Patent Application
20170183306
The present invention concerns cyclic compounds having a 1,3 diamino-functionality, capable of reactivating HIV expression, for use in the treatment of HIV infection.
At the end of 2011, an estimated 34 million people were living with Human Immunodeficiency Virus (HIV) and approximately 1.7 million people died of acquired immunodeficiency syndrome (AIDS).
HIV is an RNA-retrovirus replicating through a DNA intermediate that is integrated into the host cell's DNA. HIV infects and kills the cells of the immune system, including CD4+ T cells and macrophages, which are critical for mounting effective immune response against invading pathogens.
Once the viral DNA is integrated in the cell's chromosomes, HIV replicates directly into proteins or into RNA and infects new cells.
While significant progresses have been made in the treatment of the infection by HIV, in particular in the field of antiretroviral therapies, current treatments are not curative and must be taken by HIV-infected patients for the rest of their life in order to prevent progression of the infection to AIDS. Highly active antiretroviral therapies (HAART) have been developed in recent years. These HAART consist of drugs acting at different levels of the life cycle of HIV, inhibiting virus entry, reverse transcription, integration and/or maturation. These HAART are capable of eliminating the circulating viruses, with a viral load below the detection limits of modem assays (i.e. 50 copies of virion RNA/mL of plasma).
Yet, when the HAART is stopped, plasma viral load increases again. This rebound has been attributed to HIV reservoirs in which the pro-virus is present in a non-expressing state. The best understood reservoirs of HIV are CD4+ T cells: the cells exist in a resting state in which HIV-RNA and HIV-proteins are not expressed or expressed at very low level. As a consequence, these cells are not recognized by the immune system and form a reservoir of HIV, which, upon activation of these cells results in the proliferation of the virus and infection of other cells.
One of the approaches for eradicating these HIV reservoir cells is called the “activation/elimination” approach. The aim of this approach is to induce expression of viral HIV proteins inside the latent cells. The cells may then be killed by the damaging effects of virus production (viral cytopathic effect), apoptosis, or may be recognized by the immune system or therapeutic agents directed towards viral proteins.
One approach that has been developed consists in the stimulation of T-cells with interleukin-2 (IL-2). This approach however led to a rebound of viral load when the HAART was stopped. IL-2 in conjunction with an anti-CD3 monoclonal antibody resulted in toxic side effects.
Clinical trials are currently on-going to establish the safety and efficacy of compounds used to date as anticancer drugs, such as vorinostat (Zolinza®, Merck), LBH589 (Panibinostat®, Novartis) and Romidepsin. The first results indicate that these molecules result in important adverse effects.
Drugs intended for treating alcohol dependency have also been investigated (Disulfirame, Esperal® Sanofi-Aventis), but these compounds, studied in clinical trial, show low capacity to induce HIV replication.
Other preclinical trials are also on-going with NF-KB activators such as prostatin and bryostatin analogs, but the in-vivo safety and efficacy of these compounds has not been established to date.
To date, none of these drug classes has obtained its market authorization and there is therefore a need for new drugs capable of inducing HIV expression in latently infected reservoir cells.
Cyclic compounds having a 1,3 diamino-functionality are known from prior art. The 3,5-diamino-piperidyl scaffold has been shown to possess antiviral activity. These compounds target a structured RNA of the Hepatitis C Virus (HCV) that is essential for the initiation of viral protein synthesis, and inhibit virus replication. These compounds have also been described as antibacterial and antifungal agents. 1,3 diamino-cyclopentanes have also been described as antibacterial agents.
These cyclic 3,5 diamino-piperidines and 1,3 diamino-cyclopentanes share the property of being inhibitors of viral, bacterial and/or fungal proliferation, thereby reducing the load of pathogenic agents.
In a totally surprising and unexpected manner, the inventors of the present invention have discovered that cyclic compounds having a 1,3-diamino functionality act as promoters of HIV replication.
The unexpected potency of these compounds to induce the reactivation of HIV expression is particularly useful for the treatment of HIV infection, as it enables eradicating the reservoirs.
The present invention therefore concerns a compound of formula (I), a pharmaceutically acceptable salt, solvate or hydrate thereof, enantiomers, mixture of enantiomers, diastereoisomers and mixture of diasteroisomers thereof for use in the treatment of HIV infection of the following formula (I):
n is 0 or 1,
Y is OR3; NR4R5, or R6,
R1 and R′1 are H, or R1 and R2 and/or R′1 and R′2 form together a (C3-C8)heterocyclyl,
R2 and R′2 are independently one from the other H, (C1-C6)alkyl, aryl, heteroaryl, (C3-C8)heterocyclyl, (C3-C8)carbocyclyl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-heteroaryl, C(O)-Q, or SO2—Z,
Advantageously, NR1R2 and NR′1R′2 are in cis configuration.
