6 Hz, 2H), 6.55 (m, 1H), 7.08 (t, J = 7.4 Hz , 1H), 7.29 (t, J = 8.3 Hz, 2H), 7.41 (t, J = 1.7 Hz, 1H), 7.55 (d, J = 7.8 Hz, 2H), 7.68 (m, 1H). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6, 26.6, 29.2 (3C), 31.7, 36.5, 43.2, 50.1 (9CH 2 ), 110.1 (CH), 119.8 (2CH), 121.3 (C), 124.1 (CH ), 128.9 (2CH), 138.3 (C), 143.1, 143.2 (2CH), 165.6, 169.4 (2C). MS (ESI) 371.2 [(M + H) + ]. Caled analysis for C22H 30 N2O 3 C, 71.32 ; H, 8.16; N, 7.56; Found C, 71.15; H, 7.91; N, 7.61.
^-fenil-A^-octil-A^-íljS-oxazol-S-ilcarboni -p-alaninamida (10). Se obtuvo a partir de A/-octil-/\/-(1,3-oxazol-5-ilcarbonil)- -alanina (0.20 mmol) y anilina (0.30 mmol) con un rendimiento del 94%. Cromatografía: hexano/acetato de etilo, 1:1. Rf (hexano/acetato de etilo, 1:1)
Figure imgf000040_0002
^ -phenyl-A ^ -octyl-A ^ -íl j S-oxazol-S-ilcarboni -p-alaninamide (10). It was obtained from A / -octyl - / \ / - (1,3-oxazol-5-ylcarbonyl) -alanine (0.20 mmol) and aniline (0.30 mmol) with a yield of 94%. Chromatography: hexane / ethyl acetate, 1: 1. R f (hexane / ethyl acetate, 1: 1)
Figure imgf000040_0002
IR (ATR, cm"1) 3312, 1684, 1623, 1546, 1495, 1442. 1H RMN (CDCI3) δ 0.88 (t, J =IR (ATR, cm "1 ) 3312, 1684, 1623, 1546, 1495, 1442. 1 H NMR (CDCI 3 ) δ 0.88 (t, J =
6.7 Hz, 3H), 1.27 (m, 10H), 1.66 (m, 2H), 2.79 (m, 2H), 3.59 (m, 2H), 3.85 (m, 2H),6.7 Hz, 3H), 1.27 (m, 10H), 1.66 (m, 2H), 2.79 (m, 2H), 3.59 (m, 2H), 3.85 (m, 2H),
7.08 (t, J = 7.3 Hz, 1H), 7.28 (t, J = 7.8 Hz, 2H), 7.54-7.56 (m, 3H), 7.91 (m, 1H), 8.52 y 8.94 (s a, 1H combinado, NH). 13C RMN (CDCI3) δ 13.0 (CH3), 21.6, 25.6, 28.1, 28.2, 28.4, 30.7, 34.8, 43.3, 48.7 (9CH2), 118.9 (2CH), 123.2 (CH), 127.9 (2CH), 130.4 (CH), 137.2, 144.2 (2C), 150.7 (CH), 157.6, 168.3 (2C). HRMS (ESI) caled para
Figure imgf000040_0003
[(M+Na)+] 394.2101, encontrado 394.2908. ^-fenil-A^-octil-A^-ÍI H-pirrol^-ilcarboni -p-alaninamida (12). Se obtuvo a partir de A/-octil-A/-(1 H-pirrol-2-ilcarbonil)^-alanina (0.14 mmol) y anilina (0.21 mmol) con un rendimiento del 56%. Cromatografía: hexano/acetato de etilo, 7:3. Rf (hexano/acetato de etilo, 1 : 1 ) 0.40. p.f. 105-107 °C.
Figure imgf000041_0001
7.08 (t, J = 7.3 Hz, 1H), 7.28 (t, J = 7.8 Hz, 2H), 7.54-7.56 (m, 3H), 7.91 (m, 1H), 8.52 and 8.94 (sa, combined 1H, NH ). 13 C NMR (CDCI 3 ) δ 13.0 (CH 3 ), 21.6, 25.6, 28.1, 28.2, 28.4, 30.7, 34.8, 43.3, 48.7 (9CH 2 ), 118.9 (2CH), 123.2 (CH), 127.9 (2CH) , 130.4 (CH), 137.2, 144.2 (2C), 150.7 (CH), 157.6, 168.3 (2C). HRMS (ESI) caled for
Figure imgf000040_0003
[(M + Na) + ] 394.2101, found 394.2908. ^ -phenyl-A ^ -octyl-A ^ -ÍI H-pyrrole ^ -ylcarboni -p-alaninamide (12). It was obtained from A / -octyl-A / - (1 H -pyrrol-2-ylcarbonyl) ^-alanine (0.14 mmol) and aniline (0.21 mmol) in 56% yield. Chromatography: hexane / ethyl acetate, 7: 3. R f (hexane / ethyl acetate, 1: 1) 0.40. mp 105-107 ° C.
Figure imgf000041_0001
IR (ATR, cm"1) 3264, 1666, 1599, 1548, 1483, 1445. 1 H RMN (CDCI3) δ 0.88 (t, J = 6.7 Hz, 3H), 1.28-1.31 (m, 10H), 1.71 (m, 2H), 2.74 (t, J = 6.7 Hz, 2H), 3.58 (m, 2H), 3.87 (m, 2H), 6.25-6.28 (m, 1 H), 6.54 (m, 1 H), 6.90 (m, 1 H), 7.07 (t, J = 7.3 Hz, 1 H), 7.28 (t, J = 7.8 Hz, 2H), 7.55 (d, J = 7.8 Hz, 2H), 8.84 (s a, 1 H), 9.84 (s a, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.8, 28.6, 29.2, 29.4, 31.8, 36.7, 44.3, 49.3 (9CH2), 1 10.3, 1 12.2 (2CH), 119.9 (2CH), 121.3, 124.1 (2CH), 124.4 (C), 128.9 (2CH), 138.3, 162.5, 169.4 (3C). MS (ESI) 370.2 [(M+H)+]. Análisis caled para C22H31 N3O2 C, 71.51 ; H, 8.46; N, 1 1.37, encontrado C, 71.29; H, 8.01 ; N, 11.35. IR (ATR, cm "1 ) 3264, 1666, 1599, 1548, 1483, 1445. 1 H NMR (CDCI 3 ) δ 0.88 (t, J = 6.7 Hz, 3H), 1.28-1.31 (m, 10H), 1.71 (m, 2H), 2.74 (t, J = 6.7 Hz, 2H), 3.58 (m, 2H), 3.87 (m, 2H), 6.25-6.28 (m, 1 H), 6.54 (m, 1 H), 6.90 (m, 1 H), 7.07 (t, J = 7.3 Hz, 1 H), 7.28 (t, J = 7.8 Hz, 2H), 7.55 (d, J = 7.8 Hz, 2H), 8.84 (sa, 1 H), 9.84 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6, 26.8, 28.6, 29.2, 29.4, 31.8, 36.7, 44.3, 49.3 (9CH 2 ), 1 10.3, 1 12.2 (2CH), 119.9 (2CH), 121.3, 124.1 (2CH), 124.4 (C), 128.9 (2CH), 138.3, 162.5, 169.4 (3C). MS (ESI) 370.2 [(M + H) + ] Caled analysis for C22H 3 1 N 3 O2 C, 71.51; H, 8.46; N, 1 1.37, found C, 71.29; H, 8.01; N, 11.35.
^-fenil-A^-ÍI H-imidazol^-ilcarboni -A^-octil-p-alaninamida (16). Se obtuvo a partir de A/-(1 H-imidazol-2-ilcarbonil)-/\/-octil^-alanina (0.21 mmol) y anilina (0.32 mmol) con un rendimiento del 68%. Cromatografía: hexano/acetato de etilo, 7:3. Rf (hexano/acetato de etilo, 7:3) 0.12. p.f. 96-97 °C.
Figure imgf000041_0002
^ -phenyl-A ^ -II H-imidazol ^ -ylcarboni -A ^ -octyl-p-alaninamide (16). It was obtained from A / - (1 H-imidazol-2-ylcarbonyl) - / \ / - octyl ^ -alanine (0.21 mmol) and aniline (0.32 mmol) with a yield of 68%. Chromatography: hexane / ethyl acetate, 7: 3. R f (hexane / ethyl acetate, 7: 3) 0.12. mp 96-97 ° C.
Figure imgf000041_0002
IR (ATR, cm"1) 3201 , 1668, 1604, 1546, 1483, 1443. 1 H RMN (CDCI3) δ (mezcla de rotámeros A:B, 6: 1) 0.81 (t, J = 6.7 Hz, 3H), 1.20-1.26 (m, 10H), 1.60 (m, 2H), 2.71 (m, 2H, rotámero B), 2.82 (t, J = 8.1 Hz, 2H, rotámero A), 3.47 (t, J = 7.5 Hz, 2H, rotámero A), 3.81 (m, 2H, rotámero B), 4.21 (m, 2H, rotámero B), 4.30 (t, J = 8.0 Hz, 2H, rotámero A), 7.03 (t, J = 7.4 Hz, 1 H), 7.16 (m, 1 H), 7.19 (s, 1 H), 7.25-7.30 (m, 2H), 7.45-7.55 (m, 2H), 8.29 (s a, 1 H, rotámero B), 9.98 (s a, 1 H, rotámero A), 10.94 (s a, 1 H, rotámero B), 1 1.52 (s a, 1 H, NH, rotámero A). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 27.1 , 27.8, 29.2, 29.4, 31.8, 39.7, 46.8, 48.3 (9CH2), 1 18.8 (CH), 1 19.6 (2CH), 123.9 (CH), 129.1 (2CH), 129.8 (CH), 138.6, 141.5, 158.3, 169.1 (4C). MS (ESI): 371.2 [(M+H)+]. Análisis caled para C21 H30N4O2 C, 68.08; H, 8.16; N, 15.12; encontrado C, 68.42; H, 8.49; N, 15.18. IR (ATR, cm "1 ) 3201, 1668, 1604, 1546, 1483, 1443. 1 H NMR (CDCI 3 ) δ (mixture of rotamers A: B, 6: 1) 0.81 (t, J = 6.7 Hz, 3H ), 1.20-1.26 (m, 10H), 1.60 (m, 2H), 2.71 (m, 2H, rotamer B), 2.82 (t, J = 8.1 Hz, 2H, rotamer A), 3.47 (t, J = 7.5 Hz, 2H, rotamer A), 3.81 (m, 2H, rotamer B), 4.21 (m, 2H, rotamer B), 4.30 (t, J = 8.0 Hz, 2H, rotamer A), 7.03 (t, J = 7.4 Hz, 1 H), 7.16 (m, 1 H), 7.19 (s, 1 H), 7.25-7.30 (m, 2H), 7.45-7.55 (m, 2H), 8.29 (sa, 1 H, rotamer B) , 9.98 (sa, 1 H, rotamer A), 10.94 (sa, 1 H, rotamer B), 1 1.52 (sa, 1 H, NH, rotamer A). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ) , 22.6, 27.1, 27.8, 29.2, 29.4, 31.8, 39.7, 46.8, 48.3 (9CH 2 ), 1 18.8 (CH), 1 19.6 (2CH), 123.9 (CH), 129.1 (2CH), 129.8 (CH), 138.6, 141.5, 158.3, 169.1 (4C) .MS (ESI): 371.2 [(M + H) + ]. Caled analysis for C21 H 30 N4O2 C, 68.08; H, 8.16; N, 15.12; found C, 68.42; H, 8.49; N, 15.18.
Procedimiento general B. General Procedure B.
A una disolución de 2 equiv del ácido carboxílico correspondiente (XI) en diclorometano anhidro (4 mL/mmol), se le añaden, bajo atmósfera de argón, 2 equiv de EDC ó 2.2 equiv de DCC y 2 equiv de HOBt ó 0.4 equiv de DMAP. La mezcla de reacción se agita a temperatura ambiente durante 1 h. A continuación, se adiciona una disolución de 1 equiv de la amina correspondiente (IV) en diclorometano anhidro (2 mL/mmol). En el caso de los ácidos 1 /-/-pirrol-3-carboxílico, 1 /-/-1 ,2,4- triazol-3-carboxílico y 1 /-/-indol-2-carboxílico, no se dejan activando con los agentes de condensación durante 1 h, sino que la amina se adiciona inmediatamente después de la carbodiimida y el HOBt o la DMAP a la mezcla de reacción. A continuación, se agita la mezcla a temperatura ambiente durante toda la noche. El crudo de reacción se lava con disoluciones acuosas saturadas de NaHC03 y NaCI, consecutivamente. Los extractos orgánicos se secan sobre Na2S04 y el disolvente se elimina a presión reducida. El residuo se purifica por cromatografía en columna, obteniéndose las diamidas correspondientes (If). V^fenil-A^^-furoil-A^-octil-p-alaninamida (8). Se obtuvo a partir de /V1-fenil-/V3- octil^-alaninamida (1.4 mmol) y ácido 2-furoico (2.8 mmol) con un rendimiento del 77%. Cromatografía: hexano a hexano/acetato de etilo, 1 : 1. Rf (hexano/acetato de etilo, 1 : 1) 0.40. p.f. 90-93 °C.
Figure imgf000042_0001
To a solution of 2 equiv of the corresponding carboxylic acid (XI) in anhydrous dichloromethane (4 mL / mmol), are added, under argon, 2 equiv of EDC or 2.2 equiv of DCC and 2 equiv of HOBt or 0.4 equiv of DMAP The reaction mixture is stirred at room temperature for 1 h. Next, a solution of 1 equiv of the corresponding amine (IV) in anhydrous dichloromethane (2 mL / mmol) is added. In the case of 1 / - / - pyrrol-3-carboxylic, 1 / - / - 1, 2,4-triazol-3-carboxylic and 1 / - / - indole-2-carboxylic acids, they are not allowed to activate with condensing agents for 1 h, but the amine is added immediately after carbodiimide and HOBt or DMAP to the reaction mixture. Then, the mixture is stirred at room temperature overnight. The reaction crude is washed with saturated aqueous solutions of NaHC0 3 and NaCI, consecutively. The organic extracts are dried over Na 2 S0 4 and the solvent is removed under reduced pressure. The residue is purified by column chromatography, obtaining the corresponding diamides (If). V ^ phenyl-A ^^ - furoyl-A ^ -octyl-p-alaninamide (8). It was obtained from / V 1 -phenyl- / V 3 -octyl ^ -alaninamide (1.4 mmol) and 2-furoic acid (2.8 mmol) with a yield of 77%. Chromatography: hexane to hexane / ethyl acetate, 1: 1. R f (hexane / ethyl acetate, 1: 1) 0.40. mp 90-93 ° C.
Figure imgf000042_0001
IR (ATR, cm"1) 3315, 1668, 1605. 1 H RMN (CDCI3,) δ 0.87 (t, J = 6.6 Hz, 3H), 1.25 (m, 10H), 1.65 (m, 2H), 2.75 (t, J = 6.3 Hz, 2H), 3.61 (m, 2H), 3.83 (m, 2H), 6.43 (m, 1 H), 6.95 (m, 1 H), 7.06 (t, J = 7.4 Hz, 1 H), 7.27 (t, J = 7.8 Hz, 2H), 7.41 (m, 1 H), 7.49-7.60 (m, 2H), 9.29 (s a, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.8, 29.2, 29.3, 29.7, 31.8, 36.2, 44.3, 49.6 (9CH2), 1 1 1.4, 1 16.5 (2CH), 1 19.9 (2CH), 123.9 (CH), 128.8 (2CH), 138.5 (C), 144.0 (CH), 147.9, 160.5, 169.6 (3C). MS (ESI) 371.2 [M+H]+. Análisis caled para C22H30N2O3 C, 71.35; H, 8.03; N, 7.30; encontrado: C, 71.32; H, 8.16; N, 7.56. IR (ATR, cm "1 ) 3315, 1668, 1605. 1 H NMR (CDCI 3 ,) δ 0.87 (t, J = 6.6 Hz, 3H), 1.25 (m, 10H), 1.65 (m, 2H), 2.75 (t, J = 6.3 Hz, 2H), 3.61 (m, 2H), 3.83 (m, 2H), 6.43 (m, 1 H), 6.95 (m, 1 H), 7.06 (t, J = 7.4 Hz, 1 H), 7.27 (t, J = 7.8 Hz, 2H), 7.41 (m, 1 H), 7.49-7.60 (m, 2H), 9.29 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6, 26.8, 29.2, 29.3, 29.7, 31.8, 36.2, 44.3, 49.6 (9CH 2 ), 1 1 1.4, 1 16.5 (2CH), 1 19.9 (2CH), 123.9 (CH), 128.8 ( 2CH), 138.5 (C), 144.0 (CH), 147.9, 160.5, 169.6 (3C) MS (ESI) 371.2 [M + H] + . Caled analysis for C22H30N2O3 C, 71.35; H, 8.03; N, 7.30; Found: C, 71.32; H, 8.16; N, 7.56.
^-fenil-A^-octil-A^-ítetrahidrofuran-S-ilcarboni -p-alaninamida (9). Se obtuvo a partir de A/1-fenil-A/3-octil^-alaninamida (0.36 mmol) y ácido tetrahidrofuran-3- carboxílico (0.72 mmol) con un rendimiento del 84%. Cromatografía: hexano/acetato de etilo, 7:3. Rf (hexano/acetato de etilo, 7:3) 0.13. p.f. 68-70 °C.
Figure imgf000043_0001
^ -phenyl-A ^ -octyl-A ^ -tetrahydrofuran-S-ilcarboni -p-alaninamide (9). It was obtained from A / 1 -phenyl-A / 3- octyl ^ -alaninamide (0.36 mmol) and tetrahydrofuran-3-carboxylic acid (0.72 mmol) with a yield of 84%. Chromatography: hexane / ethyl acetate, 7: 3. R f (hexane / ethyl acetate, 7: 3) 0.13. mp 68-70 ° C.
Figure imgf000043_0001
IR (ATR, cm"1) 3309, 1684, 1624, 1545, 1494, 1442. 1 H RMN (CDCI3) δ 0.89 (t, J = 6.7 Hz, 3H), 1.28-1.30 (m, 10H), 1.56-1.61 (m, 2H), 2.01-2.23 (m, 2H), 2.69 (t, J = 6.6 Hz, 2H), 3.22 (qt, J = 7.6 Hz, 1 H), 3.34 (t, J = 6.8 Hz, 2H), 3.70 (t, J = 6.6 Hz, 2H), 3.81-4.02 (m, 4H), 7.09 (t, J = 7.4 Hz, 1 H), 7.31 (t, J = 7.9 Hz, 2H), 7.54 (d, J = 7.9 Hz, 2H), 8.47 (s a, 1 H). 13C RMN (CDCI3) δ 14.0 (CH3), 22.6, 26.8, 29.2, 29.3, 29.5, 30.8, 31.7, 36.8 (8CH2), 41.2 (CH), 43.2, 49.0, 68.6, 71.2 (4CH2), 1 19.8 (2CH), 124.1 (CH), 128.9 (2CH), 138.2 (C), 168.4, 174.1 (2C). MS (ESI) 375.2 [(M+H)+]. Análisis caled para C22H34N2O3 C, 70.55; H, 9.15; N, 7.48; encontrado C, 70.83; H, 8.67; N, 7.50.
Figure imgf000043_0002
H-pirrol-S-ilcarboni -p-alaninamida (11 ). Se obtuvo a partir de A/1-fenil-/V3-octil^-alaninamida (1.3 mmol) y ácido 1 /-/-pirrol-3-carboxílico (2.6 mmol) con un rendimiento del 75%. Cromatografía: hexano a hexano/acetato de etilo, 3:7. Rf (acetato de etilo -101 °C.
Figure imgf000043_0003
IR (ATR, cm "1 ) 3309, 1684, 1624, 1545, 1494, 1442. 1 H NMR (CDCI 3 ) δ 0.89 (t, J = 6.7 Hz, 3H), 1.28-1.30 (m, 10H), 1.56 -1.61 (m, 2H), 2.01-2.23 (m, 2H), 2.69 (t, J = 6.6 Hz, 2H), 3.22 (qt, J = 7.6 Hz, 1 H), 3.34 (t, J = 6.8 Hz , 2H), 3.70 (t, J = 6.6 Hz, 2H), 3.81-4.02 (m, 4H), 7.09 (t, J = 7.4 Hz, 1 H), 7.31 (t, J = 7.9 Hz, 2H), 7.54 (d, J = 7.9 Hz, 2H), 8.47 (bs, 1H). 13 C NMR (CDCI 3) δ 14.0 (CH 3), 22.6, 26.8, 29.2, 29.3, 29.5, 30.8, 31.7, 36.8 ( 8CH 2 ), 41.2 (CH), 43.2, 49.0, 68.6, 71.2 (4CH 2 ), 1 19.8 (2CH), 124.1 (CH), 128.9 (2CH), 138.2 (C), 168.4, 174.1 (2C). (ESI) 375.2 [(M + H) + ]. Caled analysis for C22H34N2O3 C, 70.55; H, 9.15; N, 7.48; found C, 70.83; H, 8.67; N, 7.50.
Figure imgf000043_0002
H-pyrrole-S-ylcarboni-p-alaninamide (11). It was obtained from A / 1 -phenyl- / V 3 -octyl ^ -alaninamide (1.3 mmol) and 1 / - / - pyrrol-3-carboxylic acid (2.6 mmol) in 75% yield. Chromatography: hexane to hexane / ethyl acetate, 3: 7. R f (ethyl acetate -101 ° C.
Figure imgf000043_0003
IR (ATR, cm"1) 3250, 1598, 1548. 1 H RMN (CDCI3) δ 0.79 (t, J = 6.7 Hz, 3H), 1.16 (m, 10H), 1.54 (m, 2H), 2.61 (m, 2H), 3.41 (t, J = 7.2 Hz, 2H), 3.74 (t, J = 6.6 Hz, 2H), 6.26 (m, 1 H), 6.56 (m, 1 H), 6.92 (m, 1 H), 6.97 (t, J = 7.4 Hz, 1 H), 7.18 (t, J = 7.8 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 9.37 (s a, 2H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.7, 28.9, 29.2, 29.3, 31.8, 36.6, 43.4, 49.8 (9CH2), 108.6, 1 18.3 (2CH), 1 18.4 (C), 120.0 (2CH), 121.1 , 123.9 (2CH), 128.8 (2CH), 138.5, 168.4, 170.0 (3C). MS (ESI) 370.3 [M+H]+. Análisis caled para C22H31 N3O2 C, 71 .51 ; H, 8.46; N, 1 1.37; encontrado C, 71.40; H, 8.22; N, 1 1.18. IR (ATR, cm "1 ) 3250, 1598, 1548. 1 H NMR (CDCI 3 ) δ 0.79 (t, J = 6.7 Hz, 3H), 1.16 (m, 10H), 1.54 (m, 2H), 2.61 ( m, 2H), 3.41 (t, J = 7.2 Hz, 2H), 3.74 (t, J = 6.6 Hz, 2H), 6.26 (m, 1 H), 6.56 (m, 1 H), 6.92 (m, 1 H), 6.97 (t, J = 7.4 Hz, 1 H), 7.18 (t, J = 7.8 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 9.37 (sa, 2H). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6, 26.7, 28.9, 29.2, 29.3, 31.8, 36.6, 43.4, 49.8 (9CH 2 ), 108.6, 1 18.3 (2CH), 1 18.4 (C), 120.0 (2CH), 121.1, 123.9 (2CH), 128.8 (2CH), 138.5, 168.4, 170.0 (3C). MS (ESI) 370.3 [M + H] + . Caled analysis for C22H 3 1 N 3 O2 C, 71.51; H, 8.46; N, 1 1.37; found C, 71.40; H, 8.22; N, 1 1.18.