Advantageously, R2 and R′2 are H, C(O)-Q, SO2—Z as defined above, or R1 and R2 and R′1 and R′2 form together a (C3-C8)heterocyclyl. Advantageously, Q is H, (C1-C6)alkyl, such as methyl, (C1-C6)alkyl-aryl, such as benzyl, or ORc, where Rc is as defined above and is advantageously (C1-C6)alkyl or (C1-C6)alkyl-aryl. Advantageously, Z is aryl or NRaRb.
More advantageously, R2 and R′2 are H.
Advantageously, R3 is aryl or (C1-C6)alkyl-heteroaryl-(C1-C6)alkyl-C(O)-aryl, more advantageously (C1-C6)alkyl-heteroaryl-(C1-C6)alkyl-C(O)-aryl. Preferred (C1-C6)alkyl-heteroaryl-(C1-C6)alkyl-C(O)-aryl is CH2-1,2,3-triazolyl-CH2—C(O)-p-cyclophanyl.
Advantageously, R4 and R5 are independently one from the other H, (C1-C6)alkyl, (C3-C8)heterocyclyl, (C3-C8)carbocyclyl, aryl, heteroaryl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-heteroaryl, C(O)—V, R4 and R5 form together a (C3-C8)heterocyclyl or a heteroaryl, or one of R4 or R5 is —CH(R7)—CO—V,
Advantageously, R6 is C(O)—V, where V is as defined for formula (I), V being advantageously (C1-C6)alkyl-aryl or OR10, R10 being advantageously (C1-C6)alkyl, preferably tert-butyl or (C1-C6)alkyl-aryl, preferably benzyl.
The compounds of formula (I) can be prepared according to the methods described in WO 2009/099897, U.S. Pat. No. 6,316,626, WO 2006/024784 and Journal of Organic Chemistry 2013, 78, 12236-12242 (doi: 10.1021/jo401994y).
In a first advantageous embodiment, the compounds of formula (I) are 1,3-diaminocyclopentanes, wherein n=0 and X is CH of formula (I-1):
wherein R1, R′1, R2, R′2 and Y are as defined in formula (I).
Advantageously, Y is OR3 or NR4R5, preferably OR3, as defined in formula (I).
Advantageously, NR1R2 and NR′1R′2 are in cis configuration.
Advantageously, R2 and R′2 are H, C(O)-Q, SO2—Z as defined above, or R1 and R2 and R′1 and R′2 form together a (C3-C8)heterocyclyl. Advantageously, Q is H, (C1-C6)alkyl, such as methyl, (C1-C6)alkyl-aryl, such as benzyl, or ORc, where Rc is as defined above, and is advantageously (C1-C6)alkyl or (C1-C6)alkyl-aryl. Advantageously, Z is aryl or NRaRb.
More advantageously, R2 and R′2 are H.
Advantageously, R3 is aryl or (C1-C6)alkyl-heteroaryl-(C1-C6)alkyl-C(O)-aryl, more advantageously (C1-C6)alkyl-heteroaryl-(C1-C6)alkyl-C(O)-aryl. Preferred (C1-C6)alkyl-heteroaryl-(C1-C6)alkyl-C(O)-aryl is —CH2-1,2,3-triazolyl-CH2—C(O)-p-cyclophanyl
Advantageously, R4 and R5 are independently one from the other H, (C1-C6)alkyl, (C3-C8)heterocyclyl, (C3-C8)carbocyclyl, aryl, heteroaryl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-heteroaryl, C(O)—V, R4 and R5 form together a (C3-C8)heterocyclyl or a heteroaryl, or one of R4 or R5 is —CH(R7)—CO—V,
In a second advantageous embodiment, the compounds of formula (I) are 3, 5-diaminopiperidines wherein n=1 and X is N of formula (I-2):
wherein R1, R′1, R2, R′2, X and Y are as defined for formula (I).
Advantageously, Y is R6, as defined in formula (I).
Advantageously, NR1R2 and NR′1R′2 are in cis configuration.
Advantageously, R2 and R′2 are H, C(O)-Q, SO2—Z as defined above, or R1 and R2 and R′1 and R′2 form together a (C3-C8)heterocyclyl. Advantageously, Q is H, (C1-C6)alkyl, such as methyl, (C1-C6)alkyl-aryl, such as benzyl, or ORc where Rc is as defined above. Advantageously, Z is aryl or NRaRb.
More advantageously, R2 and R′2 are H.
Advantageously, R6 is H, aryl, heteroaryl, (C1-C6)alkyl-aryl, (C1-C6)alkyl-heteroaryl, C(O)—V, or —CH(R7)—CO—V, where V is as defined for formula (I), V being advantageously (C1-C6)alkyl-aryl, CH(R11)—NH—COR12, R11 being advantageously (C1-C6)alkylamine, preferably butylamine and R12 being an aryl, preferably a phenyl or OR10, R10 being advantageously (C1-C6)alkyl, preferably tert-butyl or (C1-C6)alkyl-aryl, preferably benzyl.
Advantageously, when present, the aryl in R6 is chosen from among methoxyphenyl, advantageously 3-methoxyphenyl or 4-methoxyphenyl, ethoxyphenyl, advantageously 4-ethoxyphenyl dimethoxyphenyl, advantageously, 3,4-dimethoxyphenyl, trimethoxyphenyl, advantageously 3,4,5-trimethoxyphenyl, 9,9′-Spirobi[9H-fluorene], p-cyclophanyl (hydroxy-phenyl)amide, advantageously 3-(hydroxyphenyl)-4-benzamide, ethylphenyl, advantageously 4-ethylphenyl and phenylethanol, advantageously 4-phenylethanol.
Advantageously, when present, the heteroaryl is a 3- or 5-indolyl, advantageously substituted with a methoxy group.
Advantageously, the compound of formula (I) is selected in the list consisting of:
In a third advantageous embodiment, the compounds of formula (I) are 3, 5-diaminopiperidines wherein n=1 and X is N of formula (I-2):
wherein R1, R′1, R2, R′2, X and Y are as defined for formula (I).
Advantageously, Y is R6, as defined in formula (I).
Advantageously, NR1R2 and NR′1R′2 are in cis configuration.
Advantageously, at least one of R2 and R′2 is H, C(O)-Q or SO2—Z as defined in formula (I). Advantageously, Q is ORc, Rc being (C1-C6)alkyl, advantageously tert-butyl. Advantageously, Z is (C1-C6)alkyl.
More advantageously, R2 and R′2 are C(O)-Q, R2 is H and R′2 is SO2—Z or R2 is C(O)-Q and R′2 is H.
Advantageously, R6 is H, (C1-C6)alkyl-aryl, (C1-C6)alkyl-heteroaryl or SO2—W wherein W is a defined above.
Advantageously, when present, the aryl in R6 is chosen from among phenyl, methoxyphenyl, advantageously 3-methoxyphenyl, N,N-diméthylphénylamine and phénylpyrrolidine.
Advantageously, when present, the heteroaryl is a 1-methyl-5-indolyl, advantageously substituted with a methoxy group.
Advantageously, the compound of formula (I) is selected in the list consisting of:
The compound of formula (I) can also be used in the form of a pro-drug. By pro-drug, it is meant in the sense of the present invention, a compound that is administered in an inactive or less active form and that is metabolized in vivo into its active form, for example under the action of enzymes or gastric juice. Pro-drugs are useful to improve the physicochemical properties of a molecule, such as solubility or pharmacokinetics (bioavailability for example). In particular, a pro-drug may be obtained by acylation or phosphorylation of an amine or a hydroxyl group.
The compounds of formula (I) can also be used in combination with one or more HIV-1 inducers. HIV inducers are compounds capable of activating HIV-protein expression and include DNA methylation inhibitors, such as 5-azacytidine (azacitidine), 5-aza-2′-deoxycytidine (5-aza-CdR, decitabine), 1-Darabinofuranosyl-5-azacytosine (fazarabine), dihydro-5-azacytidine (DHAC), 5-fluorodeoxycytidine (FdC), oligodeoxynucleotide, duplexes containing 2-H pyrimidinone, zebularine, antisense oligodeoxynucleotides (ODNs), MG98, (−)-epigallocatechin-3-gallate, hydralazine, procaine and procainamide; histone deacetylase inhibitors, such as TSA, SAHA, MS-275, aminosuberoyl hydroxamic acids, M-Carboxycinnamic acid bishydroxamate, LAQ-824, LBH-589, belinostat (PXD-101) Panobinostat (LBH-589), a cinnamic hydroxamic acid analogue of M-carboxycinnamic acid bishydroxamate, IF2357, aryloxyalkanoic acid hydroxamides, depsipeptide, apicidin, cyclic hydroxamic acid-containing peptide group of molecules, FK-228, red FK, cyclic peptide mimic linked by an aliphatic chain to a hydroxamic acid, butyrate, phenylbutyrate, sodium butyrate, valproic acid, pivaloyloxymethyl butyrate, 5 NOX-275, and MGCD0103; or NF-kappa-B-inducers selected from the group comprising: PMA, prostratin, bryostatin and TNF-alpha.