^-fenil-A^-Iil-metil-I H-pirrol^-i carbonill-A^-octil-p-alaninamida (13). Se obtuvo a partir de A/1-fenil-A/3-octil^-alaninamida (0.59 mmol) y ácido 1-metil-1 - -pirrol-3- carboxílico (1.2 mmol) con un rendimiento del 49%. Cromatografía: hexano/acetato de etilo, 7:3. Rf (hexano/acetato de etilo, 7:3) 0.44.
Figure imgf000044_0001
^ -phenyl-A ^ -Iyl-methyl-I H-pyrrole ^ -i carbonill-A ^ -octyl-p-alaninamide (13). It was obtained from A / 1 -phenyl-A / 3- octyl ^ -alaninamide (0.59 mmol) and 1-methyl-1 - -pyrrole-3-carboxylic acid (1.2 mmol) with a yield of 49%. Chromatography: hexane / ethyl acetate, 7: 3. R f (hexane / ethyl acetate, 7: 3) 0.44.
Figure imgf000044_0001
IR (ATR, cm"1) 3277, 1684, 1602, 1543, 1473, 1439. 1 H RMN (CDCI3) δ 0.87 (t, J = 6.7 Hz, 3H), 1.23-1.30 (m, 10H), 1.58-1 .65 (m, 2H), 2.73 (t, J = 6.8 Hz, 2H), 3.54 (t, J = 7.6 Hz, 2H), 3.67 (s, 3H), 3.80 (t, J = 6.8 Hz, 2H), 6.06 (dd, J = 3.7, 2.7 Hz, 1 H), 6.30 (dd, J = 3.7, 1.4 Hz, 1 H), 6.66 (t, J = 2.9 Hz, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 7.28 (t, J = 7.8 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 9.1 1 (s a, 1 H). 13C RMN (CDCI3) δ 14.5 (CH3), 23.0, 26.9, 29.2, 29.6 (2C), 32.1 (6CH2), 35.9 (CH3), 36.8, 43.5, 50.6 (3CH2), 107.5, 1 12.5 (2CH), 120.2 (2CH), 124.4 (CH), 125.7 (C), 126.6 (CH), 129.2 (2CH), 138.8, 165.6, 170.1 (3C). HRMS (ESI) caled para C23H34N3O2 [(M+H)+] 384.2646; encontrado 384.2655. V^fenil-A^-octil-A^-ítien-S-ilcarboni -p-alaninamida (14). Se obtuvo a partir de Λ/1- fenil-/V3-octil^-alaninamida (1.4 mmol) y ácido tiofen-3-carboxílico (2.8 mmol) con un rendimiento del 68%. Cromatografía: hexano a hexano/acetato de etilo, 7:3. Rf (hexano/acetato de etilo, 7:3)
Figure imgf000044_0002
IR (ATR, cm "1 ) 3277, 1684, 1602, 1543, 1473, 1439. 1 H NMR (CDCI 3 ) δ 0.87 (t, J = 6.7 Hz, 3H), 1.23-1.30 (m, 10H), 1.58 -1 .65 (m, 2H), 2.73 (t, J = 6.8 Hz, 2H), 3.54 (t, J = 7.6 Hz, 2H), 3.67 (s, 3H), 3.80 (t, J = 6.8 Hz, 2H), 6.06 (dd, J = 3.7, 2.7 Hz, 1 H), 6.30 (dd, J = 3.7, 1.4 Hz, 1 H), 6.66 (t, J = 2.9 Hz, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 7.28 (t, J = 7.8 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 9.1 1 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.5 (CH 3 ), 23.0, 26.9, 29.2, 29.6 (2C), 32.1 (6CH 2 ), 35.9 (CH 3 ), 36.8, 43.5, 50.6 (3CH 2 ), 107.5, 1 12.5 (2CH), 120.2 (2CH ), 124.4 (CH), 125.7 (C), 126.6 (CH), 129.2 (2CH), 138.8, 165.6, 170.1 (3C). HRMS (ESI) caled for C23H34N3O2 [(M + H) + ] 384.2646; found 384.2655 V ^ phenyl-A ^ -octyl-A ^ -itien-S-ylcarboni -p-alaninamide (14) was obtained from Λ / 1 -phenyl- / V 3 -octyl ^ -alaninamide (1.4 mmol) and Thiophene-3-carboxylic acid (2.8 mmol) with a yield of 68% Chromatography: hexane to hexane / ethyl acetate, 7: 3. R f (hexane / acetat or ethyl, 7: 3)
Figure imgf000044_0002
IR (ATR, cm"1) 331 1 , 1685, 1605, 1546, 1440. 1 H RMN (CDCI3) δ 0.87 (t, J = 6.8 Hz, 3H), 1.21-1.30 (m, 10H), 1.58 (m, 2H), 2.77 (m, 2H), 3.37 (t, J = 7.5 Hz, 2H), 3.82 (t, J = 6.6 Hz, 2H), 7.08 (t, J = 7.4 Hz, 1 H), 7.14 (d, J = 4.1 Hz, 1 H), 7.29-7.34 (m, 3H), 7.45 (d, J = 1.8 Hz, 1 H), 7.54 (d, J = 7.7 Hz, 2H), 8.82 (s a, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.6, 28.8 (2C), 29.1 , 31.7, 36.4, 42.8, 50.5 (9CH2), 1 19.8 (2CH), 124.0, 125.6, 126.2, 126.7 (4CH), 128.9 (2CH), 136.7, 138.4, 168.1 , 169.6 (4C). HRMS caled para C22H3oN2Na02S 409.1920 [(M+Na)+]; encontrado: 409.1923. ^-fenil-A^-octil-A^-ÍI H-l^^-triazol-S-ilcarboni -p-alaninamida (15). Se obtuvo a partir de A/1-fenil-A/3-octil^-alaninamida (1.4 mmol) y ácido 1 /-/-1 ,2,4-triazol-3- carboxílico (2.8 mmol) con un rendimiento del 48%. Cromatografía: acetato de etilo. Rf (acetato de etilo) 0.25. p.f. 1 10-1 1 1 °C.
Figure imgf000045_0001
IR (ATR, cm "1 ) 331 1, 1685, 1605, 1546, 1440. 1 H NMR (CDCI 3 ) δ 0.87 (t, J = 6.8 Hz, 3H), 1.21-1.30 (m, 10H), 1.58 ( m, 2H), 2.77 (m, 2H), 3.37 (t, J = 7.5 Hz, 2H), 3.82 (t, J = 6.6 Hz, 2H), 7.08 (t, J = 7.4 Hz, 1 H), 7.14 (d, J = 4.1 Hz, 1 H), 7.29-7.34 (m, 3H), 7.45 (d, J = 1.8 Hz, 1 H), 7.54 (d, J = 7.7 Hz, 2H), 8.82 (sa, 1H). 13 C NMR (CDCI 3) δ 14.1 (CH 3 ), 22.6, 26.6, 28.8 (2C), 29.1, 31.7, 36.4, 42.8, 50.5 (9CH 2 ), 1 19.8 (2CH), 124.0, 125.6, 126.2, 126.7 (4CH), 128.9 (2CH) , 136.7, 138.4, 168.1, 169.6 (4C). HRMS caled for C 2 2H 3 oN 2 Na0 2 S 409.1920 [(M + Na) + ]; Found: 409.1923. ^ -phenyl-A ^ -octyl-A ^ -ÍI Hl ^^ - triazol-S-ilcarboni -p-alaninamide (15). It was obtained from A / 1 -phenyl-A / 3- octyl ^ -alaninamide (1.4 mmol) and 1 / - / - 1, 2,4-triazol-3- carboxylic acid (2.8 mmol) in a yield of 48 %. Chromatography: ethyl acetate. R f (ethyl acetate) 0.25. mp 1 10-1 1 1 ° C.
Figure imgf000045_0001
IR (ATR, cm"1) 3281 , 1623, 1547. 1 H RMN (CDCI3) δ (Mezcla de rotámeros A:B, 3:2) 0.84-0.89 (m, 3H), 1.25-1.29 (m, 10H), 1.61-1.78 (m, 2H), 2.81-2.87 (m, 2H), 3.55 (t, J = 7.6 Hz, 2H, rotámero B), 3.92 (t, J = 7.3 Hz, 2H, rotámero A), 4.08-4.15 (m, 2H, rotámero A), 4.27 (t, J = 7.7 Hz, 2H, rotámero B), 7.05-7.12 (m, 1 H), 7.31 (t, J = 8.1 Hz, 2H), 7.54-7.58 (m, 2H), 8.13 (s, 1 H, rotámero A), 8.22 (m, 1 H, rotámero B), 8.96 (s a, 1 H), 13.94 (s a, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.6, 27.0, 27.6, 29.2 (2C), 29.3, 31.8, 35.7, 38.9, 45.6, 46.1 , 48.1 , 50.2 (9CH2, rotámeros A y B), 1 19.7, 120.0 (2CH, rotámeros A y B), 124.3 (CH), 128.9, 129.0 (2CH, rotámeros A y B), 138.1 , 138.2 (C, rotámeros A y B), 150.8 (CH), 158.8 (C), 168.7, 169.0 (C, rotámeros A y B), 171.2 (C). MS (ESI) 372.2 [(M+H)+]. Análisis caled para C20H29N5O2 C, 64.66; H, 7.87; N, 18.85; encontrado C, 64.49; H, 7.66; N, 18.39. IR (ATR, cm "1 ) 3281, 1623, 1547. 1 H NMR (CDCI 3 ) δ (Mix of rotamers A: B, 3: 2) 0.84-0.89 (m, 3H), 1.25-1.29 (m, 10H ), 1.61-1.78 (m, 2H), 2.81-2.87 (m, 2H), 3.55 (t, J = 7.6 Hz, 2H, rotamer B), 3.92 (t, J = 7.3 Hz, 2H, rotamer A), 4.08-4.15 (m, 2H, rotamer A), 4.27 (t, J = 7.7 Hz, 2H, rotamer B), 7.05-7.12 (m, 1 H), 7.31 (t, J = 8.1 Hz, 2H), 7.54 -7.58 (m, 2H), 8.13 (s, 1 H, rotamer A), 8.22 (m, 1 H, rotamer B), 8.96 (sa, 1 H), 13.94 (sa, 1 H). 13 C NMR ( CDCI 3 ) δ 14.1 (CH 3 ), 22.6, 26.6, 27.0, 27.6, 29.2 (2C), 29.3, 31.8, 35.7, 38.9, 45.6, 46.1, 48.1, 50.2 (9CH 2 , rotamers A and B), 1 19.7 , 120.0 (2CH, rotamers A and B), 124.3 (CH), 128.9, 129.0 (2CH, rotamers A and B), 138.1, 138.2 (C, rotamers A and B), 150.8 (CH), 158.8 (C), 168.7, 169.0 (C, rotamers A and B), 171.2 (C). MS (ESI) 372.2 [(M + H) + ]. Caled analysis for C20H29N5O2 C, 64.66; H, 7.87; N, 18.85; found C, 64.49; H, 7.66; N, 18.39.
^-fenil-A^-octil-A^-Ípirrolidin^-ilcarboni -p-alaninamida (17). A partir de A/1-fenil- A/3-octil^-alaninamida (0.26 mmol) y /V-Boc-prolina (0.51 mmol) se obtuvo A/1-fenil- Λ/3-octil-Λ/3-{[(1-(tøΓC-butoxicarbonil)]-pirrolidin-2-ilcarbonil}-β-alaninamida con un rendimiento del 64%. Cromatografía: hexano/acetato de etilo, 1 : 1. Rf (hexano/acetato de etilo, 1 : 1) 0.27. IR (ATR, cm"1) 3312, 1685, 1667, 1604, 1546, 1441. 1 H RMN (CDCI3) δ (mezcla de rotámeros A:B, 2: 1) 0.80-0.88 (m, 3H), 1.17- 1.28 (m, 10H), 1.44-1.67 (m, 11 H), 1.74-1.95 (m, 2H), 2.06-2.19 (m, 2H), 2.31-2.51 (m, 2H), 2.60-2.79 (m, 2H, rotámero A), 3.00-3.32 (m, 2H), 3.52-3.65 (m, 2H), 3.67- 3.87 (m, 2H, rotámero B), 4.41 -4.57 (m, 1 H), 7.01 (t, J = 7.3 Hz, 1 H), 7.26 (d, J = 7.9 Hz, 2H), 7.52-7.57 (m, 1 H), 7.74 (d, J = 7.7 Hz, 1 H), 9.13 (s a, 1 H, rotámero A), 9.34 (s a, 1 H, rotámero B). 13C RMN (CDCI3) δ 14.0 (CH3), 22.6 (2C), 24.4, 24.7, 26.7, 27.7 (4CH2, rotámeros A y B), 28.5, 28.6 (3CH3, rotámeros A y B), 29.1 , 29.3, 30.0, 30.1 , 30.2, 31.7 (2C) (4CH2, rotámeros A y B), 37.1 , 37.9 (CH2, rotámeros A y B), 44.9, 46.0, 47.2, 47.3, 47.9, 50.0 (3CH2, rotámeros A y B), 56.1 , 56.5 (CH, rotámeros A y B), 80.0, 80.1 (C, rotámeros A y B), 120.1 , 120.2 (2CH, rotámeros A y B), 123.8, 124.0 (CH, rotámeros A y B), 128.7 (2CH), 138.5, 139.0 (C, rotámeros A y B), 154.7, 154.9 (C, rotámeros A y B), 169.6, 171.2, 172.5, 173.1 (2C, rotámeros A y B). MS (ESI) 474.3 [(M+H)+]. A una disolución de A/1-fenil-/\/3-octil-/\/3-{[(1-(ferc-butoxicarbonil)]-pirrolidin-2- ilcarbonil}^-alaninamida (63 mg, 0.13 mmol) en diclorometano (0.5 mL), se le añadió bajo atmósfera de argón ácido trifluoroacético (0.2 mL, 2.7 mmol). La mezcla de reacción se agitó a temperatura ambiente durante una hora. A continuación, el crudo de reacción se basificó con una disolución acuosa saturada de NaHC02 hasta pH 8 y se extrajo con diclorometano. Los extractos orgánicos se lavaron con una disolución acuosa saturada de NaCI, se secaron sobre Na2S04 y el disolvente se eliminó a presión reducida, obteniéndose la amina libre con un rendimiento del 70%. Rf (acetato de etilo) 0.19.
Figure imgf000046_0001
^ -phenyl-A ^ -octyl-A ^ -IPyrrolidin ^ -ylcarboni -p-alaninamide (17). From A / 1 -phenyl- A / 3 -octyl ^ -alaninamide (0.26 mmol) and / V-Boc-proline (0.51 mmol) A / 1 -phenyl- Λ / 3 -octyl-Λ / 3 - was obtained {[(1- (tøΓC-butoxycarbonyl)] - pyrrolidin-2-ylcarbonyl} -β-alaninamide with a yield of 64%. Chromatography: hexane / ethyl acetate, 1: 1. R f (hexane / ethyl acetate, 1: 1) 0.27. IR (ATR, cm "1 ) 3312, 1685, 1667, 1604, 1546, 1441. 1 H NMR (CDCI 3 ) δ (mixture of rotamers A: B, 2: 1) 0.80-0.88 ( m, 3H), 1.17-1 1.28 (m, 10H), 1.44-1.67 (m, 11 H), 1.74-1.95 (m, 2H), 2.06-2.19 (m, 2H), 2.31-2.51 (m, 2H) , 2.60-2.79 (m, 2H, rotamer A), 3.00-3.32 (m, 2H), 3.52-3.65 (m, 2H), 3.67-3.87 (m, 2H, rotamer B), 4.41 -4.57 (m, 1 H), 7.01 (t, J = 7.3 Hz, 1 H), 7.26 (d, J = 7.9 Hz, 2H), 7.52-7.57 (m, 1 H), 7.74 (d, J = 7.7 Hz, 1 H) , 9.13 (sa, 1 H, rotamer A), 9.34 (sa, 1 H, rotamer B). 13 C NMR (CDCI 3 ) δ 14.0 (CH 3 ), 22.6 (2C), 24.4, 24.7, 26.7, 27.7 (4CH 2 , rotamers A and B), 28.5, 28.6 (3CH 3 , rotamers A and B), 29.1 , 29.3, 30.0, 30.1, 30.2, 31.7 (2C) (4CH 2 , rotamers A and B), 37.1, 37.9 (CH 2 , rotamers A and B), 44.9, 46.0, 47.2, 47.3, 47.9, 50.0 (3CH 2 , rotamers A and B), 56.1, 56.5 (CH, rotamers A and B), 80.0, 80.1 (C, rotamers A and B), 120.1, 120.2 (2CH, rotamers A and B), 123.8, 124.0 (CH, rotamers A and B), 128.7 (2CH), 138.5, 139.0 (C, rotamers A and B), 154.7, 154.9 (C, rotamers A and B), 169.6, 171.2, 172.5, 173.1 (2C, rotamers A and B). MS (ESI) 474.3 [(M + H) + ]. To a solution of A / 1 -phenyl - / \ / 3 -octyl - / \ / 3 - {[(1- (ferc-butoxycarbonyl)] -pyrrolidin-2-ylcarbonyl} ^-alaninamide (63 mg, 0.13 mmol) in dichloromethane (0.5 mL), trifluoroacetic acid (0.2 mL, 2.7 mmol) was added under an argon atmosphere.The reaction mixture was stirred at room temperature for one hour, then the reaction crude was basified with an aqueous solution saturated with NaHC0 2 to pH 8 and extracted with dichloromethane The organic extracts were washed with a saturated aqueous solution of NaCl, dried over Na 2 S0 4 and the solvent was removed under reduced pressure, obtaining the free amine with a yield of 70% R f (ethyl acetate) 0.19.
Figure imgf000046_0001
IR (ATR, cm"1) 3269, 1644, 1605, 1548, 1494, 1444. 1 H RMN (CDCI3) δ (mezcla de rotámeros A:B, 2: 1) 0.83-0.88 (m, 3H), 1.21-1.24 (m, 10H), 1.45-2.30 (m, 6H), 2.56- 3.05 (m, 4H), 3.15-3.34 (m, 2H), 3.55-3.76 (m, 2H), 3.91 (t, J = 7.5 Hz, 1 H, rotámero A), 4.37 (t, J = 7.5 Hz, 1 H, rotámero B), 5.10 (s a, 1 H), 7.05 (t, J = 7.3 Hz, 1 H), 7.23- 7.30 (m, 2H), 7.56 (d, J = 7.7 Hz, 2H, rotámero A), 7.61 (d, J = 7.7 Hz, 2H, rotámero B), 8.97 (s a, 1 H, rotámero A), 9.58 (s a, 1 H, rotámero B). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 25.8, 26.3, 26.8, 27.6, 29.1 , 29.2 (2C), 29.3 (2C), 29.7, 30.6, 31.1 , 31.7, 36.3, 37.2, 43.2, 44.0, 46.8, 46.9, 47.4, 48.3 (12CH2, rotámeros A y B), 57.8, 58.2 (CH, rotámeros A y B), 119.9 (2CH), 124.1 (CH), 128.8, 128.9 (2CH), 138.4 (C), 168.7, 169.5, 171.4, 173.9 (2C, rotámeros A y B). HRMS (ESI) caled para C22H36N302 [(M+H)+] 374.2796; encontrado: 374.2802. ^-fenil-A^-octil-A^-Ípiridin^-ilcarboni -p-alaninamida (18). Se obtuvo a partir de Ay1-fenil-Ay3-octil^-alaninamida (0.54 mmol) y ácido 2-piridincarboxílico (1.1 mmol) con un rendimiento del 92%. Cromatografía: hexano a hexano/acetato de etilo, 2:8. Rf (hexano/acetato de etilo, 3:7) 0.30.
Figure imgf000047_0001
IR (ATR, cm "1 ) 3269, 1644, 1605, 1548, 1494, 1444. 1 H NMR (CDCI 3 ) δ (mixture of rotamers A: B, 2: 1) 0.83-0.88 (m, 3H), 1.21 -1.24 (m, 10H), 1.45-2.30 (m, 6H), 2.56-3.05 (m, 4H), 3.15-3.34 (m, 2H), 3.55-3.76 (m, 2H), 3.91 (t, J = 7.5 Hz, 1 H, rotamer A), 4.37 (t, J = 7.5 Hz, 1 H, rotamer B), 5.10 (sa, 1 H), 7.05 (t, J = 7.3 Hz, 1 H), 7.23-7.30 (m, 2H), 7.56 (d, J = 7.7 Hz, 2H, rotamer A), 7.61 (d, J = 7.7 Hz, 2H, rotamer B), 8.97 (sa, 1 H, rotamer A), 9.58 (sa , 1 H, rotamer B). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6, 25.8, 26.3, 26.8, 27.6, 29.1, 29.2 (2C), 29.3 (2C), 29.7, 30.6, 31.1, 31.7, 36.3, 37.2, 43.2, 44.0, 46.8, 46.9, 47.4, 48.3 (12CH 2 , rotamers A and B), 57.8, 58.2 (CH, rotamers A and B), 119.9 (2CH), 124.1 (CH), 128.8 , 128.9 (2CH), 138.4 (C), 168.7, 169.5, 171.4, 173.9 (2C, rotamers A and B) HRMS (ESI) caled for C 22 H 3 6N 3 0 2 [(M + H) + ] 374.2796 ; found: 374.2802. ^ -phenyl-A ^ -octyl-A ^ -IPyridin ^ -ylcarboni -p-alaninamide (18). It was obtained from Ay 1 -phenyl-Ay 3 -octyl ^ -alaninamide (0.54 mmol) and 2-pyridinecarboxylic acid (1.1 mmol) in 92% yield. Chromatography: hexane to hexane / ethyl acetate, 2: 8. R f (hexane / ethyl acetate, 3: 7) 0.30.
Figure imgf000047_0001
IR (ATR, cm"1) 3309, 1685, 1615, 1547, 1495, 1443. 1 H RMN (CDCI3) δ (mezcla de rotámeros A: B, 2: 1 ) 0.85 (t, J = 6.7 Hz, 3H), 1 .1 1 -1 .25 (m, 10H), 1 .57 (m, 2H), 2.81 (t, J = 6.4 Hz, 2H), 3.37 (t, J = 7.4 Hz, 2H , rotámero A), 3.46-3.47 (m, 2H , rotámero B), 3.69-3.75 (m, 2H , rotámero B), 3.87 (t, J = 6.3 Hz, 2H, rotámero A), 7.05 (t, J = 7.1 Hz, 1 H), 7.24-7.32 (m, 3H), 7.54-7.56 (m, 3H), 7.71 -7.76 (m, 1 H), 8.55 (d, J = 4.4 Hz, 1 H), 8.64 (s a, 1 H, rotámero B), 8.92 (s a, 1 H, rotámero A). 13C RMN (CDCI3) δ 14.0 (CH3), 22.6, 26.5, 28.8, 29.0 (2C), 31 .7, 36.5, 43.2, 50.0 (9CH2), 1 19.9 (2CH), 123.1 , 123.9, 124.4 (3CH), 128.8 (2CH), 137.0 (CH), 138.4 (C), 148.5 (CH), 154.5, 169.5, 169.7 (3C). HRMS (ESI) caled para C23H3i N302Na [(M+Na)+] 404.2308; encontrado 404.2276. IR (ATR, cm "1 ) 3309, 1685, 1615, 1547, 1495, 1443. 1 H NMR (CDCI 3 ) δ (mixture of rotamers A: B, 2: 1) 0.85 (t, J = 6.7 Hz, 3H ), 1 .1 1 -1 .25 (m, 10H), 1 .57 (m, 2H), 2.81 (t, J = 6.4 Hz, 2H), 3.37 (t, J = 7.4 Hz, 2H, rotamer A ), 3.46-3.47 (m, 2H, rotamer B), 3.69-3.75 (m, 2H, rotamer B), 3.87 (t, J = 6.3 Hz, 2H, rotamer A), 7.05 (t, J = 7.1 Hz, 1 H), 7.24-7.32 (m, 3H), 7.54-7.56 (m, 3H), 7.71 -7.76 (m, 1 H), 8.55 (d, J = 4.4 Hz, 1 H), 8.64 (sa, 1 H, rotamer B), 8.92 (sa, 1 H, rotamer A) 13 C NMR (CDCI 3 ) δ 14.0 (CH 3 ), 22.6, 26.5, 28.8, 29.0 (2C), 31 .7, 36.5, 43.2, 50.0 (9CH 2 ), 1 19.9 (2CH), 123.1, 123.9, 124.4 (3CH), 128.8 (2CH), 137.0 (CH), 138.4 (C), 148.5 (CH), 154.5, 169.5, 169.7 (3C). HRMS (ESI) caled for C2 3 H 3 i N 3 0 2 Na [(M + Na) + ] 404.2308; found 404.2276.