Advantageously, at least one compound of formula (I) is used in combination with an HIV therapy, such as immunotherapy, antiretrovirals, vaccines, such as therapeutic vaccines, and Highly Active Antiretroviral therapies (HAART).
Vaccines are for example therapeutic vaccines, more particularly anti-HIV vaccines, capable of restoring cell-mediated and/or humoral immunity to HIV-infected patients. These vaccines may be combined with cytokines that increase the response to the vaccine and/or restore the immune system by stimulating the growth of certain cells, such as CD4 lymphocytes.
The present invention therefore also concerns at least a compound of formula (I) for use in the treatment of HIV infection in combination with an HIV therapy. HIV therapies are known in the art and include: Lamivudine, Emtricitabine, Abacavir, Zidovudine, Didanosine, Stavudine, Adefovir, Tenofovir, Efavirenz, Etravirine, Nevirapine, Rilpivirine, Amprénavir, Fosamprénavir, Tipranavir, Lopinavir, Ritonavir, Indinavir, Saquinavir, Darunavir, Atazanavir, Nelfinavir, Raltegravir, Eviltegravir, Dolutegravir, Enfuvirtide, Maraviroc, and combinations thereof.
Advantageously, at least one product of formula (I) is used with an HIV therapy chosen, for example, from among: Lamivudine, Emtricitabine, Abacavir, Zidovudine, Didanosine, Stavudine, Adefovir, Tenofovir, Efavirenz, Etravirine, Nevirapine, Rilpivirine, Amprenavir, Fosamprenavir, Tipranavir, Lopinavir, Ritonavir, Indinavir, Saquinavir, Darunavir, Atazanavir, Nelfinavir, Raltegravir, Eviltegravir, Dolutégravir, Enfuvirtide, Maraviroc.
The present invention also concerns a pharmaceutical composition, comprising at least one compound of formula (I) as defined above for use in the treatment of HIV infection, advantageously in combination with an HIV therapy.
The pharmaceutical compositions of the invention can be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or rectal administration. The active ingredient can be administered in unit forms for administration, mixed with conventional pharmaceutical carriers, to animals or to humans. The pharmaceutical compositions may be immediate, delayed or sustained release compositions, advantageously sustained release compositions.
When a solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle and other conventional excipients known to those skilled in the art.
The compounds of the invention can be used in a pharmaceutical composition at a dose ranging from 0.01 mg to 1000 mg a day, administered in only one dose once a day or in several doses along the day, for example twice a day. The daily administered dose is advantageously comprised between 5 mg and 500 mg, and more advantageously between 10 mg and 200 mg. However, it can be necessary to use doses out of these ranges, which could be noticed by the person skilled in the art.
The present invention further concerns the use of at least one compound of formula (I) for the preparation of a medicament intended for the treatment of HIV infection, said medicament being used advantageously in combination with an HIV therapy.
The present invention further concerns a method for treating HIV infection, comprising the administration to a person in need thereof of at least one compound of formula (I), advantageously in combination with an HIV therapy.
The present invention also concerns a combination product comprising:
for simultaneous, separate or sequential use as a medicament.
Advantageously, the combination product is intended for the treatment of HIV infection.
Advantageously, the at least one antiretroviral of HIV is chosen from among entry inhibitors (or fusion inhibitors) such as Maraviroc and Enfuvirtide; nucleoside reverse transcriptase inhibitors (NRTI) and nucleotide reverse transcriptase inhibitors (NtRTI) such as Lamivudine, Emtricitabine, Abacavir, Zidovudine, Didanosine, Stavudine, Adéfovir, Tenofovir; non-Nucleoside reverse transcriptase inhibitors (NNRTI), such as, Efavirenz, Etravirine, Nevirapine, Rilpivirine; integrase inhibitors, such as Raltegravir, Elvitegravir and Dolutegravir; protease inhibitors, such as Amprenavir, Fosamprenavir, Tipranavir, Lopinavir, Ritonavir, Indinavir, Saquinavir, Darunavir, Atazanavir, Nelfinavir.
Advantageously, the compound of formula (I) is a compound of formula (I-1) or a compound of formula (I-2).
The combination product according to the invention may be administered in the form of a single pharmaceutical composition comprising at least one compound of formula (I) and at least one antiretroviral of HIV. The combination product according to the invention may also be administered in the form of a first pharmaceutical composition comprising the at least one compound of formula (I) and a second pharmaceutical composition comprising the at least one antiretroviral. In that case, the pharmaceutical compositions may be administered by the same or by different routes. For example, one pharmaceutical composition can be administered orally and the second one parenterally.
The term HIV, in the sense of the present invention, is intended to designate the three types of the human immunodeficiency virus HIV0, HIV 1 and HIV2 and their subtypes.
Within the groups, radicals or fragments defined in the description and the claims, the number of carbon atoms is specified inside the brackets. For example, (C1-C6)alkyl designates an alkyl group or radical having 1 to 6 carbon atoms.
For the groups comprising two or more subgroups, the attachment is indicated with “-”. For example, “—(C1-C6)alkyl-aryl-(C1-C6)alkenyl” indicates a radical alkyl bound to a radical aryl itself bound to an alkenyl wherein the alkyl is bound to the rest of the molecule.
In the sense of the present invention, the expression “(C1-C6)alkyl” designates an acyclic, saturated, linear or branched hydrocarbon chain comprising 1 to 6 carbon atoms. Examples of (C1-C6)alkyl groups include methyl, ethyl, propyl, butyl, pentyl or hexyl. Unless explicitly stated, the definitions propyl, butyl, pentyl and hexyl include all possible isomers. For example, butyl comprises n-butyl, iso-butyl, sec-butyl and tert-butyl.
In the sense of the present invention, the expression “(C1-C6)alkylamine” designates an amine group bound to the molecule via an “(C1-C6)alkyl” as defined above. Examples of (C1-C6) alkylamine groups include methylamine, ethylamine, propylamine, butylamine, pentylamine or hexylamine.
In the sense of the present invention, the expression “(C3-C8)carbocyclyl” designates a saturated or partially saturated mono-, di- or tri-cyclic structure comprising from 3 to 8 carbon atoms. Examples of “(C3-C8)carbocyclyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Unless explicitly stated, the cycloalkyl can be substituted by one or more groups such as methyl, ethyl, isopropyl, hydroxy, methoxy, amino, fluoro, chloro, bromo and iodo.
In the sense of the present invention, the expression “(C9-C10)carbocyclyl” designates a saturated or partially saturated di- or tri-cyclic structure comprising from 9 to 10 carbon atoms.
In the sense of the present invention, the expression “(C3-C8)heterocyclyl” designates saturated heterocycles having 3, 4, 5, 6, 7 or 8 atoms in the ring where 1, 2 or 3 heteroatoms chosen from among N, O and S replace the corresponding number of carbon atoms. Examples of “(C3-C8)heterocyclyl” include aziridinyl, oxyranyl, pyrrolidinyl, tetrahydrofuranyl, oxazolyl, piperidinyl, piperazinyl and morpholinyl. Unless explicitly stated, the cycloalkyl can be substituted by one or more groups such as methyl, ethyl, isopropyl, hydroxy, methoxy, amino, fluoro, chloro, bromo and iodo.
In the sense of the present invention, the expression “Rx and Ry form together a (C3-C8)heterocyclyl” is intended to mean that N, Rx and Ry represent together an heterocycle. For example, Rx and Ry can be connected to form a C4-alkyl chain, forming a pyrrolidinyl ring with the nitrogen atom they are connected to.
The term “aryl” designates an aromatic, monocyclic ring that may be fused with a second saturated, unsaturated or aromatic ring. The term aryl include, without restriction to the following examples, phenyl, indanyl, indenyl, naphtyl, anthracenyl, phenanthrenyl, tetrahydronaphtyl, dihydronaphtyl, 9,9′-Spirobi[9H-fluorene] and p-cyclophanyl. The preferred aryl are those comprising one six-membered aromatic ring. The aryl group may be substituted with one or more groups independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxyl, amino, nitro, cyano, trifluoro, carboxylic acid or carboxylic ester. Examples of substituted phenyl groups are 2-, 3- or 4-methoxyphenyl, 3, 5- or 3, 4-dimethoxyphenyl, 3, 4, 5-trimethoxyphenyl, 2-, 3- or 4-hydroxyphenyl, 4-acylamidophenyl or 4-acylamido-3-hydroxy-phenyl.