^-fenil-A^-octil-A^-Ípiridin-S-ilcarboni -p-alaninamida (19). Se obtuvo a partir de Ay1-fenil-Ay3-octil^-alaninamida (0.36 mmol) y ácido 3-piridincarboxílico (0.72 mmol) con un rendimiento del 36%. Cromatografía: hexano/acetato de etilo, 2:8. Rf (acetato de etilo) 0.28.
Figure imgf000047_0002
^ -phenyl-A ^ -octyl-A ^ -IPyridin-S-ilcarboni -p-alaninamide (19). It was obtained from Ay 1 -phenyl-Ay 3 -octyl ^ -alaninamide (0.36 mmol) and 3-pyridinecarboxylic acid (0.72 mmol) with a yield of 36%. Chromatography: hexane / ethyl acetate, 2: 8. R f (ethyl acetate) 0.28.
Figure imgf000047_0002
IR (ATR, cm"1) 3312, 1685, 1612, 1546, 1495, 1440. 1 H RMN (CDCI3) δ (mezcla de rotámeros A: B, 6: 1 ) 0.87 (t, J = 6.8 Hz, 3H), 1 .13-1 .18 (m, 10H), 1 .53 (m, 2H), 2.50 (m, 2H , rotámero B), 2.79 (t, J = 5.7 Hz, 2H, rotámero A), 3.28 (t, J = 7.0 Hz, 2H, rotámero A), 3.49 (m, 2H , rotámero B), 3.64 (m, 2H, rotámero B), 3.86 (m, 2H, rotámero A), 7.07 (t, J = 7.3 Hz, 1 H), 7.24-7.32 (m, 3H), 7.53 (d, J = 7.6 Hz, 2H), 7.67 (d, J = 7.7 Hz, 1 H), 8.64 (d, J = 1 .4 Hz, 2H), 9.27 (s a, 1 H). 13C RMN (CDCI3) δ 14.0 (CH3), 22.5, 26.4, 28.9, 29.0 (2C), 31 .6, 35.8, 42.7, 50.7 (9CH2), 1 19.9 (2CH), 123.4, 124.1 (2CH), 128.8 (2CH), 132.4 (C), 134.2 (CH), 138.3 (C), 147.3, 150.6 (2CH), 169.5, 169.8 (2C). HRMS (ESI) caled para C23H3iN302Na [(M+Na)+] 404.2309, encontrado: 404.2302. IR (ATR, cm "1 ) 3312, 1685, 1612, 1546, 1495, 1440. 1 H NMR (CDCI 3 ) δ (mixture of rotamers A: B, 6: 1) 0.87 (t, J = 6.8 Hz, 3H ), 1 .13-1 .18 (m, 10H), 1 .53 (m, 2H), 2.50 (m, 2H, rotamer B), 2.79 (t, J = 5.7 Hz, 2H, rotamer A), 3.28 (t, J = 7.0 Hz, 2H, rotamer A), 3.49 (m, 2H, rotamer B), 3.64 (m, 2H, rotamer B), 3.86 (m, 2H, rotamer A), 7.07 (t, J = 7.3 Hz, 1 H), 7.24-7.32 (m, 3H), 7.53 (d, J = 7.6 Hz, 2H), 7.67 (d, J = 7.7 Hz, 1 H), 8.64 (d, J = 1 .4 Hz, 2H), 9.27 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.0 (CH 3 ), 22.5, 26.4, 28.9, 29.0 (2C), 31 .6, 35.8, 42.7, 50.7 (9CH 2 ), 1 19.9 (2CH), 123.4, 124.1 (2CH), 128.8 (2CH), 132.4 (C), 134.2 (CH), 138.3 (C), 147.3, 150.6 (2CH), 169.5, 169.8 (2C). HRMS (ESI) caled for C2 3 H 3 iN 3 0 2 Na [(M + Na) + ] 404.2309, found: 404.2302.
^-fenil-A^-octil-A^-ipiridin^-ilcarboni -p-alaninamida (20). Se obtuvo a partir de Ay1-fenil-Ay3-octil^-alaninamida (1.4 mmol) y ácido 4-piridincarboxílico (2.8 mmol) con un rendimiento del 84%. Cromatografía: hexano a hexano/acetato de etilo, 2:8. Rf (acetato de etilo) 0.19.
Figure imgf000048_0001
^ -phenyl-A ^ -octyl-A ^ -ipyridin ^ -ylcarboni -p-alaninamide (20). It was obtained from Ay 1 -phenyl-Ay 3 -octyl ^ -alaninamide (1.4 mmol) and 4-pyridinecarboxylic acid (2.8 mmol) in a yield of 84%. Chromatography: hexane to hexane / ethyl acetate, 2: 8. R f (ethyl acetate) 0.19.
Figure imgf000048_0001
IR (ATR, cm"1) 3310, 1624, 1547. 1 H RMN (CDCI3) δ (mezcla de isómeros A:B, 4: 1) 0.76 (t, J = 6.9 Hz, 3H), 1.02-1.07 (m, 10H), 1.41 (qt, J = 6.9 Hz, 2H), 2.40 (m, 2H, rotámero B), 2.70 (t, J = 6.5 Hz, 2H, rotámero A), 3.12 (t, J = 7.6 Hz, 2H, rotámero A), 3.41 (m, 2H, rotámero B), 3.50 (m, 2H, rotámero B), 3.74 (t, J = 6.5 Hz, 2H, rotámero A), 7.00 (t, J = 7.3 Hz, 1 H), 7.1 1 (d, J = 5.8 Hz, 2H), 7.16-7.21 (m, 2H), 7.41 (d, J = 7.9 Hz, 2H), 8.55 (d, J = 5.7 Hz, 2H), 8.78 (s a, 1 H). 13C RMN (CDCI3) δ 14.0 (CH3), 22.5, 26.4, 28.8, 29.0 (2C), 31.6, 35.9, 42.4, 50.4 (9CH2), 1 19.8 (2CH), 120.8 (2CH), 124.2 (CH), 128.9 (2CH), 138.2, 144.1 (2C), 150.3 (2CH), 169.2, 169.9 (C, rotámeros A y B), 171.1 (C). HRMS caled para C23H31 N3Na02 404.2308 [(M+Na)+], encontrado 404.2311. IR (ATR, cm "1 ) 3310, 1624, 1547. 1 H NMR (CDCI 3 ) δ (mixture of isomers A: B, 4: 1) 0.76 (t, J = 6.9 Hz, 3H), 1.02-1.07 ( m, 10H), 1.41 (qt, J = 6.9 Hz, 2H), 2.40 (m, 2H, rotamer B), 2.70 (t, J = 6.5 Hz, 2H, rotamer A), 3.12 (t, J = 7.6 Hz , 2H, rotamer A), 3.41 (m, 2H, rotamer B), 3.50 (m, 2H, rotamer B), 3.74 (t, J = 6.5 Hz, 2H, rotamer A), 7.00 (t, J = 7.3 Hz , 1 H), 7.1 1 (d, J = 5.8 Hz, 2H), 7.16-7.21 (m, 2H), 7.41 (d, J = 7.9 Hz, 2H), 8.55 (d, J = 5.7 Hz, 2H) , 8.78 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.0 (CH 3 ), 22.5, 26.4, 28.8, 29.0 (2C), 31.6, 35.9, 42.4, 50.4 (9CH 2 ), 1 19.8 (2CH ), 120.8 (2CH), 124.2 (CH), 128.9 (2CH), 138.2, 144.1 (2C), 150.3 (2CH), 169.2, 169.9 (C, rotamers A and B), 171.1 (C). HRMS caled for C 23 H 31 N 3 Na0 2 404.2308 [(M + Na) + ], found 404.2311.
^-fenil-A^-ÍI H-indol^-ilcarboni -A^-octil-p-alaninamida (21 ). Se obtuvo a partir de Ay1-fenil-Ay3-octil^-alaninamida (1.4 mmol) y ácido 1 /-/-indol-2-carboxílico (2.8 mmol) con un rendimiento del 50%. Cromatografía: hexano a hexano/acetato de etilo, 7:3. Rf (hexano/acetato de etilo, 1 : 1) 0.47. p.f. 142-144 °C. ^ -phenyl-A ^ -ÍI H-indole ^ -ylcarboni -A ^ -octyl-p-alaninamide (21). It was obtained from Ay 1 -phenyl-Ay 3 -octyl ^ -alaninamide (1.4 mmol) and 1 / - / - indole-2-carboxylic acid (2.8 mmol) in 50% yield. Chromatography: hexane to hexane / ethyl acetate, 7: 3. R f (hexane / ethyl acetate, 1: 1) 0.47. mp 142-144 ° C.
Figure imgf000048_0002
Figure imgf000048_0002
IR (ATR, cm"1) 3284, 1666, 1600, 1533, 1442. 1 H RMN (CDCI3) δ 0.79 (t, J = 6.6 Hz, 3H), 1.16 (m, 10H), 1.59 (m, 2H), 2.62 (t, J = 6.8 Hz, 2H), 3.50 (m, 2H), 3.80 (m, 2H), 6.63 (m, 1 H), 6.92-7.03 (m, 2H), 7.09-7.16 (m, 3H), 7.26 (d, J = 8.2 Hz, 1 H), 7.40 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 7.8 Hz, 1 H), 8.53 (s a, 1 H), 9.82 (s a, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.7, 26.8, 28.8, 29.2, 29.3, 31.8, 36.3, 44.5, 49.9 (9CH2), 105.2, 1 1 1.8 (2CH), 120.0 (2CH), 120.6, 122.1 , 124.3, 124.6 (4CH), 127.9 (C), 128.9 (2CH), 129.2, 135.7, 138.1 , 163.4, 169.5 (5C). MS (ESI) 420.4 [(M+H)+]. Análisis caled para C26H33N3O2 C, 74.43; H, 7.93; N, 10.02, encontrado C, 74.19; H, 7.83; N, 10.00. IR (ATR, cm "1 ) 3284, 1666, 1600, 1533, 1442. 1 H NMR (CDCI 3 ) δ 0.79 (t, J = 6.6 Hz, 3H), 1.16 (m, 10H), 1.59 (m, 2H ), 2.62 (t, J = 6.8 Hz, 2H), 3.50 (m, 2H), 3.80 (m, 2H), 6.63 (m, 1 H), 6.92-7.03 (m, 2H), 7.09-7.16 (m, 3H), 7.26 (d, J = 8.2 Hz, 1 H), 7.40 (d, J = 7.9 Hz , 2H), 7.51 (d, J = 7.8 Hz, 1 H), 8.53 (sa, 1 H), 9.82 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.7, 26.8, 28.8, 29.2, 29.3, 31.8, 36.3, 44.5, 49.9 (9CH 2 ), 105.2, 1 1 1.8 (2CH), 120.0 (2CH), 120.6, 122.1, 124.3, 124.6 (4CH), 127.9 (C), 128.9 (2CH), 129.2, 135.7, 138.1, 163.4, 169.5 (5C). MS (ESI) 420.4 [(M + H) + ]. Caled analysis for C2 6 H 33 N 3 O2 C, 74.43; H, 7.93; N, 10.02, found C, 74.19; H, 7.83; N, 10.00.
^-(l -benzofuran-S-ilcarboni - V^fenil-A^-octil-p-alaninamida (22). Se obtuvo a partir de A/1-fenil-A/3-octil^-alaninamida (0.36 mmol) y ácido 1-benzofuran-3- carboxílico (0.72 mmol) con un rendimiento del 58%. Cromatografía: diclorometano/ etanol, 95:5. Rf (diclorometano/etanol, 95:5) 0.38.
Figure imgf000049_0001
^ - (1-benzofuran-S-ylcarboni - V ^ phenyl-A ^ -octyl-p-alaninamide (22). It was obtained from A / 1 -phenyl-A / 3- octyl ^ -alaninamide (0.36 mmol) and 1-benzofuran-3-carboxylic acid (0.72 mmol) with a yield of 58% Chromatography: dichloromethane / ethanol, 95: R f (dichloromethane / ethanol, 95: 5) 0.38.
Figure imgf000049_0001
IR (ATR, cm"1) 3313, 1683, 1609, 1548, 1492, 1443. 1 H RMN (CDCI3) δ 0.84 (t, J = 6.9 Hz, 3H), 1.14-1.26 (m, 10H), 1.54 (m, 2H), 2.76 (m, 2H), 3.45 (t, J = 7.5 Hz, 2H), 3.85 (t, J = 6.5 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1 H), 7.15 (t, J = 7.4 Hz, 1 H), 7.22-7.33 (m, 3H), 7.46-7.61 (m, 4H), 7.74 (s, 1 H), 9.15 (s a, 1 H). 13C RMN (CDCI3) δ 14.0 (CH3), 22.5, 26.5, 29.1 (3C), 31.7, 36.2, 43.0, 50.4 (9CH2), 1 1 1.7 (CH), 1 17.2 (C), 1 19.9 (2CH), 120.9, 123.7, 124.1 , 125.3 (4CH), 125.4 (C), 128.8 (2CH), 138.4 (C), 143.9 (CH), 154.6, 165.4, 169.6 (3C). HRMS (ESI) caled para C26H32N203Na [(M+Na)+] 443.2305; encontrado 443.2319. IR (ATR, cm "1 ) 3313, 1683, 1609, 1548, 1492, 1443. 1 H NMR (CDCI 3 ) δ 0.84 (t, J = 6.9 Hz, 3H), 1.14-1.26 (m, 10H), 1.54 (m, 2H), 2.76 (m, 2H), 3.45 (t, J = 7.5 Hz, 2H), 3.85 (t, J = 6.5 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1 H), 7.15 (t, J = 7.4 Hz, 1 H), 7.22-7.33 (m, 3H), 7.46-7.61 (m, 4H), 7.74 (s, 1 H), 9.15 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.0 (CH 3 ), 22.5, 26.5, 29.1 (3C), 31.7, 36.2, 43.0, 50.4 (9CH 2 ), 1 1 1.7 (CH), 1 17.2 (C), 1 19.9 (2CH) , 120.9, 123.7, 124.1, 125.3 (4CH), 125.4 (C), 128.8 (2CH), 138.4 (C), 143.9 (CH), 154.6, 165.4, 169.6 (3C). HRMS (ESI) caled for C 26 H 32 N 2 0 3 Na [(M + Na) + ] 443.2305; found 443.2319.
A^-benzoil- V^fenil-A^-octil-p-alaninamida (23). Se obtuvo a partir de A -fenil-/V3- octil^-alaninamida (0.54 mmol) y ácido benzoico (1.1 mmol) con un rendimiento del 91 %. Cromatografía: hexano/acetato de etilo, 9: 1. Rf (hexano/acetato de etilo, 7:3) 0.28. p.f. 65-67 °C.
Figure imgf000049_0002
IR (ATR, cm"1) 3307, 1686, 1607, 1546, 1498, 1439. 1 H RMN (CDCI3) δ 0.85 (t, J = 6.9 Hz, 3H), 1.09-1.15 (m, 10H), 1.50 (m, 2H), 2.75 (m, 2H), 3.25 (m, 2H), 3.81 (m, 2H), 7.04 (t, J = 7.4 Hz, 1 H), 7.21-7.27 (m, 2H), 7.32-7.40 (m, 5H), 7.51 (d, J = 7.7 Hz, 2H), 9.35 (s a, 1 H). 13C RMN (CDCI3) δ 14.0 (CH3), 22.6, 26.4, 28.8, 29.0 (2C), 31.7, 36.2, 42.6, 50.6 (9CH2), 119.9 (2CH), 123.9 (CH), 126.4 (2CH), 128.5 (2CH), 128.8 (2CH), 129.5 (CH), 136.4, 138.6, 169.8, 172.7 (4C). MS (ESI) 381.2 [(M+H)+]. Análisis caled para C24H32N2O2 C, 75.75; H, 8.48; N, 7.36, encontrado C, 75.45; H, 8.21 ; N, 7.41. A ^ -benzoyl- V ^ phenyl-A ^ -octyl-p-alaninamide (23). It was obtained from A -phenyl- / V 3 -octyl ^ -alaninamide (0.54 mmol) and benzoic acid (1.1 mmol) with a yield of 91%. Chromatography: hexane / ethyl acetate, 9: 1. R f (hexane / ethyl acetate, 7: 3) 0.28. mp 65-67 ° C.
Figure imgf000049_0002
IR (ATR, cm "1 ) 3307, 1686, 1607, 1546, 1498, 1439. 1 H NMR (CDCI 3 ) δ 0.85 (t, J = 6.9 Hz, 3H), 1.09-1.15 (m, 10H), 1.50 (m, 2H), 2.75 (m, 2H), 3.25 (m, 2H), 3.81 (m, 2H), 7.04 (t, J = 7.4 Hz, 1 H), 7.21-7.27 (m, 2H), 7.32 -7.40 (m, 5H), 7.51 (d, J = 7.7 Hz, 2H), 9.35 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.0 (CH 3 ), 22.6, 26.4, 28.8, 29.0 ( 2C), 31.7, 36.2, 42.6, 50.6 (9CH 2 ), 119.9 (2CH), 123.9 (CH), 126.4 (2CH), 128.5 (2CH), 128.8 (2CH), 129.5 (CH), 136.4, 138.6, 169.8 , 172.7 (4C) .MS (ESI) 381.2 [(M + H) + ]. Caled analysis for C24H 3 2N2O2 C, 75.75; H, 8.48; N, 7.36, found C, 75.45; H, 8.21; N, 7.41 .
^-(ciclopentilcarboni - V^fenil-A^-octil-p-alaninamida (24). Se obtuvo a partir de Ay1-fenil-Ay3-octil^-alaninamida (0.54 mmol) y ácido ciclopentanocarboxílico (1.1 mmol) con un rendimiento del 69%. Cromatografía: hexano/acetato de etilo, 9: 1. Rf (hexano/acetato de etilo, 7:3) 0.22. p.f. 67-70 °C.
Figure imgf000050_0001
^ - (cyclopentylcarboni - V ^ phenyl-A ^ -octyl-p-alaninamide (24). It was obtained from Ay 1 -phenyl-Ay 3 -octyl ^ -alaninamide (0.54 mmol) and cyclopentanecarboxylic acid (1.1 mmol) with a yield of 69% Chromatography: hexane / ethyl acetate, 9: 1. R f (hexane / ethyl acetate, 7: 3) 0.22, mp 67-70 ° C.
Figure imgf000050_0001
IR (ATR, cm"1) 3281 , 1682, 161 1 , 1547, 1494, 1442. 1 H RMN (CDCI3) δ (mezcla de rotámeros A:B, 7: 1) 0.88 (t, J = 6.8 Hz, 3H), 1.29 (m, 10H), 1 .57 (m, 4H), 1.76-1.79 (m, 6H), 2.61 (t, J = 6.5 Hz, 2H, rotámero B), 2.69 (t, J = 6.5 Hz, 2H, rotámero A), 2.86 (qt, J = 7.7 Hz, 1 H), 3.33 (t, J = 7.8 Hz, 2H), 3.69 (t, J = 6.5 Hz, 2H, rotámero A), 3.75 (t, J = 6.5 Hz, 2H, rotámero B), 7.06 (t, J = 7.3 Hz, 1 H), 7.29 (t, J = 7.8 Hz, 2H), 7.50 (d, J = 7.8 Hz, 2H, rotámero B), 7.58 (d, J = 7.8 Hz, 2H, rotámero A), 8.02IR (ATR, cm "1 ) 3281, 1682, 161 1, 1547, 1494, 1442. 1 H NMR (CDCI 3 ) δ (mixture of rotamers A: B, 7: 1) 0.88 (t, J = 6.8 Hz, 3H), 1.29 (m, 10H), 1.57 (m, 4H), 1.76-1.79 (m, 6H), 2.61 (t, J = 6.5 Hz, 2H, rotamer B), 2.69 (t, J = 6.5 Hz, 2H, rotamer A), 2.86 (qt, J = 7.7 Hz, 1 H), 3.33 (t, J = 7.8 Hz, 2H), 3.69 (t, J = 6.5 Hz, 2H, rotamer A), 3.75 ( t, J = 6.5 Hz, 2H, rotamer B), 7.06 (t, J = 7.3 Hz, 1 H), 7.29 (t, J = 7.8 Hz, 2H), 7.50 (d, J = 7.8 Hz, 2H, rotamer B), 7.58 (d, J = 7.8 Hz, 2H, rotamer A), 8.02
(s a, 1 H, rotámero B), 8.96 (s a, 1 H, rotámero A). 13C RMN (CDCI3) δ 14.0 (CH3),(sa, 1 H, rotamer B), 8.96 (sa, 1 H, rotamer A). 13 C NMR (CDCI 3 ) δ 14.0 (CH 3 ),
22.6, 25.9, 26.2, 26.9, 27.0, 27.7, 29.2 (2C), 29.3, 29.4, 29.5, 30.2, 30.7, 30.8, 31.7,22.6, 25.9, 26.2, 26.9, 27.0, 27.7, 29.2 (2C), 29.3, 29.4, 29.5, 30.2, 30.7, 30.8, 31.7,
36.7, 37.2 (H CH2, rotámeros A y B), 41.0 (CH), 43.0, 43.7, 46.0, 48.8 (2CH2, rotámeros A y B), 1 19.9, 120.0 (2CH, rotámeros A y B), 123.9, 124.3 (CH, rotámeros A y B), 128.8, 128.9 (2CH, rotámeros A y B), 138.1 , 138.6, 169.1 , 169.6, 176.4, 177.4 (3C, rotámeros A y B). MS (ESI) 373.2 [(M+H)+]. Análisis caled para C23H36N2O2 C, 74.15; H, 9.74; N, 7.52, encontrado C, 74.44; H, 9.29; N, 7.43. 36.7, 37.2 (H CH2, rotamers A and B), 41.0 (CH), 43.0, 43.7, 46.0, 48.8 (2CH 2 , rotamers A and B), 1 19.9, 120.0 (2CH, rotamers A and B), 123.9, 124.3 (CH, rotamers A and B), 128.8, 128.9 (2CH, rotamers A and B), 138.1, 138.6, 169.1, 169.6, 176.4, 177.4 (3C, rotamers A and B). MS (ESI) 373.2 [(M + H) + ]. Caled analysis for C2 3 H 36 N2O2 C, 74.15; H, 9.74; N, 7.52, found C, 74.44; H, 9.29; N, 7.43.
A^-ÍS-butoxipropilJ- V^fenil-A^-S-furoil-p-alaninamida (46). Se obtuvo a partir de Ay3-(3-butoxipropil)-Ay1-fenil^-alaninamida (0.44 mmol) y ácido 3-furanocarboxílico (0.89 mmol) con un rendimiento del 75%. Cromatografía: hexano a hexano/acetato de etilo, 7:3. Rf (diclorometano/metanol/amoniaco, 9: 1 :0.1) 0.41. p.f. 78-80 °C. A ^ -IS-butoxypropylJ- V ^ phenyl-A ^ -S-furoyl-p-alaninamide (46). It was obtained from Ay 3 - (3-butoxypropyl) -Ay 1 -phenyl ^ -alaninamide (0.44 mmol) and 3-furancarboxylic acid (0.89 mmol) with a yield of 75%. Chromatography: hexane to hexane / ethyl acetate, 7: 3. R f (dichloromethane / methanol / ammonia, 9: 1: 0.1) 0.41. mp 78-80 ° C.
Figure imgf000051_0001
Figure imgf000051_0001
IR (ATR, cm"1) 3276, 1666, 1600, 1545, 1499, 1438. 1 H RMN (CDCI3) δ 0.88 (t, J = 7.3 Hz, 3H), 1.32 (sx, J = 7.5 Hz, 2H), 1.51 (qt, J = 6.7 Hz, 2H), 1.84-1.93 (m, 2H), 2.75 (m, 2H), 3.33 (t, J = 6.5 Hz, 2H), 3.37 (t, J = 5.1 Hz, 2H), 3.61 (m, 2H), 3.80 (t, J = 6.5 Hz, 2H), 6.64 (d, J = 1.1 Hz, 1 H), 7.03 (t, J = 7.4 Hz, 1 H), 7.24 (t, J = 7.9 Hz, 2H), 7.34 (t, J = 1.1 Hz, 1 H), 7.54 (d, J = 7.8 Hz, 2H), 7.87 (m, 1 H), 8.79 (s a, 1 H). 13C RMN (CDCIs) δ 13.9 (CH3), 19.4, 29.5, 31.8, 36.0, 43.3, 47.3, 67.5, 70.9 (8CH2), 1 10.6 (CH), 1 19.9 (2CH), 121.0 (C), 123.9 (CH), 128.8 (2CH), 138.5 (C), 142.8, 144.1 (2CH), 165.2, 169.8 (2C). MS (ESI) 373.2 [(M+H)+]. Análisis caled para C21 H28N2O4 C, 67.72; H, 7.58; N, 7.52, encontrado C, 67.34; H, 7.54; N, 7.57. IR (ATR, cm "1 ) 3276, 1666, 1600, 1545, 1499, 1438. 1 H NMR (CDCI 3 ) δ 0.88 (t, J = 7.3 Hz, 3H), 1.32 (sx, J = 7.5 Hz, 2H ), 1.51 (qt, J = 6.7 Hz, 2H), 1.84-1.93 (m, 2H), 2.75 (m, 2H), 3.33 (t, J = 6.5 Hz, 2H), 3.37 (t, J = 5.1 Hz , 2H), 3.61 (m, 2H), 3.80 (t, J = 6.5 Hz, 2H), 6.64 (d, J = 1.1 Hz, 1 H), 7.03 (t, J = 7.4 Hz, 1 H), 7.24 (t, J = 7.9 Hz, 2H), 7.34 (t, J = 1.1 Hz, 1 H), 7.54 (d, J = 7.8 Hz, 2H), 7.87 (m, 1 H), 8.79 (sa, 1 H ). 13 C NMR (CDCIs) δ 13.9 (CH 3), 19.4, 29.5, 31.8, 36.0, 43.3, 47.3, 67.5, 70.9 (8CH 2), 1 10.6 (CH), 1 19.9 (2CH), 121.0 (C ), 123.9 (CH), 128.8 (2CH), 138.5 (C), 142.8, 144.1 (2CH), 165.2, 169.8 (2C). MS (ESI) 373.2 [(M + H) + ]. Caled analysis for C21 H2 8 N2O4 C, 67.72; H, 7.58; N, 7.52, found C, 67.34; H, 7.54; N, 7.57.
W1-fenil-W3-3-furoil-W3-[3-(2-metoxietoxi)propil]-p-alaninamida (47). Se obtuvo a partir de Λ/1-fenil-Λ/3-[3-(2-metoxietoxi)propil]-β-alaninamida (0.25 mmol) y ácido 3- furanocarboxílico (0.49 mmol) con un rendimiento del 72%. Cromatografía: hexano/acetato de etilo, 1 : 1. Rf (diclorometano/metanol/amoniaco, 9: 1 :0.1) 0.45. p.f. 75-77 °C. W 1 -phenyl-W 3 -3-furoyl-W 3 - [3- (2-methoxyethoxy) propyl] -p-alaninamide (47). It was obtained from Λ / 1 -phenyl-Λ / 3 - [3- (2-methoxyethoxy) propyl] -β-alaninamide (0.25 mmol) and 3- furan-carboxylic acid (0.49 mmol) in 72% yield. Chromatography: hexane / ethyl acetate, 1: 1. R f (dichloromethane / methanol / ammonia, 9: 1: 0.1) 0.45. mp 75-77 ° C.
Figure imgf000051_0002
Figure imgf000051_0002
IR (ATR, cm"1) 3307, 1683, 1603, 1546, 1500, 1442. 1 H RMN (CDCI3) δ 1.96 (qt, J = 6.9 Hz, 2H), 2.80 (t, J = 6.7 Hz, 2H), 3.40 (s, 3H), 3.49 (t, J = 5.6 Hz, 2H), 3.55 (m, 4H), 3.65 (t, J = 6.5 Hz, 2H), 3.86 (t, J = 6.5 Hz, 2H), 6.72 (s, 1 H), 7.1 1 (t, J = 7.4 Hz, 1 H), 7.32 (t, J = 7.9 Hz, 2H), 7.43 (t, J = 1.7 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 2H), 7.93 (s, 1 H), 8.55 (s a, 1 H). 13C RMN (CDCI3) δ 29.5, 36.7 (2CH2), 59.1 (CH3), 43.4, 47.1 , 68.2, 70.4, 72.1 (5CH2), 1 10.8 (CH), 1 19.9 (2CH), 121.2 (C), 124.3 (CH), 129.0 (2CH), 138.4 (C), 143.0, 144.2 (2CH), 165.6, 169.4 (2C). MS (ESI) 347.9 [(M+H)+]. Análisis caled para C20H26N2O5 ½H2O C, 62.65; H, 7.10; N, 7.31 , encontrado C, 62.20; H, 6.95; N, 6.99. IR (ATR, cm "1 ) 3307, 1683, 1603, 1546, 1500, 1442. 1 H NMR (CDCI 3 ) δ 1.96 (qt, J = 6.9 Hz, 2H), 2.80 (t, J = 6.7 Hz, 2H ), 3.40 (s, 3H), 3.49 (t, J = 5.6 Hz, 2H), 3.55 (m, 4H), 3.65 (t, J = 6.5 Hz, 2H), 3.86 (t, J = 6.5 Hz, 2H ), 6.72 (s, 1 H), 7.1 1 (t, J = 7.4 Hz, 1 H), 7.32 (t, J = 7.9 Hz, 2H), 7.43 (t, J = 1.7 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 2H), 7.93 (s, 1 H), 8.55 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 29.5, 36.7 (2CH 2 ), 59.1 (CH 3 ), 43.4 , 47.1, 68.2, 70.4, 72.1 (5CH 2 ), 1 10.8 (CH), 1 19.9 (2CH), 121.2 (C), 124.3 (CH), 129.0 (2CH), 138.4 (C), 143.0, 144.2 (2CH ), 165.6, 169.4 (2C). MS (ESI) 347.9 [(M + H) + ]. Caled analysis for C 20 H 26 N 2 O 5 ½ H 2 OC, 62.65; H, 7.10; N, 7.31, found C, 62.20; H, 6.95; N, 6.99.
W3-[2-(2-etoxietoxi)etil]- V1-fenil-AT5-3-furoil-p-alaninamida (48). Se obtuvo a partir de A/3-[2(2-etoxietoxi)etil)-/\/1-fenil^-alaninamida (0.36 mmol) y ácido 3- furanocarboxílico (0.71 mmol) con un rendimiento del 91 %. Cromatografía: hexano a hexano/acetato de etilo, 3:7. Rf (hexano/acetato de etilo, 2:8) 0.32. W 3 - [2- (2-ethoxyethoxy) ethyl] - V 1 -phenyl-AT 5 -3-furoyl-p-alaninamide (48). It was obtained from A / 3 - [2 (2-ethoxyethoxy) ethyl) - / \ / 1 -phenyl ^ -alaninamide (0.36 mmol) and 3- furan-carboxylic acid (0.71 mmol) in a yield of 91%. Chromatography: hexane to hexane / ethyl acetate, 3: 7. R f (hexane / ethyl acetate, 2: 8) 0.32.
Figure imgf000052_0001
Figure imgf000052_0001
IR (ATR, cm"1) 3308, 1684, 1604, 1546, 1502, 1442. 1 H RMN (CDCI3) δ 1.18 (m, 3H), 2.80 (t, J = 6.4 Hz, 2H), 3.60 (m, 2H), 3.88 (t, J = 6.4 Hz, 2H), 6.66 (s, 1 H), 7.08 (t, J = 7.4 Hz, 1 H), 7.30 (t, J = 7.9 Hz, 2H), 7.39 (s, 1 H), 7.56 (d, J = 7.9 Hz, 2H), 7.83 (m, 1 H), 8.73 (s a, 1 H). 13C RMN (CDCI3) δ 15.2 (CH3), 36.6, 43.3, 49.9, 66.7, 68.6, 69.8, 70.6 (7CH2), 1 10.7 (CH), 1 19.9 (2CH), 121.0 (C), 124.2 (CH), 129.0 (2CH), 138.5 (C), 142.9, 144.3 (2CH), 166.4, 169.8 (2C). HRMS (ESI) caled para C2oH26N205Na [(M+Na)+] 397.1734, encontrado 397.1728. IR (ATR, cm "1 ) 3308, 1684, 1604, 1546, 1502, 1442. 1 H NMR (CDCI 3 ) δ 1.18 (m, 3H), 2.80 (t, J = 6.4 Hz, 2H), 3.60 (m , 2H), 3.88 (t, J = 6.4 Hz, 2H), 6.66 (s, 1 H), 7.08 (t, J = 7.4 Hz, 1 H), 7.30 (t, J = 7.9 Hz, 2H), 7.39 (s, 1 H), 7.56 (d, J = 7.9 Hz, 2H), 7.83 (m, 1 H), 8.73 (sa, 1 H) 13 C NMR (CDCI 3 ) δ 15.2 (CH 3 ), 36.6 , 43.3, 49.9, 66.7, 68.6, 69.8, 70.6 (7CH 2 ), 1 10.7 (CH), 1 19.9 (2CH), 121.0 (C), 124.2 (CH), 129.0 (2CH), 138.5 (C), 142.9 , 144.3 (2CH), 166.4, 169.8 (2C) HRMS (ESI) caled for C 2 oH2 6 N 2 0 5 Na [(M + Na) + ] 397.1734, found 397.1728.
EJEMPLO 11. Síntesis de los ésteres (lf,g). Procedimiento general. EXAMPLE 11. Synthesis of esters (lf, g). General procedure.
A una disolución de 1 equiv del ácido carboxílico correspondiente (XI) en diclorometano anhidro (4 mL/mmol), se le añaden, bajo atmósfera de argón, 1 equiv de EDC y 1 equiv de HOBt. La mezcla de reacción se agita a temperatura ambiente durante una hora. A continuación, se adiciona una disolución de 1.5 equiv del alcohol correspondiente (XII) en diclorometano anhidro (2 mL/mmol). En el caso de los ácidos carboxílicos que poseen otros hidrógenos ácidos, como por ejemplo N- octil-/V-(1 /-/-pirrol-2-ilcarbonil)^-alanina y Λ/-(1 H-imidazol-2-ilcarbonil)- V-octil- - alanina, no se dejan activando con los agentes de condensación durante 1 h, sino que el alcohol se adicionan inmediatamente después de la EDC y el HOBt a la mezcla de reacción. A continuación, la mezcla se agita a temperatura ambiente durante toda la noche. El crudo de reacción se lava con disoluciones acuosas saturadas de NaHC03 y NaCI, consecutivamente. Los extractos orgánicos se secan sobre Na2S04 y el disolvente se elimina a presión reducida. El residuo se purifica por cromatografía en columna, obteniéndose los amidoesteres correspondientesTo a solution of 1 equiv of the corresponding carboxylic acid (XI) in anhydrous dichloromethane (4 mL / mmol), 1 equiv of EDC and 1 equiv of HOBt are added under argon. The reaction mixture is stirred at room temperature for one hour. Next, a solution of 1.5 equiv of the corresponding alcohol (XII) in anhydrous dichloromethane (2 mL / mmol) is added. In the case of carboxylic acids that possess other acidic hydrogens, such as, for example, N-octyl- / V- (1 / - / - pyrrol-2-ylcarbonyl) ^-alanine and Λ / - (1 H-imidazol-2- ilcarbonyl) - V-octyl- - alanine, they are not allowed to activate with the condensing agents for 1 h, but the alcohol is added immediately after EDC and HOBt to the reaction mixture. Then, the mixture is stirred at room temperature overnight. The reaction crude is washed with saturated aqueous solutions of NaHC0 3 and NaCI, consecutively. The organic extracts are dried on Na 2 S0 4 and the solvent is removed under reduced pressure. The residue is purified by column chromatography, obtaining the corresponding amido esters.
(if,g)- V-3-furoil- V-octil-p-alaninato de fenilo (26). Se obtuvo a partir de A/-3-furoil-/V-octil- β-alanina (0.21 mmol) y fenol (0.32 mmol) con un rendimiento del 53%. Cromatografía: hexano/acet acetato de etilo, 7:3) 0.49.
Figure imgf000053_0001
(if, g) - V-3-furoyl-V-octyl-p-phenyl alaninate (26). It was obtained from A / -3-furoyl- / V-octyl-β-alanine (0.21 mmol) and phenol (0.32 mmol) in 53% yield. Chromatography: hexane / acet ethyl acetate, 7: 3) 0.49.
Figure imgf000053_0001
IR (ATR, cm"1) 1758, 1627, 1496, 1428. 1 H RMN (CDCI3) δ 0.88 (t, J = 6.7 Hz, 3H), 1.26 (m, 10H), 1.63 (m, 2H), 2.94 (m, 2H), 3.48 (t, J = 7.8 Hz, 2H), 3.84 (t, J = 7.0 Hz, 2H), 6.59 (d, J = 0.9 Hz, 1 H), 7.09 (d, J = 7.6 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1 H), 7.37 (t, J = 7.8 Hz, 2H), 7.42 (t, J = 1.7 Hz, 1 H), 7.72 (s, 1 H). 13C RMN (CDCI3) δ 13.0 (CH3), 21.6, 25.7, 28.1 , 28.2, 28.7, 30.7, 32.0, 41.4, 48.8 (9CH2), 109.1 (CH), 120.4 (2CH), 120.5 (C), 124.9 (CH), 128.4 (2CH), 141.9, 142.1 (2CH), 149.5, 163.9, 169.4 (3C). HRMS (ESI) caled para C22H29N04Na [(M+Na)+] 394.1989, encontrado 394.1973. V-3-furoil- V-heptil-p-alaninato de fenilo (27). Se obtuvo a partir de A/-3-furoil-/V- heptil-p-alanina (0.18 mmol) y fenol (0.27 mmol) con un rendimiento del 32%. Cromatografía: hexano/acet acetato de etilo, 7:3) 0.40.
Figure imgf000053_0002
IR (ATR, cm "1 ) 1758, 1627, 1496, 1428. 1 H NMR (CDCI 3 ) δ 0.88 (t, J = 6.7 Hz, 3H), 1.26 (m, 10H), 1.63 (m, 2H), 2.94 (m, 2H), 3.48 (t, J = 7.8 Hz, 2H), 3.84 (t, J = 7.0 Hz, 2H), 6.59 (d, J = 0.9 Hz, 1 H), 7.09 (d, J = 7.6 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1 H), 7.37 (t, J = 7.8 Hz, 2H), 7.42 (t, J = 1.7 Hz, 1 H), 7.72 (s, 1 H ). 13 C NMR (CDCI 3) δ 13.0 (CH 3), 21.6, 25.7, 28.1, 28.2, 28.7, 30.7, 32.0, 41.4, 48.8 (9CH 2), 109.1 (CH), 120.4 (2CH), 120.5 ( C), 124.9 (CH), 128.4 (2CH), 141.9, 142.1 (2CH), 149.5, 163.9, 169.4 (3C). HRMS (ESI) caled for C 22 H 29 N0 4 Na [(M + Na) + ] 394.1989, found 394.1973. V-3-Furoyl-V-heptyl-p-phenyl alaninate (27) It was obtained from A / -3-furoyl- / V-heptyl-p-alanine (0.18 mmol) and phenol (0.27 mmol) with a yield of 32% Chromatography: hexane / acet ethyl acetate, 7: 3) 0.40.
Figure imgf000053_0002
IR (ATR, cm"1) 1735, 1675, 1624, 1461. 1 H RMN (CDCI3) δ 0.89 (t, J = 6.6 Hz, 3H), 1.28-1.34 (m, 8H), 1.61 -1.68 (m, 2H), 2.96 (m, 2H), 3.48 (t, J = 7.9 Hz, 2H), 3.84 (t, J = 7.0 Hz, 2H), 6.59 (d, J = 0.9 Hz, 1 H), 7.09 (d, J = 8.5 Hz, 2H), 7.21-7.24 (m, 1 H), 7.38 (t, J = 7.9 Hz, 2H), 7.43 (t, J = 1.6 Hz, 1 H), 7.72 (m, 1 H). 13C RMN (CDCI3) δ 14.5 (CH3), 23.0, 27.1 , 29.4, 29.6, 32.2, 33.4, 42.8, 50.2 (8CH2), 1 10.6 (CH), 121.9 (2CH, C), 126.4 (CH), 129.9 (2CH), 143.3, 143.5 (2CH), 151.0, 165.4, 171.0 (3C). HRMS (ESI) caled para C2i H27N04Na [(M+Na)+] 380.1838, encontrado 380.1839. V-octil- V-(1 H-pirrol-2-ilcarbonil)-p-alaninato de fenilo (28). Se obtuvo a partir de A/-octil-A/-(1 H-pirrol-2-ilcarbonil)-p-alanina (0.20 mmol) y fenol (0.30 mmol) con un rendimiento del 56%. Cromatografía: hexano/acetato de etilo, 7:3. Rf (hexano/acetato de etilo, 7:3)
Figure imgf000054_0001
IR (ATR, cm "1 ) 1735, 1675, 1624, 1461. 1 H NMR (CDCI 3 ) δ 0.89 (t, J = 6.6 Hz, 3H), 1.28-1.34 (m, 8H), 1.61 -1.68 (m , 2H), 2.96 (m, 2H), 3.48 (t, J = 7.9 Hz, 2H), 3.84 (t, J = 7.0 Hz, 2H), 6.59 (d, J = 0.9 Hz, 1 H), 7.09 ( d, J = 8.5 Hz, 2H), 7.21-7.24 (m, 1 H), 7.38 (t, J = 7.9 Hz, 2H), 7.43 (t, J = 1.6 Hz, 1 H), 7.72 (m, 1 H). 13 C NMR (CDCI 3) δ 14.5 (CH 3), 23.0, 27.1, 29.4, 29.6, 32.2, 33.4, 42.8, 50.2 (8CH 2), 1 10.6 (CH), 121.9 (2CH, C), 126.4 (CH), 129.9 (2CH), 143.3, 143.5 (2CH), 151.0, 165.4, 171.0 (3C). HRMS (ESI) caled for C 2 i H 27 N0 4 Na [(M + Na) + ] 380.1838, found 380.1839. V-octyl- V- (1 H-pyrrol-2-ylcarbonyl) -p-phenyl alaninate (28). It was obtained from A / -octyl-A / - (1 H -pyrrole-2-ylcarbonyl) -p-alanine (0.20 mmol) and phenol (0.30 mmol) in 56% yield. Chromatography: hexane / ethyl acetate, 7: 3. R f (hexane / ethyl acetate, 7: 3)
Figure imgf000054_0001
IR (ATR, cm"1) 3261 , 1757, 1592, 1484, 1441. 1 H RMN (CDCI3) δ 0.89 (t, J = 6.7 Hz, 3H), 1.29-1.36 (m, 10H), 1.75 (m, 2H), 3.00 (t, J = 7.2 Hz, 2H), 3.65 (t, J = 7.8 Hz, 2H), 3.93 (m, 2H), 6.26-6.29 (m, 1 H), 6.57 (m, 1 H), 6.95 (td, J = 2.6, 1.1 Hz, 1 H), 7.10 (d, J = 8.7 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1 H), 7.38 (t, J = 7.8 Hz, 2H), 10.01 (s a, 1 H). 13C RMN (CDCIs) δ 14.1 (CH3), 22.6, 26.9, 28.7, 29.3, 29.4, 31.8, 33.4, 43.9, 49.2 (9CH2), 1 10.1 , 1 11.8, 121.1 (3CH), 121.5 (2CH), 124.7 (C), 126.0 (CH), 129.5 (2CH), 150.6, 162.1 , 170.5 (3C). HRMS (ESI) caled para C22H3oN203Na [(M+Na)+]: 393.2149, encontrado: 393.2132. IR (ATR, cm "1 ) 3261, 1757, 1592, 1484, 1441. 1 H NMR (CDCI 3 ) δ 0.89 (t, J = 6.7 Hz, 3H), 1.29-1.36 (m, 10H), 1.75 (m , 2H), 3.00 (t, J = 7.2 Hz, 2H), 3.65 (t, J = 7.8 Hz, 2H), 3.93 (m, 2H), 6.26-6.29 (m, 1 H), 6.57 (m, 1 H), 6.95 (td, J = 2.6, 1.1 Hz, 1 H), 7.10 (d, J = 8.7 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1 H), 7.38 (t, J = 7.8 Hz, 2H), 10.01 (brs, 1H). 13 C NMR (CDCIs) δ 14.1 (CH 3), 22.6, 26.9, 28.7, 29.3, 29.4, 31.8, 33.4, 43.9, 49.2 (9CH 2), 1 10.1 , 1 11.8, 121.1 (3CH), 121.5 (2CH), 124.7 (C), 126.0 (CH), 129.5 (2CH), 150.6, 162.1, 170.5 (3C). HRMS (ESI) caled for C 2 2H 3 oN 2 0 3 Na [(M + Na) + ]: 393.2149, found: 393.2132.
/V-(1 H-imidazol-2-ilcarbonil)-/V-octil-p-alaninato de fenilo (29). Se obtuvo a partir de A/-(1 /-/-imidazol-2-ilcarbonil)-/\/-octil- -alanina (0.23 mmol) y fenol (0.35 mmol) con un rendimiento del 58%. Cromatografía: hexano/acetato de etilo, 7:3. Rf / V- (1 H-imidazol-2-ylcarbonyl) - / V-octyl-p-phenyl alaninate (29). It was obtained from A / - (1 / - / - imidazol-2-ylcarbonyl) - / \ / - octyl--alanine (0.23 mmol) and phenol (0.35 mmol) with a yield of 58%. Chromatography: hexane / ethyl acetate, 7: 3. R f
(hexano/acetato de etilo, 7:3) 0.31. p.f. 65-67 °C.
Figure imgf000054_0002
(hexane / ethyl acetate, 7: 3) 0.31. mp 65-67 ° C.