The term heteroaryl designates a mono- or polycyclic aryl as defined above where one or more carbon atoms have been replaced with one or more heteroatoms chosen from among N, O and S. Unless explicitly stated, the term “heteroaryl” includes all possible isomers. Examples of heteroaryl groups include furyl, thienyl, imidazolyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazolyl and triazinyl. The heteroaryl group may be substituted with one or more groups independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxyl, amino, nitro, cyano, trifluoro, carboxylic acid or carboxylic ester. Preferred heteroaryls are those having 5 or 6 atoms in the ring, such as indolyl, pyrrolyl, pyridinyl, pyrrazolyl, triazolyl, furanyl or thienyl.
In the sense of the present invention, the term “halogen” designates a fluorine, chlorine, bromine or iodine atom.
The term “amino acid” as used in the present invention refers to natural α-amino acids (e.g. Alanine (Ala), Arginine (Arg), Asparagine (Asn), Aspartic acid (Asp), Cysteine (Cys), Glutamine (Gln), Glutamic acid (Glu), Glycine (Gly), Histidine (His), Isoleucine (Ile), Leucine (Leu), Lysine (Lys), Méthionine (Met), Phenylalanine (Phe), Proline (Pro), Serine (Ser), Threonine (Thr), Tryptophan (Trp), Tyrosine (Tyr) and Valine (Val)) in the D or L form, as well as non-natural amino acid. In the sense of the present invention, the definition “R7 is the side chain of an aminoacid” is to be understood in its common meaning. By way of illustration, R7 is a CH2-phenyl group in phenylalanine.
For the purpose of the invention, the term “pharmaceutically acceptable” is intended to mean what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non-toxic, for a pharmaceutical use.
The term <<pharmaceutically acceptable salt, hydrate of solvate>> is intended to mean, in the framework of the present invention, a salt of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound. Such salts comprise:
(1) hydrates and solvates,
(2) acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid and the like; or formed with organic acids such as acetic, benzenesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphtoic, 2-hydroxyethanesulfonic, lactic, maleic, malic, mandelic, methanesulfonic, muconic, 2-naphtalenesulfonic, propionic, succinic, dibenzoyl-L-tartaric, tartaric, p-toluenesulfonic, trimethylacetic, and trifluoroacetic acid and the like, and
(3) salts formed when an acid proton present in the compound is either replaced by a metal ion, such as an alkali metal ion, an alkaline-earth metal ion, or an aluminium ion; or coordinated with an organic or inorganic base. Acceptable organic bases comprise diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
Hela-4 Cells
HeLa-p4 cells are HeLa CD4 LTR-LacZ wherein LacZ expression is induced by the trans-activating protein Tat of HIV, making possible the precise quantification of HIV-1 infectivity from a single replication cycle. HeLa-CD4 cells growing exponentially at a density of 1×104/mL were placed in 96-well plates and infected the following day with 1 ng of HIV p24 antigen in the presence of different concentrations of compounds. The titles for a single cycle of the viruses were determined 48 hours after infection by quantifying the beta-galactosidase activity in lysates P4 by colorimetric test (CPRG, Promega) based on the cleavage of chlorophenol red-beta-D-galactopyranoside (CPRG) by beta-galactosidase. A cell viability assay measuring the absorbance at 690 nm using the yellow tetrazolium reagent MTS [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide] (Promega) was carried out.
J-Lat Cells
The J-Lat were grown in RPMI 1640 medium (Gibco-BRL) supplemented with 10% fetal bovine serum, 50 U/ml of penicillin, 50 mg/ml of streptomycin at 37 uC in a humidified 95% air/5% CO2 atmosphere. The cells were plated at 5.105 cells in a 96 well-plate. TNF was purchased from Immunosource. SAHA (suberoylanilide hydroxamic acid), prostratin (12-deoxyphorbol-13-acetate) and vorinostat were obtained from Sigma-Aldrich. The J-Lat cells were treated for 24 h with the different compounds alone. The cells were washed twice in PBS, re-suspended in PBS containing 4% paraformaldehyde and fixed for 30 min. Cells were next washed and re-suspended in PBS. The percentage of GFP-positive cells was measured with a LSRFortessa cytometer (Becton-Dickinson) using FACSDiva Version 6.1.3 according to the manufacturer's instructions.