Figure imgf000054_0002
IR (ATR, cm"1) 3216, 1758, 1604, 1484, 1446. 1 H RMN (CDCI3) δ (mezcla de rotámeros A:B, 1 : 1) 0.88 (t, J = 6.7 Hz, 3H), 1.23-1.34 (m, 10H), 1.70-1.73 (m, 2H), 3.00 (t, J = 7.1 Hz, 2H, rotámero A), 3.10 (t, J = 7.1 Hz, 2H, rotámero B), 3.59 (t, J = 7.6 Hz, 2H, rotámero B), 3.91 (t, J = 7.1 Hz, 2H, rotámero A), 4.35 (t, J = 7.6 Hz, 2H, rotámero A), 4.60 (t, J = 7.1 Hz, 2H, rotámero B), 7.07-7.10 (m, 2H), 7.15 (m, 2H, 2CH), 7.22 (t, J = 7.4 Hz, 1 H, CH), 7.37 (t, J = 7.6 Hz, 2H, 2CH), 11.91 (s a, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.7, 26.7, 27.1 , 27.7, 29.2, 29.3 (2C), 29.4, 31.8, 32.9, 34.7, 43.8, 44.6, 48.1 , 49.6 (9CH2, rotámeros A y B), 121.5 (2CH), 125.9, 126.0, 129.4, 129.5, 130.1 (5CH), 141.3, 150.6 (2C), 159.3, 159.6, 170.4, 170.5 (2C, rotámeros A y B). MS (ESI): 372.2 [(M+H)+]. Análisis caled para C21 H29N3O3 C, 67.90; H, 7.87; N, 1 1.31 ; encontrado: C, 67.77; H, 7.67; N, 1 1.24. V-octil- V-(1 ,3-oxazol-5-ilcarbonil)-p-alaninato de fenilo (30). Se obtuvo a partir de A/-octil-/\/-(1 ,3-oxazol-5-ilcarbonil)^-alanina (0.29 mmol) y fenol (0.44 mmol) con un rendimiento del 61 %. Cromatografía: hexano/acetato de etilo, 7:3. Rf (hexano/acetato de etilo, 7:3)
Figure imgf000055_0001
IR (ATR, cm "1 ) 3216, 1758, 1604, 1484, 1446. 1 H NMR (CDCI 3 ) δ (mixture of rotamers A: B, 1: 1) 0.88 (t, J = 6.7 Hz, 3H), 1.23-1.34 (m, 10H), 1.70-1.73 (m, 2H), 3.00 (t, J = 7.1 Hz, 2H, rotamer A), 3.10 (t, J = 7.1 Hz, 2H, rotamer B), 3.59 ( t, J = 7.6 Hz, 2H, rotamer B), 3.91 (t, J = 7.1 Hz, 2H, rotamer A), 4.35 (t, J = 7.6 Hz, 2H, rotamer A), 4.60 (t, J = 7.1 Hz, 2H, rotamer B), 7.07-7.10 (m, 2H), 7.15 (m, 2H, 2CH), 7.22 (t, J = 7.4 Hz, 1 H, CH), 7.37 (t, J = 7.6 Hz, 2H, 2CH), 11.91 (brs, 1H). 13 C NMR (CDCI 3) δ 14.1 (CH 3), 22.7, 26.7, 27.1, 27.7, 29.2, 29.3 (2C), 29.4, 31.8, 32.9, 34.7, 43.8, 44.6, 48.1, 49.6 (9CH 2 , rotamers A and B), 121.5 (2CH), 125.9, 126.0, 129.4, 129.5, 130.1 (5CH), 141.3, 150.6 (2C), 159.3, 159.6, 170.4, 170.5 ( 2 C, rotamers A and B). MS (ESI): 372.2 [(M + H) + ]. Caled analysis for C21 H29N3O3 C, 67.90; H, 7.87; N, 1 1.31; Found: C, 67.77; H, 7.67; N, 1 1.24. V-octyl- V- (1,3-oxazol-5-ylcarbonyl) -p-phenyl alaninate (30). It was obtained from A / -octyl - / \ / - (1,3-oxazol-5-ylcarbonyl) ^-alanine (0.29 mmol) and phenol (0.44 mmol) with a yield of 61%. Chromatography: hexane / ethyl acetate, 7: 3. R f (hexane / ethyl acetate, 7: 3)
Figure imgf000055_0001
IR (ATR, cm"1) 1757, 1633, 1490, 1430. 1 H RMN (CDCI3) δ 0.86 (t, J = 6.7 Hz, 3H), 1.25-1.28 (m, 10H), 1.66 (m, 2H), 2.96 (t, J = 7.0 Hz, 2H), 3.57 (m, 2H), 3.84 (m, 2H), 7.06 (d, J = 7.6 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1 H), 7.33-7.38 (m, 2H), 7.61 (m, 1 H), 7.93 (m, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.7, 29.2 (2C), 29.5, 31.7, 32.7, 43.5 49.5 (9CH2), 121.4 (2CH), 126.0 (CH), 129.5 (2CH), 131.6 (CH), 145.5, 150.5 (2C), 151.5 (CH), 158.4, 170.4 (2C). HRMS (ESI) caled para C2i H28N204Na [(M+Na)+] 395.1941 , encontrado 395.1924. IR (ATR, cm "1 ) 1757, 1633, 1490, 1430. 1 H NMR (CDCI 3 ) δ 0.86 (t, J = 6.7 Hz, 3H), 1.25-1.28 (m, 10H), 1.66 (m, 2H ), 2.96 (t, J = 7.0 Hz, 2H), 3.57 (m, 2H), 3.84 (m, 2H), 7.06 (d, J = 7.6 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1 H), 7.33-7.38 (m, 2H), 7.61 (m, 1 H), 7.93 (m, 1 H). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6, 26.7, 29.2 (2C) , 29.5, 31.7, 32.7, 43.5 49.5 (9CH 2 ), 121.4 (2CH), 126.0 (CH), 129.5 (2CH), 131.6 (CH), 145.5, 150.5 (2C), 151.5 (CH), 158.4, 170.4 ( 2C) HRMS (ESI) caled for C 2 and H2 8 N 2 04Na [(M + Na) + ] 395.1941, found 395.1924.
EJEMPLO 10. Síntesis de los derivados (Ih). Procedimiento general. EXAMPLE 10. Synthesis of derivatives (Ih). General procedure.
A una disolución de 1 equiv del ácido carboxílico correspondiente (XI) en diclorometano anhidro (5 mL/mmol), se le añaden, bajo atmósfera de argón, 1 equiv de EDC y 1 equiv de HOBt. La mezcla de reacción se agita a temperatura ambiente durante 1 h. A continuación, se añade una disolución de 1 equiv de la diamina correspondiente (XVI) en diclorometano anhidro (2.5 mL/mmol) y se agita a temperatura ambiente durante toda la noche. El crudo de reacción se lava con disoluciones acuosas saturadas de NaHC03 y NaCI, consecutivamente. Los extractos orgánicos se secan sobre Na2S04 y el disolvente se elimina a presión reducida. El residuo se purifica por cromatografía en columna, obteniéndose las amidas (Ih). V-(3-anilinopropil)- V-octil-3-furamida (25). Se obtuvo a partir de ácido 3-furoico (0.19 mmol) y A/-octil-A/'-fenilpropano-1 ,3-diamina (0.19 mmol) con un rendimiento del 35%. Cromatografía: hexano/acetato de etilo, 7:3. Rf (hexano/acetato de etilo, 7:3) 0.42.
Figure imgf000056_0001
To a solution of 1 equiv of the corresponding carboxylic acid (XI) in anhydrous dichloromethane (5 mL / mmol), 1 equiv of EDC and 1 equiv of HOBt are added under argon. The reaction mixture is stirred at room temperature for 1 h. Then, a solution of 1 equiv of the corresponding diamine (XVI) in anhydrous dichloromethane (2.5 mL / mmol) is added and stirred at room temperature overnight. The reaction crude is washed with saturated aqueous solutions of NaHC0 3 and NaCI, consecutively. The organic extracts are dried over Na 2 S0 4 and the solvent is removed under reduced pressure. The residue is purified by column chromatography, obtaining the amides (Ih). V- (3-anilinopropyl) - V-octyl-3-furamide (25). It was obtained from 3-furoic acid (0.19 mmol) and A / -octyl-A / '-phenylpropane-1,3-diamine (0.19 mmol) with a yield 35% Chromatography: hexane / ethyl acetate, 7: 3. R f (hexane / ethyl acetate, 7: 3) 0.42.
Figure imgf000056_0001
IR (ATR, cm"1) 3356, 1726, 1610, 1507, 1463. 1 H RMN (CDCI3) δ 0.88 (t, J = 6.7 Hz, 3H), 1.26 (m, 10H), 1.59 (m, 2H), 1.91 (qt, J = 6.8 Hz, 2H), 3.16 (m, 2H), 3.39 (t, J = 7.3 Hz, 2H), 3.57 (t, J = 7.0 Hz, 2H), 4.21 (s a, 1 H), 6.56 (d, J = 1.0 Hz, 1 H), 6.62 (d, J = 6.5 Hz, 2H), 6.69 (t, J = 7.3 Hz, 1 H), 7.17 (t, J = 7.4 Hz, 2H), 7.42 (s, 1 H), 7.68 (s, 1 H). 13C RMN (CDCIs) δ 14.1 (CH3), 22.6, 26.8, 27.0, 29.2, 29.3, 29.4, 31.8, 41.0, 43.1 , 49.1 (I OCH2), 1 10.2 (CH), 1 12.9 (2CH), 1 17.3 (CH), 121.7 (C), 129.3 (2CH), 142.9 (2CH), 148.2, 164.9 (2C). HRMS (ESI) caled para C22H33N2O2 [(M+H)+] 357.2537, encontrado: 357.2538. IR (ATR, cm "1 ) 3356, 1726, 1610, 1507, 1463. 1 H NMR (CDCI 3 ) δ 0.88 (t, J = 6.7 Hz, 3H), 1.26 (m, 10H), 1.59 (m, 2H ), 1.91 (qt, J = 6.8 Hz, 2H), 3.16 (m, 2H), 3.39 (t, J = 7.3 Hz, 2H), 3.57 (t, J = 7.0 Hz, 2H), 4.21 (sa, 1 H), 6.56 (d, J = 1.0 Hz, 1 H), 6.62 (d, J = 6.5 Hz, 2H), 6.69 (t, J = 7.3 Hz, 1 H), 7.17 (t, J = 7.4 Hz, 2H), 7.42 (s, 1 H), 7.68 (s, 1 H) 13 C NMR (CDCIs) δ 14.1 (CH 3 ), 22.6, 26.8, 27.0, 29.2, 29.3, 29.4, 31.8, 41.0, 43.1, 49.1 (I OCH 2 ), 1 10.2 (CH), 1 12.9 (2CH), 1 17.3 (CH), 121.7 (C), 129.3 (2CH), 142.9 (2CH), 148.2, 164.9 (2C). HRMS (ESI) ) caled for C22H 33 N2O2 [(M + H) + ] 357.2537, found: 357.2538.
EJEMPLO 11. Síntesis de los derivados (Ij).EXAMPLE 11. Synthesis of derivatives (Ij).
V-fenil- V-{3-[3-furoil(octil)amino]propil}-3-furamida (31 ). Se obtuvo a partir de ácido 3-furoico (0.38 mmol) y A/-octil-A/'-fenilpropano-1 ,3-diamina (0.19 mmol), siguiendo el procedimiento general B descrito para la síntesis de amidas (If) en el ejemplo 8, con un rendimiento del 45%. Cromatografía: hexano/acetato de etilo, 7:3. Rf (hexano/acetato de etilo, 7:3) 0.16. V-phenyl- V- {3- [3-furoyl (octyl) amino] propyl} -3-furamide (31). It was obtained from 3-furoic acid (0.38 mmol) and A / -octyl-A / '-phenylpropane-1,3-diamine (0.19 mmol), following the general procedure B described for the synthesis of amides (If) in Example 8, with a yield of 45%. Chromatography: hexane / ethyl acetate, 7: 3. R f (hexane / ethyl acetate, 7: 3) 0.16.
Figure imgf000056_0002
Figure imgf000056_0002
IR (ATR, cm"1) 1630, 1568, 1502, 1432. 1 H RMN (CDCI3) δ 0.87 (t, J = 6.7 Hz, 3H), 1.25 (m, 10H), 1.54-1.59 (m, 2H), 1.94 (m, 2H), 3.38 (t, J = 7.8 Hz, 2H), 3.51 (t, J = 7.9 Hz, 2H), 3.86 (m, 2H), 6.10 (m, 1 H), 6.54 (m, 1 H), 6.78 (s, 1 H), 7.13 (t, J = 1.7 Hz, 1 H), 7.26 (m, 2H), 7.38-7.42 (m, 4H), 7.66 (s, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.8 (2C), 29.2, 29.3 (2C), 31.8, 43.6, 47.8, 47.9 (10CH2), 1 10.2, 1 1 1.1 (2CH), 121.7, 121.9 (2C), 128.4 (2CH), 128.7 (CH), 129.8 (2CH), 142.0 (CH), 142.4 (C), 142.8 (2CH), 145.8 (CH), 163.1 , 164.7 (2C). HRMS (ESI) caled para C27H34N204Na [(M+Na)+] 473.241 1 , encontrado 473.2398. V-[3-(3-furoilamino)propil]- V-octil-3-furamida (49). Se obtuvo a partir de ácido 3- furoico (2.1 mmol) y A/-octilpropano-1 ,3-diamina (1.1 mmol), siguiendo el procedimiento general B descrito para la síntesis de amidas (If) en el ejemplo 8, con un rendimiento del 79%. Cromatografía: diclorometano/metanol, 8:2. Rf (hexano/acetato de etilo/a
Figure imgf000057_0001
IR (ATR, cm "1 ) 1630, 1568, 1502, 1432. 1 H NMR (CDCI 3 ) δ 0.87 (t, J = 6.7 Hz, 3H), 1.25 (m, 10H), 1.54-1.59 (m, 2H ), 1.94 (m, 2H), 3.38 (t, J = 7.8 Hz, 2H), 3.51 (t, J = 7.9 Hz, 2H), 3.86 (m, 2H), 6.10 (m, 1 H), 6.54 ( m, 1 H), 6.78 (s, 1 H), 7.13 (t, J = 1.7 Hz, 1 H), 7.26 (m, 2H), 7.38-7.42 (m, 4H), 7.66 (s, 1 H) . 13 C NMR (CDCI 3) δ 14.1 (CH 3), 22.6, 26.8 (2C), 29.2, 29.3 (2C), 31.8, 43.6, 47.8, 47.9 (10CH 2), 1 10.2, 1 1 1.1 (2CH) , 121.7, 121.9 (2C), 128.4 (2CH), 128.7 (CH), 129.8 (2CH), 142.0 (CH), 142.4 (C), 142.8 (2CH), 145.8 (CH), 163.1, 164.7 (2C). HRMS (ESI) caled for C 27 H 34 N 2 0 4 Na [(M + Na) + ] 473.241 1, found 473.2398. V- [3- (3-Furoylamino) propyl] - V-octyl-3-furamide (49). It was obtained from 3- furoic acid (2.1 mmol) and A / -octylpropane-1,3-diamine (1.1 mmol), following the general procedure B described for the synthesis of amides (If) in example 8, with a 79% yield. Chromatography: dichloromethane / methanol, 8: 2. R f (hexane / ethyl acetate / a
Figure imgf000057_0001
IR (ATR, cm"1) 3316, 1616, 1538, 1507, 1432. 1 H RMN (CDCI3) δ 0.88 (t, J = 6.5 Hz, 3H), 1.22-1.32 (m, 10H), 1.59-1.67 (m, 2H), 1.84 (qt, J = 6.4 Hz, 2H), 3.38 (t, J = 7.8 Hz, 2H), 3.39 (t, J = 7.9 Hz, 2H), 3.62 (t, J = 6.2 Hz, 2H), 6.58 (d, J = 1.9 Hz, 1 H), 6.80 (s, 1 H), 7.41 (s, 1 H), 7.46 (s, 1 H), 7.68 (s a, 1 H), 7.72 (s, 1 H), 8.02 (s a, 1 H). 13C RMN (CDCIs) δ 13.9 (CH3), 22.5, 26.5, 27.1 (3CH2), 29.0 (3CH2), 31.6, 35.7, 42.3, 48.7 (4CH2), 108.5, 110.0 (2CH), 121.2, 122.8 (2C), 142.9 (2CH), 143.4, 144.8 (2CH), 162.7, 165.6 (2C). HRMS (El) caled para C21 H30N2O4 [M +] 374.2206, encontrado 374.2189. IR (ATR, cm "1 ) 3316, 1616, 1538, 1507, 1432. 1 H NMR (CDCI 3 ) δ 0.88 (t, J = 6.5 Hz, 3H), 1.22-1.32 (m, 10H), 1.59-1.67 (m, 2H), 1.84 (qt, J = 6.4 Hz, 2H), 3.38 (t, J = 7.8 Hz, 2H), 3.39 (t, J = 7.9 Hz, 2H), 3.62 (t, J = 6.2 Hz , 2H), 6.58 (d, J = 1.9 Hz, 1 H), 6.80 (s, 1 H), 7.41 (s, 1 H), 7.46 (s, 1 H), 7.68 (sa, 1 H), 7.72 (s, 1H), 8.02 (brs, 1H). 13 C NMR (CDCIs) δ 13.9 (CH 3), 22.5, 26.5, 27.1 (3CH 2), 29.0 (3CH 2), 31.6, 35.7, 42.3, 48.7 (4CH 2 ), 108.5, 110.0 (2CH), 121.2, 122.8 (2C), 142.9 (2CH), 143.4, 144.8 (2CH), 162.7, 165.6 (2C). HRMS (El) caled for C21 H30N2O4 [M + ] 374.2206, found 374.2189.
EJEMPLO 12. Síntesis de los derivados (le). EXAMPLE 12. Synthesis of derivatives (le).
2-{[(anilinosulfonil)etil](octil)amino}-/V-feniletanosulfonamida (42). Se obtuvo a partir de /V-feniletenosulfonamida (0.33 mmol) y octilamina (0.13 mmol) siguiendo el procedimiento descrito para la síntesis de las diamidas (le) en el ejemplo 7 con un rendimiento del 27%. Cromatografía: hexano a acetato de etilo. Rf (hexano/acetato de etilo, 1 : 1) 0.34.
Figure imgf000057_0002
2 - {[(anilinosulfonyl) ethyl] (octyl) amino} - / V-phenylethanesulfonamide (42). It was obtained from / V-phenyletenesulfonamide (0.33 mmol) and octylamine (0.13 mmol) following the procedure described for the synthesis of diamides (le) in example 7 with a yield of 27%. Chromatography: hexane to ethyl acetate. R f (hexane / ethyl acetate, 1: 1) 0.34.
Figure imgf000057_0002
IR (ATR, cm"1) 3277, 1597, 1493, 1341 , 1 149 cm"1. 1 H RMN (CDCI3) δ 0.88 (t, J = 6.7 Hz, 3H), 1.26 (m, 10H), 1.41-1.50 (m, 2H), 2.59 (t, J = 7.2 Hz, 2H), 3.1 1 (t, J = 6.3 Hz, 2H), 3.26 (t, J = 6.4 Hz, 2H), 3.29 (t, J = 6.3 Hz, 2H), 4.17 (t, J = 6.4 Hz, 4H), 7.16-7.28 (m, 5H), 7.31-7.39 (m, 5H). 13C RMN (CDCI3) δ 14.2 (CH3), 22.8, 27.3, 29.3, 29.5, 29.5, 31.9, 43.6, 46.4, 49.5, 49.8, 50.8 (11 CH2), 120.7 (2CH), 125.3 (2CH), 129.0 (2CH), 129.8 (2CH), 130.0 (2CH), 136.8, 138.0 (2C). HRMS (ESI) caled para C24H38N3O4S2 [(M+H)+] 496.2298, encontrado 496.2304. EJEMPLO 13. Síntesis de los derivados (Ik). Procedimiento general. IR (ATR, cm "1 ) 3277, 1597, 1493, 1341, 1 149 cm " 1 . 1 H NMR (CDCI 3 ) δ 0.88 (t, J = 6.7 Hz, 3H), 1.26 (m, 10H), 1.41-1.50 (m, 2H), 2.59 (t, J = 7.2 Hz, 2H), 3.1 1 (t, J = 6.3 Hz, 2H), 3.26 (t, J = 6.4 Hz, 2H), 3.29 (t, J = 6.3 Hz, 2H), 4.17 (t, J = 6.4 Hz, 4H), 7.16-7.28 (m, 5H), 7.31-7.39 (m, 5H). 13 C NMR (CDCI 3 ) δ 14.2 (CH 3 ), 22.8, 27.3, 29.3, 29.5, 29.5, 31.9, 43.6, 46.4, 49.5, 49.8, 50.8 (11 CH 2 ), 120.7 (2CH), 125.3 (2CH) , 129.0 (2CH), 129.8 (2CH), 130.0 (2CH), 136.8, 138.0 (2C). HRMS (ESI) caled for C24H38N3O4S2 [(M + H) + ] 496.2298, found 496.2304. EXAMPLE 13. Synthesis of derivatives (Ik). General procedure.
A una suspensión de 1 equiv de la amina (IV) correspondiente y 1.5 equiv de la vinilsulfonamida (VII) en acetonitrilo seco (0.5 mL/mmol de amina), se le añaden 1.5 equiv de DBU bajo atmósfera de argón. La mezcla de reacción se calienta a reflujo durante 5 h. Una vez alcanzada la temperatura ambiente, se elimina el disolvente a presión reducida y el residuo se purifica por cromatografía en columna, obteniéndose las amidosulfonamidas (Ik).  To a suspension of 1 equiv of the corresponding amine (IV) and 1.5 equiv of the vinyl sulfonamide (VII) in dry acetonitrile (0.5 mL / mmol of amine), 1.5 equiv of DBU is added under argon atmosphere. The reaction mixture is heated at reflux for 5 h. Once the room temperature is reached, the solvent is removed under reduced pressure and the residue is purified by column chromatography, obtaining amidosulfonamides (Ik).
A^-^-íanilinosulfoni ethyll- V^fenil-A^-octil-p-alaninamida (43). Se obtuvo a partir de A/1-fenil-/V3-octil-p-alaninamida (0.55 mmol) y /V-feniletenosulfonamida (0.82 mmol) con un rendimiento del 12%. Cromatografía: hexano/acetato de etilo, 7:3. Rf (hexano/acetato de etilo, 1 : 1) 0.35. A ^ - ^ - ianilinosulfoni ethyll- V ^ phenyl-A ^ -octyl-p-alaninamide (43). It was obtained from A / 1 -phenyl- / V 3 -octyl-p-alaninamide (0.55 mmol) and / V-phenyletenesulfonamide (0.82 mmol) in 12% yield. Chromatography: hexane / ethyl acetate, 7: 3. R f (hexane / ethyl acetate, 1: 1) 0.35.
h h
IR (ATR, cm"1) 3253, 1661 , 1599, 1545, 1498, 1 148 cm"1. 1 H RMN (CDCI3) δ 0.81 (t, J = 6.8 Hz, 3H), 1.04-1.29 (m, 10H), 1.36 (m, 2H), 2.35 (t, J = 7.7 Hz, 2H), 2.44 (t, J = 5.8 Hz, 2H), 2.71 (t, J = 5.7 Hz, 2H), 2.96 (t, J = 6.5 Hz, 2H), 3.21 (t, J = 6.5 Hz, 2H), 6.99-7.12 (m, 4H), 7.19-7.32 (m, 4H), 7.48 (d, J = 7.7 Hz, 2H), 9.12 (s a, 1 H). 13C RMN (CDCIs) δ 14.1 (CH3), 22.6, 26.3, 27.5, 29.2, 29.4, 31.8, 34.6, 47.4, 48.1 , 50.5, 53.7 (H CH2), 1 19.9 (2CH), 120.5 (2CH), 124.1 , 125.0 (2CH), 128.9 (2CH), 129.6 (2CH), 136.9, 138.1 , 170.8 (3C). IR (ATR, cm "1 ) 3253, 1661, 1599, 1545, 1498, 1 148 cm " 1 . 1 H NMR (CDCI 3 ) δ 0.81 (t, J = 6.8 Hz, 3H), 1.04-1.29 (m, 10H), 1.36 (m, 2H), 2.35 (t, J = 7.7 Hz, 2H), 2.44 ( t, J = 5.8 Hz, 2H), 2.71 (t, J = 5.7 Hz, 2H), 2.96 (t, J = 6.5 Hz, 2H), 3.21 (t, J = 6.5 Hz, 2H), 6.99-7.12 ( m, 4H), 7.19-7.32 (m, 4H), 7.48 (d, J = 7.7 Hz, 2H), 9.12 (sa, 1 H). 13 C NMR (CDCIs) δ 14.1 (CH 3 ), 22.6, 26.3, 27.5, 29.2, 29.4, 31.8, 34.6, 47.4, 48.1, 50.5, 53.7 (H CH 2 ), 1 19.9 (2CH), 120.5 (2CH) , 124.1, 125.0 (2CH), 128.9 (2CH), 129.6 (2CH), 136.9, 138.1, 170.8 (3C).
W1-fenil-W3-(2-{[metil(fenil)amino]sulfonil}etil)-W3-octil-p-alaninamida (44). Se obtuvo a partir de A/1-fenil-A/3-octil-p-alaninamida (0.35 mmol) y /V-fenil-A- metiletenosulfonamida (0.52 mmol) con un rendimiento del 68%. Cromatografía: hexano a hexano/acetato de etilo 4:6. Rf (hexano/acetato de etilo, 1 : 1) 0.38.
Figure imgf000058_0001
W 1 -phenyl-W 3 - (2 - {[methyl (phenyl) amino] sulfonyl} ethyl) -W 3 -octyl-p-alaninamide (44). It was obtained from A / 1 -phenyl-A / 3- octyl-p-alaninamide (0.35 mmol) and / V-phenyl-A-methylenesulfonamide (0.52 mmol) in 68% yield. Chromatography: hexane to hexane / ethyl acetate 4: 6. R f (hexane / ethyl acetate, 1: 1) 0.38.
Figure imgf000058_0001
IR (ATR, cm"1) 3322, 1664, 1599, 1543, 1494, 1 144 cm"1. 1 H RMN (CDCI3) δ 0.79 (t, J = 6.8 Hz, 3H), 1.03-1.26 (m, 10H), 1.41 (m, 2H), 2.37-2.45 (m, 4H), 2.69 (t, J = 5.8 Hz, 2H), 2.93-2.98 (m, 2H), 3.08-3.12 (m, 2H), 3.25 (s, 3H), 7.01 (t, J = 7.4 Hz, 1 H), 7.18-7.33 (m, 7H), 7.45 (d, J = 7.7 Hz, 2H), 9.63 (s a, 1 H). 13C RMN (CDCI3) δ 14.1 (CH3), 22.6, 26.8, 27.5, 29.2, 29.4, 31.8, 34.4 (7CH2), 38.3 (CH3), 46.1 , 47.0, 50.5, 53.6 (4CH2), 1 19.7 (2CH), 123.8 (CH), 126.2 (2CH), 127.5 (CH), 128.9 (2CH), 129.5 (2CH), 138.4, 141.1 , 170.4 (3C). ^-^-(anilinosulfoni etill-A^-ÍS-butoxipropi -^-fenil-p-alaninamida (45). Se obtuvo a partir de A/3-(3-butoxipropil)-A/1-fenil-p-alaninamida (0.72 mmol) y N- feniletenosulfonamida (1.1 mmol) con un rendimiento del 10%. Cromatografía: hexano/acetato de etilo 1 : 1. Rf (hexano/acetato de etilo, 1 : 1) 0.20.
Figure imgf000059_0001
IR (ATR, cm"1) 3313, 3283, 1662, 1600, 1548, 1499, 1444 cm"1. 1 H RMN (CDCI3) δ 0.83 (t, J = 6.7 Hz, 3H), 1.23-1.31 (m, 2H), 1.38-1.48 (m, 2H), 1.58-1.67 (m, 2H), 2.41-2.50 (m, 4H), 2.68-2.71 (m, 2H), 2.93 (t, J = 6.5 Hz, 2H), 3.18-3.32 (m, 6H), 7.01 (t, J = 7.4 Hz, 1 H), 7.06 (t, J = 7.1 Hz, 1 H), 7.13 (d, J = 7.3 Hz, 2H), 7.19-7.25 (m, 4H), 7.48 (t, J = 7.7 Hz, 2H), 9.01 (s a, 1 H). 13C RMN (CDCI3) δ 13.9 (CH3), 19.3, 26.4, 31.7, 34.9, 47.7, 48.5, 50.4, 50.6, 68.1 , 70.6 (10CH2), 1 19.9 (2CH), 120.6 (2CH), 124.1 , 125.1 (2CH), 128.9 (2CH), 129.6 (2CH), 136.9, 138.5, 170.9 (3C). IR (ATR, cm "1 ) 3322, 1664, 1599, 1543, 1494, 1 144 cm " 1 . 1 H NMR (CDCI 3 ) δ 0.79 (t, J = 6.8 Hz, 3H), 1.03-1.26 (m, 10H), 1.41 (m, 2H), 2.37-2.45 (m, 4H), 2.69 (t, J = 5.8 Hz, 2H), 2.93-2.98 (m, 2H), 3.08-3.12 (m, 2H), 3.25 (s, 3H), 7.01 (t, J = 7.4 Hz, 1 H), 7.18-7.33 (m , 7H), 7.45 (d, J = 7.7 Hz, 2H), 9.63 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 14.1 (CH 3 ), 22.6, 26.8, 27.5, 29.2, 29.4, 31.8, 34.4 (7CH 2 ), 38.3 (CH 3 ), 46.1, 47.0, 50.5, 53.6 (4CH 2 ), 1 19.7 (2CH), 123.8 (CH ), 126.2 (2CH), 127.5 (CH), 128.9 (2CH), 129.5 (2CH), 138.4, 141.1, 170.4 (3C). ^ - ^ - (anilinosulfoni etill-A ^ -IS-butoxypropyl - ^ - phenyl-p-alaninamide (45). It was obtained from A / 3 - (3-butoxypropyl) -A / 1 -phenyl-p-alaninamide (0.72 mmol) and N-phenyletenesulfonamide (1.1 mmol) in 10% yield Chromatography: hexane / ethyl acetate 1: 1. R f (hexane / ethyl acetate, 1: 1) 0.20.
Figure imgf000059_0001
IR (ATR, cm "1 ) 3313, 3283, 1662, 1600, 1548, 1499, 1444 cm " 1 . 1 H NMR (CDCI 3 ) δ 0.83 (t, J = 6.7 Hz, 3H), 1.23-1.31 (m, 2H), 1.38-1.48 (m, 2H), 1.58-1.67 (m, 2H), 2.41-2.50 (m, 4H), 2.68-2.71 (m, 2H), 2.93 (t, J = 6.5 Hz, 2H), 3.18-3.32 (m, 6H), 7.01 (t, J = 7.4 Hz, 1 H), 7.06 (t, J = 7.1 Hz, 1 H), 7.13 (d, J = 7.3 Hz, 2H), 7.19-7.25 (m, 4H), 7.48 (t, J = 7.7 Hz, 2H), 9.01 (sa, 1 H). 13 C NMR (CDCI 3 ) δ 13.9 (CH 3 ), 19.3, 26.4, 31.7, 34.9, 47.7, 48.5, 50.4, 50.6, 68.1, 70.6 (10CH 2 ), 1 19.9 (2CH), 120.6 (2CH), 124.1 , 125.1 (2CH), 128.9 (2CH), 129.6 (2CH), 136.9, 138.5, 170.9 (3C).
EJEMPLO 14. Determinación de la capacidad de inhibición de la enzima isoprenilcarboximetil transferasa de los derivados de fórmula general (I). EXAMPLE 14. Determination of the inhibitory capacity of the enzyme isoprenylcarboxymethyl transferase of the derivatives of general formula (I).
La determinación de la capacidad de los compuestos sintetizados para inhibir la actividad ICMT se realizó empleando como fuente de enzima membranas procedentes de células Sf9 (ovario de Spodoptera frugiperda) que sobreexpresan ICMT, y como sustratos biotinil-S-farnesilcisteína (BFC) y S-adenosilmetionina marcada con tritio ([3H]SAM). En este caso, tras preincubar la enzima con el compuesto objeto de estudio durante 10 min a temperatura ambiente, se añadieron los sustratos BFC y [3H]SAM siendo las concentraciones finales de 5 y 2 μΜ, respectivamente. La mezcla se incubó durante 30 min a 37 °C. Pasado este tiempo, la reacción se terminó con la adición de Tween 20 y mediante el posterior enriquecimiento con estreptavidina unida a un soporte sólido, se cuantificó la radiactividad por medio de espectrometría de centelleo líquido. Alternativamente, se puede emplear un ensayo basado en fluorescencia en el que la enzima ICMT se incuba en condiciones análogas a las indicadas anteriormente empleando como sustrato y cosustrato /V-acetil-S-geranilgeranilcisteína (AGGC) y SAM, respectivamente, y en presencia de enzima S-adenosilhomocisteína hidrolasa (SAHH) y el sustrato fluorescente ThioGIol En estas condiciones, la S- adenosilhomocisteína generada en la reacción catalizada por la ICMT es hidrolizada por la enzima SAHH generándose adenosina y homocisteína. Esta última reacciona con el ThioGIol generándose un aducto fluorescente que puede ser cuantificado en un espectrofluorímetro (Aex = 400 nm, Aem = 515 nm). En cualquiera de los dos casos, el análisis de los datos obtenidos respecto al control positivo de ICMT obtenido en ausencia de inhibidor (100% de actividad) permitió determinar la capacidad inhibitoria de los compuestos. The ability of synthesized compounds to inhibit ICMT activity was determined using membranes from Sf9 cells (Spodoptera frugiperda ovary) that overexpress ICMT as a source of enzyme, and as biotinyl-S-farnesylcysteine (BFC) and S- substrates Tritium-labeled adenosylmethionine ([ 3 H] SAM). In this case, after preincubating the enzyme with the compound under study for 10 min at room temperature, the BFC and [ 3 H] SAM substrates were added, the final concentrations being 5 and 2 μΜ, respectively. The mixture was incubated for 30 min at 37 ° C. After this time, the reaction was terminated with the addition of Tween 20 and by subsequent enrichment with streptavidin bound to a solid support, the radioactivity was quantified by means of liquid scintillation spectrometry. Alternatively, a fluorescence based assay can be used in which the ICMT enzyme is incubate under conditions similar to those indicated above using as substrate and cosustrate / V-acetyl-S-geranylgeranylcysteine (AGGC) and SAM, respectively, and in the presence of enzyme S-adenosylhomocysteine hydrolase (SAHH) and the fluorescent substrate ThioGIol Under these conditions, the S-adenosylhomocysteine generated in the reaction catalyzed by the ICMT is hydrolyzed by the enzyme SAHH generating adenosine and homocysteine. The latter reacts with ThioGIol generating a fluorescent adduct that can be quantified in a spectrofluorimeter (A ex = 400 nm, A em = 515 nm). In either case, the analysis of the data obtained regarding the positive control of ICMT obtained in the absence of inhibitor (100% activity) allowed to determine the inhibitory capacity of the compounds.
Los compuestos ensayados se consideran activos frente a la enzima ICMT cuando presentan un porcentaje de inhibición enzimática superior al 50% a una concentración de 50 μΜ (Tabla 1). The compounds tested are considered active against the ICMT enzyme when they have a percentage of enzyme inhibition greater than 50% at a concentration of 50 μΜ (Table 1).
Tabla 1. Valores de inhibición de los compuestos (I) Table 1. Inhibition values of compounds (I)
Compuesto Inhibición (%)a Inhibition Compound (%) a
1 71  1 71
3 62  3 62
4 93  4 93
7 84  7 84
10 56  10 56
11 81  11 81
12 79  12 79
13 75  13 75
17 62  17 62
18 63  18 63
23 57  23 57
24 66  24 66
25 51  25 51
26 60  26 60
27 70 30 61 27 70 30 61
31 92  31 92
33 91  33 91
34 95  34 95
42 90 a Los valores de inhibición se han determinado a una concentración de compuesto de 50 μΜ y corresponden al valor medio de dos experimentos independientes realizados por triplicado con un error asociado menor del 10% en todos los casos. 42 90 a The inhibition values have been determined at a compound concentration of 50 μΜ and correspond to the average value of two independent experiments performed in triplicate with an associated error of less than 10% in all cases.
Brevemente, estos resultados ponen de manifiesto que la mayoría de los compuestos de fórmula general (I) inhiben la enzima ICMT. Briefly, these results show that most of the compounds of general formula (I) inhibit the enzyme ICMT.
EJEMPLO 15. Determinación de la estabilidad de los derivados de fórmula general (I) en suero y microsomas humano y de ratón. EXAMPLE 15. Determination of the stability of derivatives of general formula (I) in human and mouse microsomes and serum.
Se ha determinado la estabilidad de los compuestos de fórmula general (I) que presentan una inhibición de la enzima ICMT superior al 70% a una concentración de 50 μΜ. Para ello se midió la cantidad de compuesto remanente tras la incubación en suero o microsomas humanos o de ratón a diferentes tiempos con el fin de determinar el tiempo de vida media.  The stability of the compounds of general formula (I) having an inhibition of the ICMT enzyme greater than 70% at a concentration of 50 μ 50 has been determined. For this, the amount of the remaining compound was measured after incubation in human or mouse microsomes or serum at different times in order to determine the half-life.
Estabilidad en suero. A 900 de suero humano (Sigma, S7023) o de ratón (Europa Bioproducts, EQSM-0100) previamente termostatizado a 37 °C se añadieron 300 de una disolución 2 mM del compuesto objeto de estudio en tampón fosfato (phosphate buffered saline, PBS) y la mezcla se incubó a 37 °C durante el tiempo de interés. Una vez transcurrido éste, 200 μΙ_ de la mezcla se añadieron sobre 200 μΙ_ de acetonitrilo frío, se agitó y se incubó durante 10 min en hielo para precipitar las proteínas. El sobrenadante se separó del precipitado por centrifugación a 39000g durante 10 min y se hizo pasar a través de un filtro de teflón de tamaño de poro de 0.22 μηι (Albet Labscience). A continuación, 50 μΙ_ del sobrenadante filtrado se analizó mediante HPLC-MS en un espectrómetro Agilent 1200LC-MSD VL, empleando una columna Eclipse XDB-C18 (5 μι ι, 4.6 mm x 150 mm) junto con una precolumna (5 μηι, 4.6 mm x 12.5 mm). La fase móvil empleada consistió en un gradiente de disoluciones A (agua:metanol 95:5) y B (agua:metanol 5:95) con un 0.1 % de hidróxido amónico y 0.1 % de ácido fórmico como aditivos. En todos los casos se usó un flujo constante de 0.5 mL/min, un tiempo total de 15 min y el siguiente gradiente: 0 min, 60% A; 1 min, 100% B; 1-14 min, 100% B; 15 min, 60% A. El análisis de EM se llevó a cabo utilizando la técnica de ionización ESI en modo positivo SIM. El voltaje del capilar fue de 3.0 kV y el voltaje del fragmentador de 70 eV. La temperatura del gas secante fue de 350 °C, el flujo de 10 L/min y la presión del nebulizador de 20 psi. Stability in serum. At 900 human serum (Sigma, S7023) or mouse (Europa Bioproducts, EQSM-0100) previously thermostatized at 37 ° C, 300 of a 2 mM solution of the compound under study in phosphate buffer (phosphate buffered saline, PBS) were added and the mixture was incubated at 37 ° C during the time of interest. After this, 200 μΙ_ of the mixture was added over 200 μΙ_ of cold acetonitrile, stirred and incubated for 10 min on ice to precipitate the proteins. The supernatant was separated from the precipitate by centrifugation at 39000g for 10 min and was passed through a 0.22 μηι pore size Teflon filter (Albet Labscience). Next, 50 μΙ_ of the filtered supernatant was analyzed by HPLC-MS on an Agilent 1200LC-MSD VL spectrometer, using an Eclipse XDB-C18 column (5 μι ι, 4.6 mm x 150 mm) together with a pre-column (5 μηι, 4.6 mm x 12.5 mm). The mobile phase used consisted of a gradient of solutions A (water: methanol 95: 5) and B (water: methanol 5:95) with 0.1% ammonium hydroxide and 0.1% formic acid as additives. In all cases a constant flow of 0.5 mL / min was used, a total time of 15 min and the following gradient: 0 min, 60% A; 1 min, 100% B; 1-14 min, 100% B; 15 min, 60% A. The EM analysis was carried out using the ESI ionization technique in SIM positive mode. The capillary voltage was 3.0 kV and the fragmenter voltage 70 eV. The temperature of the drying gas was 350 ° C, the flow of 10 L / min and the pressure of the nebulizer of 20 psi.
Estabilidad en microsomas. A 1 185 μΙ_ de PBS termostatizado a 37 °C, se añadieron 150 μΙ_ de una disolución 10 mM de NADPH (Aldrich, N7505) en PBS y 15 μΙ_ de una disolución 1 mM del compuesto objeto de estudio en PBS y la mezcla se incubó durante 5 min a 37 °C. A continuación se añadieron 150 μΙ_ de una suspensión de microsomas humanos (Aldrich, M0567) o de ratón (Aldrich, M9441) a una concentración de 5 mg/mL y se incubó a 37 °C durante el tiempo de interés, siendo las concentraciones finales de compuesto, NADPH y microsomas en la mezcla de 10 μΜ, 1 mM y 0.5 mg/mL, respectivamente. Una vez transcurrido éste, 250 μΙ_ de la mezcla se añadieron sobre 250 μΙ_ de acetonitrilo frío, se agitó y se incubó durante 10 min en hielo para precipitar las proteínas. El sobrenadante se separó del precipitado por centrifugación a 10000g durante 5 min y se hizo pasar a través de un filtro de teflón de tamaño de poro de 0.22 μηι (Albet Labscience). A continuación, 50 μΙ_ del sobrenadante filtrado se analizaron mediante HPLC-MS de forma análoga a la descrita para el caso de los ensayos de estabilidad en suero. Stability in microsomes. At 1 185 μΙ_ of PBS thermostatized at 37 ° C, 150 μΙ_ of a 10 mM solution of NADPH (Aldrich, N7505) in PBS and 15 μΙ_ of a 1 mM solution of the compound under study in PBS were added and the mixture was incubated for 5 min at 37 ° C. Then 150 μΙ_ of a suspension of human microsomes (Aldrich, M0567) or mouse (Aldrich, M9441) were added at a concentration of 5 mg / mL and incubated at 37 ° C during the time of interest, the final concentrations being of compound, NADPH and microsomes in the mixture of 10 μΜ, 1 mM and 0.5 mg / mL, respectively. After this, 250 μΙ_ of the mixture was added over 250 μΙ_ of cold acetonitrile, stirred and incubated for 10 min on ice to precipitate the proteins. The supernatant was separated from the precipitate by centrifugation at 10,000g for 5 min and was passed through a 0.22 μηι pore size Teflon filter (Albet Labscience). Next, 50 μΙ_ of the filtered supernatant was analyzed by HPLC-MS in a manner analogous to that described in the case of serum stability tests.
Tabla 2. Estabilidad de los compuestos de fórmula general (I) en suero y Table 2. Stability of the compounds of general formula (I) in serum and
microsomas. microsomes
Estabilidad en suero Estabilidad en microsomasStability in serum Stability in microsomes
Compuesto (t1/2, min)a (t1/2, min)a Compound (t 1/2 , min) a (t 1/2 , min) a
Humano Ratón Humano Ratón  Human Mouse Human Mouse
1 > 90 > 90 9 ± 3 16.6 ± 0.6  1> 90> 90 9 ± 3 16.6 ± 0.6
4 8 ± 3 27 ± 8 4.9 ± 0.6 6 ± 3  4 8 ± 3 27 ± 8 4.9 ± 0.6 6 ± 3
7 > 90 6 ± 3 1.3 ± 0.1 6.2 ± 0.3  7> 90 6 ± 3 1.3 ± 0.1 6.2 ± 0.3
11 > 90 21 ± 9 6 ± 3 4.0 ± 0.2  11> 90 21 ± 9 6 ± 3 4.0 ± 0.2
12 > 90 54 ± 19 5.4 ± 0.5 32 ± 4 13 > 90 1 1.70 ± 0.02 5 ± 3 NT 12> 90 54 ± 19 5.4 ± 0.5 32 ± 4 13> 90 1 1.70 ± 0.02 5 ± 3 NT
17 > 90 25 ± 7 7 ± 3 NT  17> 90 25 ± 7 7 ± 3 NT
31 > 90 > 90 1 1 ± 3 8.7 ± 0.6 a Los valores corresponden a la media ± E.E. de dos experimentos independientes realizados por duplicado. EJEMPLO 16. Determinación de la citotoxicidad de los derivados de fórmula general (I). 31>90> 90 1 1 ± 3 8.7 ± 0.6 a The values correspond to the mean ± EE of two independent experiments performed in duplicate. EXAMPLE 16. Determination of the cytotoxicity of derivatives of general formula (I).
La sensibilidad de las células MCF-7, MDA-MB-231 y PC3 a los compuestos de fórmula general (I) se determinó mediante un ensayo estándar basado en el uso del colorante bromuro de 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolio (MTT). Brevemente, el día anterior al experimento, las células se sembraron en placas de 96 pocilios con una densidad de 5 ó 10- 103/100 μί/ροοΝΙο. El día del experimento se retiró el medio y las células se incubaron durante 48 h en un medio fresco el cual contenía diferentes concentraciones de los compuestos a ensayar. Pasado este tiempo se retiró el medio, se añadió medio fresco (100 μί/ροοΝΙο) que llevaba disuelto MTT (2 mg/mL) y se incubó durante 4 h a 37 °C. Después de retirar el sobrenadante, los cristales de formazán que habían formado las células metabólicamente viables se disolvieron en DMSO (100 μί/ροοΝΙο) y se cuantificó la absorbancia a 570 nm en un lector de placas multipocillo (Modelo Anthos Labtec 2010 1.7). The sensitivity of MCF-7, MDA-MB-231 and PC3 cells to the compounds of general formula (I) was determined by a standard test based on the use of 3- (4,5-dimethylthiazol-2- bromide dye il) -2,5-diphenyltetrazolium (MTT). Briefly, the day before the experiment, cells were seeded in 96 - well plates at a density of 5 or 10- 10 March / 100 μί / ροοΝΙο. On the day of the experiment, the medium was removed and the cells were incubated for 48 h in a fresh medium which contained different concentrations of the compounds to be tested. After this time, the medium was removed, fresh medium (100 μί / ροοΝΙο) containing dissolved MTT (2 mg / mL) was added and incubated for 4 h at 37 ° C. After removing the supernatant, the formazan crystals that had formed the metabolically viable cells were dissolved in DMSO (100 μί / ροοΝΙο) and the absorbance was quantified at 570 nm in a multiwell plate reader (Anthos Labtec 2010 1.7 Model).