For the helap4 cells experiments, the efficacy of the compounds is determined in comparison with control cells containing wild type NL4-3 virus alone (i.e. without any added compound) and is expressed as percentage of control. Then, the viral replication was increased for several compounds at the 50 and 100 μM concentrations with an absence of cytotoxic effects at the same concentrations (MTS test) (table 1).
The results for the J-Lat cells experiments are expressed as a percentage of the living fluorescent cells. In this model, some slight increase of viral production measured by fluorescence are quantified (table 1).
CD4+ T Cells
For experiments using primary cells obtained from HIV-infected, antiretroviral-treated, aviremic patients, total CD4+ cells are isolated by a MACS) Whole Blood MicroBead Technology (Miltenyi). Briefly, T CD4+ cells from whole blood are magnetically labeled with MACS MicroBeads and specific antibodies. Cells are separated in a MACS Column placed in a MACS Separator. The flow-through fraction can be collected as the negative fraction depleted of the labeled cells. The column is removed from the separator and the retained cells are eluted as the enriched, positively selected cell fraction. The T CD4+ cells were then cultured with a T cell activation/expansion kit (Miltenyi). The cells are activated for up to 3 days with Anti-Biotin MACSiBead Particle conjugated to monoclonal anti-biotin antibodies (anti CD2-biotin, anti CD3-CD3 and anti CD28-biotin). Expansion is achieved by adding IL-2 and fresh medium for 4 days. Then, these T CD4+ cells are considered as positive culture. A negative control was the same proportion of cells cultured without stimuli like antibodies and IL-2. The T CD4+ cells were cultured with compounds alone or in combination with antibodies or IL-2. The HIV production in cell culture media was measured by real time PCR (Cobas AmpliPrep/Cobas Taqman HIV-1 test, V2.0, Roche). The results are expressed in table 2 as a ratio of the viral load of interest/viral load of negative control or as a ratio of the viral load of interest/viral load of positive control.
In the T CD4+ cell model, some compounds were efficient to increase the production of HIV from cells of HIV-infected, ART-treated, aviremic patients. Depending of the compounds, they were efficient alone, or in combination with antibodies or IL2.
The following compounds were assessed:
In an experiment, MT2 cells (human lymphocytic cell line) are infected with the Laï virus to a multiplicity of infection of 0.3 and incubated with compounds A, B, C or D at four different concentrations.
After 3 days of culture, real-time PCR quantification of the viral RNA of the supernatant is performed (COBAS Ampliprep/COBAS TaqMan HIV-1 assay, version 2).
The results are expressed as percentage of control (virus without any added compound) in Table 3.
These results demonstrate that compounds A, B, C and D induce viral replication at an extremely high level in human lymphocytes.
All the above results show that the compounds of formula (I) according to the present invention are capable of increasing viral replication, are not cytotoxic, and are hence useful for eradicating HIV reservoirs.
Compounds were prepared according to the Journal of Organic Chemistry 2013, 78, 12236-12242
ECO01-003-Cdibenzyl 3-(2,3-dihydro-1H-inden-1-yl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 233 mg, 43%, colorless oil;
1H NMR (500 MHz, (CD3)2SO, 70° C.) δ 1.86 (s, 2H), 1.94-1.97 (m, 2H), 2.30 (br s, 1H), 2.51 (br s, 1H), 2.70 (bs s, 1H), 2.73-2.78 (m, 1H), 2.82-2.85 (m, 1H), 3.10 (br s, 1H), 4.20 (br s, 1H), 4.31 (br s, 1H), 4.42 (br s, 1H), 5.13-5.26 (m, 4H), 7.17-7.19 (m, 4H), 7.32-73.8 (m, 10H); 13C NMR (125 MHz, (CD3)2SO, 70° C.) δ 24.4, 30.3 (2C), 35.7, 53.6, 55.8, 56.4, 66.9 (2C), 67.8, 124.3 (2C), 125.1, 126.0, 127.3-128.4 (8C), 136.4 (2C), 142.2 (2C), 143.3 (2C), 156.9 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C30H32N3O4, 498.2387. found 498.2381.