Tabla 3. Citotoxicidad de los compuestos de fórmula (I) Table 3. Cytotoxicity of the compounds of formula (I)
Compuest Compuest
Cl50 (MCF-7, μΜ)3 Cl50 (MDA-MB-231 , μΜ)3 Cl50 (PC3, μΜ)3 o Cl 50 (MCF-7, μΜ) 3 Cl 50 (MDA-MB-231, μΜ) 3 Cl 50 (PC3, μΜ) 3 or
4 10.5 ± 0.9 17.3 ± 0.7 22.9 ± 0.6  4 10.5 ± 0.9 17.3 ± 0.7 22.9 ± 0.6
7 26 ± 1 32 ± 1 41 ± 1  7 26 ± 1 32 ± 1 41 ± 1
33 16 ± 5 29.1 ± 0.6 29 ± 3  33 16 ± 5 29.1 ± 0.6 29 ± 3
34 15 ± 2 13.7 ± 0.1 14.4 ± 0.5 34 15 ± 2 13.7 ± 0.1 14.4 ± 0.5
35 5.9 ± 0.6 7.2 ± 0.2 8 ± 2 35 5.9 ± 0.6 7.2 ± 0.2 8 ± 2
36 19 ± 1 27.9 ± 0.5 22 ± 1 42 10.5 ± 0.1 9.7 ± 0.1 8.8 ± 0.3 a Los valores corresponden a la media ± E.E. de tres experimentos independientes realizados por duplicado. Brevemente, estos resultados ponen de manifiesto que en general los compuestos (I) que presentan mayor porcentaje de inhibición de la enzima ICMT son citotoxicos en las líneas celulares ensayadas. 36 19 ± 1 27.9 ± 0.5 22 ± 1 42 10.5 ± 0.1 9.7 ± 0.1 8.8 ± 0.3 a The values correspond to the mean ± EE of three independent experiments performed in duplicate. Briefly, these results show that in general the compounds (I) that have the highest percentage of inhibition of the ICMT enzyme are cytotoxic in the cell lines tested.

Claims

REIVINDICACIONES
1. Compuesto de fórmula (I) 1. Compound of formula (I)
Figure imgf000065_0001
Figure imgf000065_0001
(I)  (I)
o una sal farmacéuticamente aceptable del mismo, o una forma cristalina del compuesto de fórmula (I) o de cualquiera de sus sales o un estéreoisómero del, compuesto de fórmula (I) o de cualquiera de sus sales, en donde: or a pharmaceutically acceptable salt thereof, or a crystalline form of the compound of formula (I) or any of its salts or a stereoisomer of, the compound of formula (I) or any of its salts, wherein:
n es un número entero seleccionado entre 0, 1 y 2; n is an integer selected from 0, 1 and 2;
m es un número entero seleccionado entre 1 y 2; m is an integer selected from 1 to 2;
Q es un radical seleccionado entre -(CHUCHU, -(CH2)5CH3, -0(CH2)3CH3,Q is a radical selected from - (CHUCHU, - (CH 2 ) 5CH 3 , -0 (CH 2 ) 3CH 3 ,
-0(CH2)4CH3, -CH20(CH2)2CH3, -CH20(CH2)3CH3, -(CH2)2OCH2CH3, -(CH2)20(CH2)2CH3, -(CH2)3OCH3, -(CH2)3OCH2CH3, -0(CH2)2OCH2CH3,-0 (CH 2 ) 4 CH 3 , -CH 2 0 (CH 2 ) 2CH3, -CH 2 0 (CH 2 ) 3 CH 3 , - (CH 2 ) 2 OCH 2 CH 3 , - (CH 2 ) 2 0 (CH 2 ) 2 CH 3 , - (CH 2 ) 3 OCH 3 , - (CH 2 ) 3 OCH 2 CH 3 , -0 (CH 2 ) 2 OCH 2 CH 3 ,
-0(CH2)2OCH3, y -CH20(CH2)2OCH3; -0 (CH 2 ) 2 OCH 3 , and -CH 2 0 (CH 2 ) 2 OCH 3 ;
es un radical seleccionado entre -CONR3R4, -COR4, -S02R4, y -S02NR3R4; it is a radical selected from -CONR 3 R 4 , -COR 4 , -S0 2 R 4 , and -S0 2 NR 3 R 4 ;
R2 es un radical seleccionado entre -CONR5R6, -CONR5CH2R6, -COR6, -COCH2R6,R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R 6 , -COR 6 , -COCH 2 R 6 ,
-COOR6, -COOCH2R6, -S02R6, -S02CH2R6, -S02NR5R6, -CH2NR5R6, -CH2NR5CH2R6, -CH2NR5COR6 y -CH2NR5S02R6; -COOR 6 , -COOCH 2 R 6 , -S0 2 R 6 , -S0 2 CH 2 R 6 , -S0 2 NR 5 R 6 , -CH 2 NR 5 R 6 , -CH 2 NR 5 CH 2 R 6 , -CH 2 NR 5 COR 6 and -CH 2 NR 5 S0 2 R 6 ;
R3 y R5 son independientemente seleccionados entre H o un grupo alquilo(C C4), ciclilo(C3-C6), arilo(C6-Cio) o heterociclilo(C5-Ci0); R 3 and R 5 are independently selected from H or an alkyl (CC 4 ), cycloyl (C 3 -C 6 ), aryl (C 6 -Cio) or heterocyclyl (C 5 -Ci 0 ) group;
R4 y R6 son independientemente seleccionados entre un grupo ciclilo(C3-C6), arilo(C6-Cio) o heterociclilo(C5-Ci0) opcionalmente sustituidos por al menos un grupo seleccionado entre: H, alquilo(C C4), alcoxi(C C4), halógeno, CF3, OH, N02, NH2,R 4 and R 6 are independently selected from a cyclyl (C 3 -C 6 ), aryl (C 6 -Cio) or heterocyclyl (C 5 -Ci 0 ) group optionally substituted by at least one group selected from: H, alkyl ( CC 4 ), alkoxy (CC 4 ), halogen, CF 3 , OH, N0 2 , NH 2 ,
COOH, CN, alquil(CrC4)arilo(C6-C10), alquil(C C4)carbonilo, alquil(C C4)éster, alquil(CrC4)amida; COOH, CN, alkyl (CrC 4 ) aryl (C 6 -C 10 ), alkyl (CC 4 ) carbonyl, alkyl (CC 4 ) ester, alkyl (CrC 4 ) amide;
con la condición de que el compuesto no es A/1-etil-/\/2-{2-[etil(2,2,6,6- tetrametilpiperidin-4-il)amino]-2-oxoetil}-/\/2-octyl-/\/1-(2,2,6,6-tetrametilpiperidin-4- il)glicinamida. with the proviso that the compound is not A / 1 -ethyl - / \ / 2 - {2- [ethyl (2,2,6,6-tetramethylpiperidin-4-yl) amino] -2-oxoethyl} - / \ / 2 -octyl - / \ / 1 - (2,2,6,6-tetramethylpiperidin-4-yl) glycinamide.
2. Compuesto según la reivindicación 1 caracterizado porque: 2. Compound according to claim 1 characterized in that:
R2 es un radical seleccionado entre -CONR5R6, -CONR5CH2R6, -COOR6, -S02NR5R6, -CH2NR5R6 y -CH2NR5COR6. R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R6, -COOR 6 , -S0 2 NR 5 R 6 , -CH 2 NR 5 R 6 and -CH 2 NR 5 COR 6 .
3. Compuesto según cualquiera de las reivindicaciones 1-2, caracterizado porque: es un radical seleccionado entre -CONR3R4, -COR4 y -S02NR3R4. 3. Compound according to any of claims 1-2, characterized in that: it is a radical selected from -CONR 3 R 4 , -COR 4 and -S0 2 NR 3 R 4 .
4. Compuesto según la reivindicación 3, caracterizado porque: 4. Compound according to claim 3, characterized in that:
R es un radical seleccionado entre -CONR3R4, -COR4 y -S02NR3R4; R is a radical selected from -CONR 3 R 4 , -COR 4 and -S0 2 NR 3 R 4 ;
R2 es un radical seleccionado entre -CONR5R6, -CONR5CH2R6, -COOR6,R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R 6 , -COOR 6 ,
-S02NR5R6, -CH2NR5R6 y -CH2NR5COR6; -S0 2 NR 5 R 6 , -CH 2 NR 5 R 6 and -CH 2 NR 5 COR 6 ;
R4 y R6 se seleccionan independientemente uno del otro entre R 4 and R 6 are independently selected from each other among
Figure imgf000066_0001
estando cada uno de los anillos opcionalmente sustituido por al menos un grupo seleccionado entre: H, alquilo(C C4), alcoxi(C C4), halógeno, CF3, OH, N02, NH2, COOH, CN, alquil(CrC4)arilo(C6-C10), alquil(C C4)carbonilo, alquil(C C4)éster, alquil(C C4)amida.
Figure imgf000066_0001
each of the rings being optionally substituted by at least one group selected from: H, alkyl (CC 4 ), alkoxy (CC 4 ), halogen, CF 3 , OH, N0 2 , NH 2 , COOH, CN, alkyl (CrC 4 ) aryl (C 6 -C 10 ), alkyl (CC 4 ) carbonyl, alkyl (CC 4 ) ester, alkyl (CC 4 ) amide.
5. Compuesto según cualquiera de las reivindicaciones 1-4, caracterizado porque: es un radical seleccionado entre -CONR3R4 y -COR4; 5. Compound according to any of claims 1-4, characterized in that: it is a radical selected from -CONR 3 R 4 and -COR 4 ;
R2 es un radical seleccionado entre -CONR5R6, -CONR5CH2R6, -COOR6, -S02NR5R6, -CH2NR5R6 y -CH2NR5COR6; R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R 6 , -COOR 6 , -S0 2 NR 5 R 6 , -CH 2 NR 5 R 6 and -CH 2 NR 5 COR 6 ;
R4 y R6 se seleccionan independientemente uno del otro entre
Figure imgf000067_0001
estando cada uno de los anillos opcionalmente sustituido por al menos un grupo seleccionado entre: H, alquilo(CrC4), alcoxi(d-C4), halógeno, CF3, OH, N02, NH2, COOH, CN, alquil(CrC4)arilo(C6-C10), alquil(C C4)carbonilo, alquil(C C4)éster, alquil(CrC4)amida. R 4 and R 6 are independently selected from each other among
Figure imgf000067_0001
each of the rings being optionally substituted by at least one group selected from: H, alkyl (CrC 4 ), alkoxy (dC 4 ), halogen, CF 3 , OH, N0 2 , NH 2 , COOH, CN, alkyl (CrC 4 ) aryl (C 6 -C 10 ), alkyl (CC 4 ) carbonyl, alkyl (CC 4 ) ester, alkyl (CrC 4 ) amide.
6. Compuesto según cualquiera de las reivindicaciones 1-5 caracterizado porque R3 y R5 se seleccionan independientemente uno del otro entre H, -CH3, -CH2CH3, - -I3, -CH(CH3)2 o un radical 6. Compound according to any of claims 1-5 characterized in that R 3 and R 5 are independently selected from each other from H, -CH 3 , -CH 2 CH 3 , - -I 3 , -CH (CH 3 ) 2 or a radical
Figure imgf000067_0002
Figure imgf000067_0002
7. Compuesto según cualquiera de las reivindicaciones 1-6 caracterizado porque:7. Compound according to any of claims 1-6 characterized in that:
Q es un radical seleccionado entre -(CH2)4CH3, -(CH2)5CH3, -CH20(CH2)3CH3, -0(CH2)2OCH2CH3 y -CH20(CH2)2OCH3. Q is a radical selected from - (CH 2 ) 4 CH 3 , - (CH 2 ) 5 CH 3 , -CH 2 0 (CH 2 ) 3 CH 3 , -0 (CH 2 ) 2 OCH 2 CH 3 and -CH 2 0 (CH 2 ) 2 OCH 3 .
8. Compuesto según cualquiera de las reivindicaciones 1-7 caracterizado porque: R3 y R5 se seleccionan independientemente uno del otro entre H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, 3-furoilo, 2-furoilo, 3-tetrahidrofuranilo, 1 ,3-oxazol-5-ilo, 1 /-/-pirrol-3-ilo, 1 /-/-pirrol-2-ilo, 1-metil-1 /-/-pirrol-2-ilo, tien-3-ilo, 1 /-/-1 ,2,4-triazol-3-ilo, 1 /-/-imidazol-2-ilo, pirrolidin-2-ilo, piridin-2-ilo, piridin-3-ilo, piridin-4-ilo, 1 /-/-indol-2-ilo, 1-benzofuran-3-ilo, morfolin-4-ilo, fenilo, ciclohexilo y ciclopentilo; R4 y R6 se seleccionan independientemente uno del otro entre 3-furoilo, 2-furoilo, 3- tetrahidrofuranilo, 1 ,3-oxazol-5-ilo, 1 /-/-pirrol-3-ilo, 1 /-/-pirrol-2-ilo, 1-metil-1 - -pirrol-2- ilo, tien-3-ilo, 1 /-/-1 ,2,4-triazol-3-ilo, 1 /-/-imidazol-2-ilo, pirrolidin-2-ilo, piridin-2-ilo, piridin-3-ilo, piridin-4-ilo, 1 /-/-indol-2-ilo, 1-benzofuran-3-ilo, morfolin-4-ilo, fenilo, ciclohexilo y ciclopentilo; opcionalmente sustituidos por al menos un grupo seleccionado entre: H, alquilo(C C4), alcoxi(C C4), halógeno, CF3, OH, N02, NH2, COOH, CN, alquil(CrC4)arilo(C6-C10), alquil(C C4)carbonilo, alquil(C C4)éster, y alquil(CrC4)amida. 8. Compound according to any of claims 1-7 characterized in that: R 3 and R 5 are independently selected from each other from H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3) 2, 3-furoyl, 2-furoyl, 3-tetrahydrofuranyl, 1, 3-oxazol-5-yl, 1 / - / - pyrrole-3-yl, 1 / - / - pyrrol-2-yl, 1- methyl-1 / - / - pyrrol-2-yl, tien-3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2-yl, pyrrolidin-2 -yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morpholin-4-yl, phenyl, cyclohexyl and cyclopentyl; R 4 and R 6 are independently selected from each other from 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 - -pyrrol-2- yl, tien-3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2 -yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morpholin-4- yl, phenyl, cyclohexyl and cyclopentyl; optionally substituted by at least one group selected from: H, alkyl (CC 4 ), alkoxy (CC 4 ), halogen, CF 3 , OH, N0 2 , NH 2 , COOH, CN, alkyl (CrC 4 ) aryl (C 6 -C 10 ), alkyl (CC 4 ) carbonyl, alkyl (CC 4 ) ester, and alkyl (CrC 4 ) amide.
9. Compuesto según cualquiera de las reivindicaciones 1-4, caracterizado porque: Q es un radical seleccionado entre -(CH2)4CH3, -(CH2)5CH3, -CH20(CH2)3CH3, -0(CH2)2OCH2CH3 y -CH20(CH2)2OCH3; 9. Compound according to any of claims 1-4, characterized in that: Q is a radical selected from - (CH 2 ) 4 CH 3 , - (CH 2 ) 5CH 3 , -CH 2 0 (CH 2 ) 3 CH 3 , -0 (CH 2 ) 2 OCH 2 CH 3 and -CH 2 0 (CH 2 ) 2 OCH 3 ;
es un radical seleccionado entre -CONR3R4, -COR4 y -S02NR3R4; it is a radical selected from -CONR 3 R 4 , -COR 4 and -S0 2 NR 3 R 4 ;
R2 es un radical seleccionado entre -CONR5R6, -CONR5CH2R6, -COOR6, -S02NR5R6, -CH2NR5R6 y -CH2NR5COR6; R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R 6 , -COOR 6 , -S0 2 NR 5 R 6 , -CH 2 NR 5 R 6 and -CH 2 NR 5 COR 6 ;
R3 y R5 se seleccionan independientemente uno del otro entre H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, 3-furoilo, 2-furoilo, 3-tetrahidrofuranilo, 1 ,3-oxazol-5-ilo, 1 /-/-pirrol-3-ilo, 1 /-/-pirrol-2-ilo, 1-metil-1 /-/-pirrol-2-ilo, tien-3-ilo, 1 /-/-1 ,2,4-triazol-3-ilo, 1 /-/-imidazol-2-ilo, pirrolidin-2-ilo, piridin-2-ilo, piridin-3-ilo, piridin-4-ilo, 1 /-/-indol-2-ilo, 1-benzofuran-3-ilo, morfolin-4-ilo, fenilo, ciclohexilo y ciclopentilo; R 3 and R 5 are independently selected from each other from H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 / - / - pyrrole-2-yl, thien -3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2-yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl , pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morpholin-4-yl, phenyl, cyclohexyl and cyclopentyl;
R4 y R6 se seleccionan independientemente uno del otro entre 3-furoilo, 2-furoilo, 3- tetrahidrofuranilo, 1 ,3-oxazol-5-ilo, 1 /-/-pirrol-3-ilo, 1 /-/-pirrol-2-ilo, 1-metil-1 - -pirrol-2- ilo, tien-3-ilo, 1 /-/-1 ,2,4-triazol-3-ilo, 1 /-/-imidazol-2-ilo, pirrolidin-2-ilo, piridin-2-ilo, piridin-3-ilo, piridin-4-ilo, 1 /-/-indol-2-ilo, 1-benzofuran-3-ilo, morfolin-4-ilo, fenilo, ciclohexilo y ciclopentilo; opcionalmente sustituidos por al menos un grupo seleccionado entre: H, alquilo(C C4), alcoxi(C C4), halógeno, CF3, OH, N02, NH2, COOH, CN, alquil(CrC4)arilo(C6-C10), alquil(C C4)carbonilo, alquil(C C4)éster, alquil(CrC4)amida; R 4 and R 6 are independently selected from each other from 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 - -pyrrol-2- yl, tien-3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2 -yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morpholin-4- yl, phenyl, cyclohexyl and cyclopentyl; optionally substituted by at least one group selected from: H, alkyl (CC 4 ), alkoxy (CC 4 ), halogen, CF 3 , OH, N0 2 , NH 2 , COOH, CN, alkyl (CrC 4 ) aryl (C 6 -C 10 ), alkyl (CC 4 ) carbonyl, alkyl (CC 4 ) ester, alkyl (CrC 4 ) amide;
n es un número entero seleccionado entre 0, 1 y 2; n is an integer selected from 0, 1 and 2;
m es un número entero seleccionado entre 1 y 2. m is an integer selected between 1 and 2.
10. Compuesto según cualquiera de las reivindicaciones 1-9, caracterizado porque: Q es un radical seleccionado entre -(CH2)4CH3, -(CH2)5CH3, -CH20(CH2)3CH3, y -CH20(CH2)2OCH3; es un radical seleccionado entre -CONR3R4 y -COR4; 10. Compound according to any of claims 1-9, characterized in that: Q is a radical selected from - (CH 2 ) 4 CH 3 , - (CH 2 ) 5 CH 3 , -CH 2 0 (CH 2 ) 3 CH 3 , and -CH 2 0 (CH 2 ) 2 OCH 3 ; it is a radical selected from -CONR 3 R 4 and -COR 4 ;
R2 es un radical seleccionado entre -CONR5R6, -CONR5CH2R6, -COOR6, -CH2NR5R6 y -CH2NR5COR6; R 2 is a radical selected from -CONR 5 R 6 , -CONR 5 CH 2 R6, -COOR 6 , -CH 2 NR 5 R 6 and -CH 2 NR 5 COR 6 ;
R3 y R5 se seleccionan independientemente uno del otro entre H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, 3-furoilo, 2-furoilo, 3-tetrahidrofuranilo, 1 ,3-oxazol-5-ilo, 1 /-/-pirrol-3-ilo, 1 /-/-pirrol-2-ilo, 1-metil-1 /-/-pirrol-2-ilo, tien-3-ilo, 1 /-/-1 ,2,4-triazol-3-ilo, 1 /-/-imidazol-2-ilo, pirrolidin-2-ilo, piridin-2-ilo, piridin-3-ilo, piridin-4-ilo, 1 /-/-indol-2-ilo, 1-benzofuran-3-ilo, morfolin-4-ilo, fenilo y ciclopentilo; R 3 and R 5 are independently selected from each other from H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 / - / - pyrrole-2-yl, thien -3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2-yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl , pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morpholin-4-yl, phenyl and cyclopentyl;
R4 y R6 se seleccionan independientemente uno del otro entre 3-furoilo, 2-furoilo, 3- tetrahidrofuranilo, 1 ,3-oxazol-5-ilo, 1 /-/-pirrol-3-ilo, 1 /-/-pirrol-2-ilo, 1-metil-1 - -pirrol-2- ilo, tien-3-ilo, 1 /-/-1 ,2,4-triazol-3-ilo, 1 /-/-imidazol-2-ilo, pirrolidin-2-ilo, piridin-2-ilo, piridin-3-ilo, piridin-4-ilo, 1 /-/-indol-2-ilo, 1-benzofuran-3-ilo, morfolin-4-ilo, fenilo y ciclopentilo; opcionalmente sustituidos por al menos un grupo seleccionado entre: H, alquilo(C C4), alcoxi(C C4), halógeno, CF3, OH, N02, NH2, COOH, CN, alquil(CrC4)arilo(C6-Cio), alquil(C C4)carbonilo, alquil(CrC4)éster, alquil(CrC4)amida; R 4 and R 6 are independently selected from each other from 3-furoyl, 2-furoyl, 3- tetrahydrofuranyl, 1,3-oxazol-5-yl, 1 / - / - pyrrol-3-yl, 1 / - / - pyrrol-2-yl, 1-methyl-1 - -pyrrol-2- yl, tien-3-yl, 1 / - / - 1, 2,4-triazol-3-yl, 1 / - / - imidazol-2 -yl, pyrrolidin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1 / - / - indole-2-yl, 1-benzofuran-3-yl, morpholin-4- yl, phenyl and cyclopentyl; optionally substituted by at least one group selected from: H, alkyl (CC 4 ), alkoxy (CC 4 ), halogen, CF 3 , OH, N0 2 , NH 2 , COOH, CN, alkyl (CrC 4 ) aryl (C 6 -Cio), alkyl (CC 4 ) carbonyl, alkyl (CrC 4 ) ester, alkyl (CrC 4 ) amide;
n es 0; n is 0;
m es un número entero seleccionado entre 1 y 2. m is an integer selected between 1 and 2.
1 1. Compuesto según la reivindicación 1 , caracterizado porque se selecciona entre Λ/3-(2-anilino-2-oxoetil)-Λ/1-fenil-Λ/3-octil-β-alaninamida; Compound according to claim 1, characterized in that it is selected from Λ / 3 - (2-anilino-2-oxoethyl) -Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide;
Λ/1-fenil-Λ/3-(3-morfolin-4-il-3-oxopropil)-Λ/3-octil-β-alaninamida; Λ / 1 -phenyl-Λ / 3 - (3-morpholin-4-yl-3-oxopropyl) -Λ / 3- octyl-β-alaninamide;
A/2-(2-anilino-2-oxoetil)-/\/1-fenil-/\/2-octilglicinamida; A / 2 - (2-anilino-2-oxoethyl) - / \ / 1 -phenyl - / \ / 2 -octylglycinamide;
Λ/3-(3-anilino-3-oxopropil)-Λ/1-fenil-Λ/3-octil-β-alaninamida; Λ / 3 - (3-anilino-3-oxopropyl) -Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide;
Λ/3-(3-anilino-3-oxopropil)-Λ/1-fenil-Λ/3-(3-butoxipropil)-β-alaninamida; Λ / 3 - (3-anilino-3-oxopropyl) -Λ / 1 -phenyl-Λ / 3 - (3-butoxypropyl) -β-alaninamide;
Λ/3-(3-anilino-3-oxopropil)-Λ/1-fenil-Λ/3-[3-(2-metoxietoxi)propil]-β-alaninamida; Λ / 3 - (3-anilino-3-oxopropyl) -Λ / 1 -phenyl-Λ / 3 - [3- (2-methoxyethoxy) propyl] -β-alaninamide;
Λ/1-fenil-Λ/3-3-furoil-Λ/3-octil-β-alaninamida; Λ / 1 -phenyl-Λ / 3 -3-furoyl-Λ / 3 -octyl-β-alaninamide;
Λ/1-fenil-Λ/3-2-furoil-Λ/3-octil-β-alaninamida; Λ / 1 -phenyl-Λ / 3 -2-furoyl-Λ / 3 -octyl-β-alaninamide;
Λ/1-fenil-Λ/3-octil-Λ/3-(tetrahidrofuran-3-ilcarbonil)-β-alaninamida; Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (tetrahydrofuran-3-ylcarbonyl) -β-alaninamide;
A/1-fenil-/V3-octil-/V3-(1 ,3-oxazol-5-ilcarbonil)-β-alaninamida; A / 1 -phenyl- / V 3 -octyl- / V 3 - (1,3-oxazol-5-ylcarbonyl) -β-alaninamide;
Λ/1-fenil-Λ/3-octil-Λ/3-(1 /-/-pirrol-3-ilcarbonil)-β-alaninamida; Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (1 / - / - pyrrol-3-ylcarbonyl) -β-alaninamide;
Λ/1-fenil-Λ/3-octil-Λ/3-(1 /-/-pirrol-2-ilcarbonil)-β-alaninamida; Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (1 / - / - pyrrol-2-ylcarbonyl) -β-alaninamide;
Λ/1-fenil-Λ/3-[(1-metil-1 /-/-pirrol-2-il)carbonil]-Λ/3-octil-β-alaninamida; Λ / 1 -phenyl-Λ / 3 - [(1-methyl-1 / - / - pyrrol-2-yl) carbonyl] -Λ / 3- octyl-β-alaninamide;
Λ/1-fenil-Λ/3-octil-Λ/3-(tien-3-ilcarbonil)-β-alaninamida; Λ/1-ί8ηίΙ-Λ/3-οοΐίΙ-Λ/3-(1 Η-1 ,2,4-ΐΠ3ζοΙ-3-ίΙθ3Γ οηίΙ)-β-3ΐ3ηίη3ΓΤΐί(-ΐ3; Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (tien-3-ylcarbonyl) -β-alaninamide; Λ / 1 -ί8ηίΙ-Λ / 3 -οοΐίΙ-Λ / 3 - (1 Η-1, 2,4-ΐΠ3ζοΙ-3-ίΙθ3Γ οηίΙ) -β-3ΐ3ηίη3ΓΤΐί ( -ΐ3;
A/1-fenil-A/3-(1 H-imidazol-2-ilcarbonil)-/\/3-octil^-alaninarTiida; A / 1 -phenyl-A / 3 - (1 H-imidazol-2-ylcarbonyl) - / \ / 3 -octyl ^ -alaninate Thiide;
Λ/1-fenil-Λ/3-octil-Λ/3-(pirrolidin-2-ilcarbonil)-β-alaninamida; Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (pyrrolidin-2-ylcarbonyl) -β-alaninamide;
Λ/1-fenil-Λ/3-octil-Λ/3-(piridin-2-ilcarbonil)-β-alaninamida; Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (pyridin-2-ylcarbonyl) -β-alaninamide;
Λ/1-fenil-Λ/3-octil-Λ/3-(piridin-3-ilcarbonil)-β-alaninamida; Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (pyridin-3-ylcarbonyl) -β-alaninamide;
Λ/1-fenil-Λ/3-octil-Λ/3-(piridin-4-ilcarbonil)-β-alaninamida; Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (pyridin-4-ylcarbonyl) -β-alaninamide;
Λ/1-fenil-Λ/3-(1 /-/-indol-2-ilcarbonil)-Λ/3-octil-β-alaninamida; Λ / 1 -phenyl-Λ / 3 - (1 / - / - indole-2-ylcarbonyl) -Λ / 3- octyl-β-alaninamide;
Λ/3-(1 -benzofuran-3-ilcarbonil)-Λ/1-fenil-Λ/3-octil-β-alaninamida; Λ / 3 - (1-benzofuran-3-ylcarbonyl) -Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide;
Λ/3-benzoil-Λ/1-fenil-Λ/3-octil-β-alaninamida; Λ / 3 -benzoyl-Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide;
Λ/3-(ciclopentilcarbonil)-Λ/1-fenil-Λ/3-octil-β-alaninamida; Λ / 3 - (cyclopentylcarbonyl) -Λ / 1 -phenyl-Λ / 3- octyl-β-alaninamide;
A/-(3-anilinopropil)-A/-octil-3-furamida;  A / - (3-anilinopropyl) -A / -octyl-3-furamide;
A/-3-furoil-/\/-octil-p-alaninato de fenilo;  A / -3-furoyl - / \ / - octyl-p-phenyl alaninate;
A/-3-furoil-/\/-heptil-p-alaninato de fenilo;  A / -3-furoyl - / \ / - phenyl-phenyl-p-alaninate;
A/-octil-/\/-(1 /-/-pirrol-2-ilcarbonil)-p-alaninato de fenilo;  A / -octyl - / \ / - (1 / - / - pyrrol-2-ylcarbonyl) -p-phenyl alaninate;
Λ/-(1 H-imidazol-2-ilcarbonil)-A/-octil- -alaninato de fenilo; Λ / - (1 H-imidazol-2-ylcarbonyl) -A / -octyl- -phenyl alaninate;
A/-octil-/\/-(1 ,3-oxazol-5-ilcarbonil)- -alaninato de fenilo;  A / -octyl - / \ / - (1,3-oxazol-5-ylcarbonyl) -phenyl alaninate;
A/-fenil-/\/-{3-[3-furoil(octil)amino]propil}-3-furamida,  A / -phenyl - / \ / - {3- [3-furoyl (octyl) amino] propyl} -3-furamide,
A/1-fenil-/\/3-[3-(4-metilpiperazin-1-il)-3-oxopropil]-/\/3-octil- -alaninamida;A / 1 -phenyl - / \ / 3 - [3- (4-methylpiperazin-1-yl) -3-oxopropyl] - / \ / 3 -octyl- -alaninamide;
A/3-[3-(ciclohexilamino)-3-oxopropil]-/\/1-fenil-/\/3-octil- -alaninamida; A/1-fenil-A/3-{3-[(4-fluorofenil)amino]-3-oxopropil}-/\/3-octil- -alaninarTiida;A / 3 - [3- (cyclohexylamino) -3-oxopropyl] - / \ / 1 -phenyl - / \ / 3 -octyl- -alaninamide; A / 1 -phenyl-A / 3 - {3 - [(4-fluorophenyl) amino] -3-oxopropyl} - / \ / 3 -octyl--alanine Thiide;
A/1-fenil-A/3-{3-[metil(fenil)amino]-3-oxopropil}-/\/3-octil- -alaninarTiida;A / 1 -phenyl-A / 3 - {3- [methyl (phenyl) amino] -3-oxopropyl} - / \ / 3 -octyl--alanine Thiide;
A/1-fenil-/\/3-octil-/\/3-[3-oxo-3-(piridin-2-ilarTiino)propil]- -alaninarTiida;A / 1 -phenyl - / \ / 3 -octyl - / \ / 3 - [3-oxo-3- (pyridin-2-ylthiino) propyl] - -alaninate Thiide;
A/1-fenil-/\/3-octil-/\/3-[3-oxo-3-(piridin-3-ilarTiino)propil]- -alaninarTiida;A / 1 -phenyl - / \ / 3 -octyl - / \ / 3 - [3-oxo-3- (pyridin-3-ylthiino) propyl] - -alaninate Thiide;
A/1-fenil-/\/3-[3-(metilamino)-3-oxopropil]-/\/3-octil- -alaninamida; A / 1 -phenyl - / \ / 3 - [3- (methylamino) -3-oxopropyl] - / \ / 3 -octyl- -alaninamide;
A/3-[3-(etilamino)-3-oxopropil]-/\/1-fenil-/\/3-octil- -alaninamida; A / 3 - [3- (ethylamino) -3-oxopropyl] - / \ / 1 -phenyl - / \ / 3 -octyl- -alaninamide;
A/1-fenil-/\/3-[3-(isopropilamino)-3-oxopropil]-/\/3-octil- -alaninamida; A / 1 -phenyl - / \ / 3 - [3- (isopropylamino) -3-oxopropyl] - / \ / 3 -octyl- -alaninamide;
A/3-(3-anilino-3-oxopropil)-/\/3-[2-(2-etoxietoxi)etil]-/\/1-fenil- -alaninamida; 2-{[(anilinosulfonil)etil](octil)amino}-/\/-feniletanosulfonamida; A / 3 - (3-anilino-3-oxopropyl) - / \ / 3 - [2- (2-ethoxyethoxy) ethyl] - / \ / 1 -phenyl- -alaninamide; 2 - {[(anilinosulfonyl) ethyl] (octyl) amino} - / \ / - phenylethanesulfonamide;
A/3-[2-(anilinosulfonil)ethyl]-/\/1-fenil-/\/3-octil- -alaninamida; A / 3 - [2- (anilinosulfonyl) ethyl] - / \ / 1 -phenyl - / \ / 3 -octyl- -alaninamide;
A/1-fenil-A/3-(2-{[metil(fenil)amino]sulfonil}etil)-/\/3-octil- -alaninarTiida;A / 1 -phenyl-A / 3 - (2 - {[methyl (phenyl) amino] sulfonyl} ethyl) - / \ / 3 -octyl--alanine Thiide;
A/3-[2-(anilinosulfonil)etil]-/\/3-(3-butoxipropil)-/\/1-fenil- -alaninamida; A/3-(3-butoxipropil)-/\/1-fenil-/\/3-3-furoil- -alaninamida; A / 3 - [2- (anilinosulfonyl) ethyl] - / \ / 3 - (3-butoxypropyl) - / \ / 1 -phenyl- -alaninamide; A / 3 - (3-butoxypropyl) - / \ / 1 -phenyl - / \ / 3 -3-furoyl--alaninamide;
A/1-fenil-/\/3-3-furoil-/\/3-[3-(2-metoxietoxi)propil]- -alaninamida; A / 1 -phenyl - / \ / 3 -3-furoyl - / \ / 3 - [3- (2-methoxyethoxy) propyl] - -alaninamide;
A/3-[2-(2-etoxietoxi)etil]-/\/1-fenil-/\/3-3-furoil- -alaninamida; y /\/-[3-(3-furoilamino)propil]-/\/-octil-3-furamida. A / 3 - [2- (2-ethoxyethoxy) ethyl] - / \ / 1 -phenyl - / \ / 3 -3-furoyl- -alaninamide; Y / \ / - [3- (3-Furoylamino) propyl] - / \ / - octyl-3-furamide.
12. Compuesto según la reivindicación 1 , caracterizado porque se selecciona entre:12. Compound according to claim 1, characterized in that it is selected from:
Λ/3-(2-anilino-2-oxoetil)-Λ/1-fenil-Λ/3-octil-β-alaninamida (1); Λ / 3 - (2-anilino-2-oxoethyl) -Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide (1);
A/2-(2-anilino-2-oxoetil)-/\/1-fenil-/\/2-octilglicinamida (3); A / 2 - (2-anilino-2-oxoethyl) - / \ / 1 -phenyl - / \ / 2 -octylglycinamide (3);
Λ/3-(3-anilino-3-oxopropil)-Λ/1-fenil-Λ/3-octil-β-alaninamida (4); Λ / 3 - (3-anilino-3-oxopropyl) -Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide (4);
Λ/1-fenil-Λ/3-3-furoil-Λ/3-octil-β-alaninamida (7); Λ / 1 -phenyl-Λ / 3 -3-furoyl-Λ / 3 -octyl-β-alaninamide (7);
A/1-fenil-/V3-octil-/V3-(1 ,3-oxazol-5-ilcarbonil)^-alaninamida (10); A / 1 -phenyl- / V 3 -octyl- / V 3 - (1,3-oxazol-5-ylcarbonyl) ^ -alaninamide (10);
Λ/1-fenil-Λ/3-octil-Λ/3-(1 /-/-pirrol-3-ilcarbonil)-β-alaninamida (1 1); Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (1 / - / - pyrrol-3-ylcarbonyl) -β-alaninamide (1 1);
Λ/1-fenil-Λ/3-octil-Λ/3-(1 /-/-pirrol-2-ilcarbonil)-β-alaninamida (12); Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (1 / - / - pyrrol-2-ylcarbonyl) -β-alaninamide (12);
Λ/1-fenil-Λ/3-[(1-metil-1 /-/-pirrol-2-il)carbonil]-Λ/3-octil-β-alaninamida (13); Λ / 1 -phenyl-Λ / 3 - [(1-methyl-1 / - / - pyrrol-2-yl) carbonyl] -Λ / 3- octyl-β-alaninamide (13);
Λ/1-fenil-Λ/3-octil-Λ/3-(pirrolidin-2-ilcarbonil)-β-alaninamida (17); Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (pyrrolidin-2-ylcarbonyl) -β-alaninamide (17);
Λ/1-fenil-Λ/3-octil-Λ/3-(piridin-2-ilcarbonil)-β-alaninamida (18); Λ / 1 -phenyl-Λ / 3 -octyl-Λ / 3 - (pyridin-2-ylcarbonyl) -β-alaninamide (18);
A/3-benzoil-A/1-fenil-A/3-octil^-alaninamida (23); A / 3 -benzoyl-A / 1 -phenyl-A / 3 -octyl ^ -alaninamide (23);
Λ/3-(ciclopentilcarbonil)-Λ/1-fenil-Λ/3-octil-β-alaninamida (24); Λ / 3 - (cyclopentylcarbonyl) -Λ / 1 -phenyl-Λ / 3 -octyl-β-alaninamide (24);
A/-(3-anilinopropil)-A/-octil-3-furamida (25);  A / - (3-anilinopropyl) -A / -octyl-3-furamide (25);
A/-3-furoil-/\/-octil-p-alaninato de fenilo (26);  A / -3-furoyl - / \ / - octyl-p-phenyl alaninate (26);
A/-3-furoil-/V-heptil-p-alaninato de fenilo (27);  A / -3-furoyl- / V-heptyl-p-phenyl alaninate (27);
A/-octil-/\/-(1 ,3-oxazol-5-ilcarbonil)-p-alaninato de fenilo (30);  A / -octyl - / \ / - (1,3-oxazol-5-ylcarbonyl) -p-phenyl alaninate (30);
A/-fenil-/\/-{3-[3-furoil(octil)amino]propil}-3-furamida (31); A / -phenyl - / \ / - {3- [3-furoyl (octyl) amino] propyl} -3-furamide (31);
A/3-[3-(ciclohexilamino)-3-oxopropil]-/\/1-fenil-/\/3-octil- -alaninamida (33); A / 3 - [3- (cyclohexylamino) -3-oxopropyl] - / \ / 1 -phenyl - / \ / 3 -octyl- -alaninamide (33);
A/1-fenil-/\/3-{3-[(4-fluorofenil)amino]-3-oxopropil}-/\/3-octil- -alaninamida (34); A / 1 -phenyl - / \ / 3 - {3 - [(4-fluorophenyl) amino] -3-oxopropyl} - / \ / 3 -octyl- -alaninamide (34);
2-{[(anilinosulfonil)etil](octil)amino}-/V-feniletanosulfonamida (42).  2 - {[(anilinosulfonyl) ethyl] (octyl) amino} - / V-phenylethanesulfonamide (42).
13. Composición farmacéutica que comprende una cantidad terapéuticamente efectiva de al menos un compuesto de fórmula (I), según se ha definido en las reivindicaciones anteriores 1-12, y al menos un vehículo o adyuvante farmacéuticamente aceptable. 13. Pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I), as defined in the preceding claims 1-12, and at least one pharmaceutically acceptable carrier or adjuvant.
14. Compuesto de fórmula (I), según se ha definido en cualquiera de las reivindicaciones anteriores 1 -12 para su uso como medicamento. 14. Compound of formula (I), as defined in any of the preceding claims 1-12 for use as a medicament.
15. Uso de un compuesto de fórmula (I), según se ha definido en cualquiera de las reivindicaciones anteriores 1-12 para la preparación de un medicamento para la prevención y/o el tratamiento de una patología mediada por la enzima ICMT que se selecciona entre cáncer y trastornos celulares proliferativos. 15. Use of a compound of formula (I), as defined in any of the preceding claims 1-12 for the preparation of a medicament for prevention and / or treatment of a pathology mediated by the ICMT enzyme that is selected from cancer and proliferative cell disorders.
16. Uso según la reivindicación 15 para la preparación de un medicamento para la prevención y/o tratamiento del cáncer o trastornos celulares proliferativos. 16. Use according to claim 15 for the preparation of a medicament for the prevention and / or treatment of cancer or proliferative cell disorders.
17. Uso de un compuesto de fórmula (I), según se ha definido en cualquiera de las reivindicaciones anteriores 1-12 para la preparación de un medicamento para su uso en el tratamiento o prevención de cáncer o trastornos celulares proliferativos en un paciente cuando dicho medicamento se administra en terapia simultánea, secuencial o combinada con un régimen de radioterapia o quimioterapia con uno o más agentes quimioterapéuticos. 17. Use of a compound of formula (I), as defined in any of the preceding claims 1-12 for the preparation of a medicament for use in the treatment or prevention of cancer or proliferative cell disorders in a patient when said The drug is administered in simultaneous, sequential or combined therapy with a radiotherapy or chemotherapy regimen with one or more chemotherapeutic agents.
18. Un producto o kit que comprende un compuesto de fórmula (I), según se ha definido en cualquiera de las reivindicaciones anteriores 1-12, o composiciones farmacéuticas de los mismos como se define en la reivindicación 13 y uno o más agentes quimioterapéuticos, como una preparación combinada para el uso en terapia simultánea, individual o secuencial contra el cáncer o trastornos celulares proliferativos. 18. A product or kit comprising a compound of formula (I), as defined in any of the preceding claims 1-12, or pharmaceutical compositions thereof as defined in claim 13 and one or more chemotherapeutic agents, as a combined preparation for use in simultaneous, individual or sequential therapy against cancer or proliferative cell disorders.
19. Procedimiento de preparación de los compuestos de fórmula (la), (Ib) y (le) que comprende: 19. Method of preparing the compounds of formula (la), (Ib) and (le) comprising:
a) alquilación de las aminas de fórmula (II) con bromoalquilamidas (III) y (V) o con acrilamidas (VI);  a) alkylation of the amines of formula (II) with bromoalkylamides (III) and (V) or with acrylamides (VI);
b) aislar el compuesto de fórmula (la), (Ib) o (le) obtenido. b) isolate the compound of formula (la), (Ib) or (le) obtained.
Figure imgf000073_0001
Figure imgf000073_0001
20. Procedimiento de preparación de los compuestos de fórmula (Id) y (le) que comprende: 20. Method of preparing the compounds of formula (Id) and (le) comprising:
a) alquilaciones sucesivas de las aminas de fórmula (II) con dos etilensulfonamidas (VII) diferentes, en el caso de los derivados (Id), o con la misma etilensulfonamida en exceso para obtener las sulfonamidas simétricas (le);  a) successive alkylations of the amines of formula (II) with two different ethylene sulfonamides (VII), in the case of derivatives (Id), or with the same excess ethylene sulfonamide to obtain symmetric sulfonamides (le);
b) aislar el compuesto de fórmula (Id) o (le) obtenido.  b) isolate the compound of formula (Id) or (le) obtained.
H2N^Q R, S.N, R4 H 2 N ^ QR, S. N , R 4
Π2 HN 6^ Π2 HN 6 ^
N N
O O 1 1O O 1 1
R3 R6^ s^ Rfi RaR 3 R 6 ^ s ^ R fi Ra
Q QQ Q
O O 1 O O 1
R. R3 ^5 (Id) R. R 3 ^ 5 (Id)
(Vi l) (VI I)  (Vi l) (VI I)
R3 R 3
(VII)
Figure imgf000073_0002
(VII)
Figure imgf000073_0002
21. Procedimiento de preparación de los compuestos de fórmula (If) y (Ig) que comprende: a) alquilación de las aminas de fórmula (II) con los bromoésteres (IX), seguido de condensación con los ácidos carboxílicos (XI), hidrólisis de los ésteres obtenidos y tratamiento de los ácidos carboxílicos libres con los alcoholes o aminas (XIV) o (XV); 21. Method of preparing the compounds of formula (If) and (Ig) comprising: a) alkylation of the amines of formula (II) with the bromoesters (IX), followed by condensation with the carboxylic acids (XI), hydrolysis of the esters obtained and treatment of the free carboxylic acids with the alcohols or amines (XIV) or (XV);
b) aislar el compuesto de fórmula (If) o (Ig) obtenido.  b) isolate the compound of formula (If) or (Ig) obtained.
Figure imgf000074_0001
Figure imgf000074_0001
(If): X=0, NR5 (XIV) (Xlll) (If): X = 0, NR 5 (XIV) (Xlll)
R6CH2OH o R 6 CH 2 OH or
(XV) (d)
Figure imgf000074_0002
(XV) (d)
Figure imgf000074_0002
(Ig): X=0, NR5 (Ig): X = 0, NR 5
22. Procedimiento alternativo de preparación de los compuestos de fórmula (If) y (Ig), así como de los compuestos de fórmula (Ih) y (li) que comprende: 22. Alternative method of preparation of the compounds of formula (If) and (Ig), as well as of the compounds of formula (Ih) and (li) comprising:
a) condensación de las aminoamidas previamente obtenidas de fórmula (IV) con los ácidos carboxílicos (XI), en el caso de los derivados (If), o la reducción de dichas aminoamidas, seguido de la alquilación con los derivados halogenados (III), para obtener los compuestos de fórmula (Ig), o el acoplamiento con los ácidos (XI) o con los cloruros de sulfonilo (XVII), en el caso de las amidas (Ih) o las sulfonamidas (li), respectivamente;  a) condensation of previously obtained aminoamides of formula (IV) with carboxylic acids (XI), in the case of derivatives (If), or reduction of said aminoamides, followed by alkylation with halogenated derivatives (III), to obtain the compounds of formula (Ig), or coupling with acids (XI) or with sulphonyl chlorides (XVII), in the case of amides (Ih) or sulfonamides (li), respectively;
b) aislar el compuesto de fórmula (If), (Ig), (Ih) o (li) obtenido.
Figure imgf000075_0001
b) isolate the compound of formula (If), (Ig), (Ih) or (li) obtained.
Figure imgf000075_0001
23. Procedimiento de preparación de los compuestos de fórmula (Ij) que comprende: 23. Method of preparing the compounds of formula (Ij) comprising:
a) acilaciones sucesivas de las diaminas (XVI-a) con dos ácidos carboxílicos (XI) diferentes o doble acilación con el mismo ácido en exceso;  a) successive acylations of the diamines (XVI-a) with two different carboxylic acids (XI) or double acylation with the same excess acid;
b) aislar el compuesto de fórmula (Ij) obtenido.  b) isolate the compound of formula (Ij) obtained.
Figure imgf000075_0002
Figure imgf000075_0002
24. Procedimiento de preparación de los compuestos de fórmula (Ik) que comprende: 24. Method of preparing the compounds of formula (Ik) comprising:
a) alquilación de las aminas (IV) con vinilsulfonamidas (VII); el compuesto de fórmula (Ik) obtenido. a) alkylation of the amines (IV) with vinylsulfonamides (VII); the compound of formula (Ik) obtained.
Figure imgf000076_0001
Figure imgf000076_0001
PCT/ES2014/070071 2013-02-04 2014-02-03 Novel inhibitors of the enzyme isoprenylcysteine carboxyl methyltransferase (icmt) WO2014118418A1 (en)

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