ECO01-004-C dibenzyl 3-(2-methoxyphenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 357 mg, 63%, pale yellow oil;
1H NMR (500 MHz, (CD3)2SO, 70° C.) δ 1.86 (m, 2H), 2.25 (br s, 2H), 2.50-2.61 (m, 4H), 3.16 (br s, 2H), 3.77 (s, 3H), 4.38 (br s, 2H), 5.14 (s, 4H), 6.86 (t, J=7.3 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 7.10 (dd, J=7.4 Hz, 1.3 Hz, 1H), 7.16 (td, J=7.8, 0.85 Hz, 1H), 7.31-7.37 (m, 10H); 13C NMR (125 MHz, (CD3)2SO, 70° C.) δ 26.9, 35.7, 55.4, 56.0 (2C), 56.4, 66.0, 66.8 (2C), 110.9, 120.3, 127.0-128.3 (13C), 130.8, 136.5 (2C), 156.8 (2C), 157.2; HRMS (ESI-Orbitrap) [M+H]+ calcd for C30H34N3O5, 516.24930. found 516.24811.
ECO0-005-C dibenzyl 3-(2,3-dihydro-1H-inden-2-yl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 168 mg, 30%, orange solid;
1H NMR (500 MHz, (CD3)2SO, 70° C.) δ 1.83-1.87 (m, 2H), 2.26 (br s, 2H), 2.60 (d, J=7.7 Hz, 1H), 2.61 (d, J=7.7 Hz, 1H), 2.88 (q, J=7.4 Hz, 1H), 2.90 (d, J=7.4 Hz, 1H), 3.04 (br s, 2H), 3.23 (m, 1H), 4.38 (br s, 2H), 5.10-5.18 (m, 4H), 7.11-7.14 (m, 4H), 7.34 (br s, 10H); 13C NMR (125 MHz, (CD3)2SO, 70° C.) δ 35.7, 36.0 (2C), 49.9, 53.8, 55.9 (2C), 64.4, 66.7 (2C), 124.0 (2C), 126.2 (2C), 127.5-128.4 (10C), 136.4 (2C), 141.3 (2C), 156.9 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C30H32N3O4, 498.23873. found 498.23785.
ECO01-006-C dibenzyl 3-(4-methylphenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 317 mg, 59%, yellow oil;
1H NMR (500 MHz, (CD3)2SO, 70° C.) δ 1.86 (br s, 2H), 2.26 (s, 5H), 2.52 (br s, 3H), 3.17 (br s, 3H), 4.39 (br s, 2H), 5.13 (br s, 4H), 7.02-7.11 (m, 4H), 7.30-7.34 (m, 10H); 13C NMR (125 MHz, (CD3)2SO, 70° C.) δ 20.9, 32.1, 35.6, 54.8 (2C), 55.9 (2C), 57.8, 66.8 (2C), 126.4-128.6 (13C), 130.8 (2C), 134.6, 136.5, 137.0, 156.7 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C30H34N3O4, 500.25438. found 500.25446.
ECO01-008-C dibenzyl 3-(3-methylphenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 230 mg, 42%, yellow oil;
1H NMR (500 MHz, (CD3)2SO, 70° C.) δ 1.87 (br s, 2H), 2.28 (s, 5H), 2.56 (br s, 3H), 3.16 (br s, 3H), 4.40 (br s, 2H), 5.13 (br s, 4H), 6.94-6.99 (m, 3H), 7.14 (t, J=7.3 Hz, 1H), 7.30-7.35 (m, 10H); 13C NMR (125 MHz, (CD3)2SO, 70° C.) δ 20.9, 32.5, 35.6, 54.8 (2C), 55.9 (2C), 57.8, 66.8 (2C), 125.4, 126.4, 127.1, 127.5-128.4 (11C), 129.1, 136.4, 137.2, 140.0, 156.6 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C30H34N3O4, 500.25438. found 500.25406.
ECO01-009-C dibenzyl 3-(1,2,3,4-tetrahydronaphthalen-1-yl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 353 mg, 63%, white solid;
1H NMR (500 MHz, (CD3)2SO, 70° C.) δ 1.59-1.70 (m, 2H), 1.80-1.87 (m, 4H), 2.32 (br s, 1H), 2.61-2.73 (m, 4H), 2.99 (br s, 1H), 3.67 (br s, 1H), 4.34 (br s, 1H), 4.43 (br s, 1H), 5.12-5.17 (m, 4H), 7.02-7.07 (m, 3H), 7.31-7.36 (m, 10H), 7.52 (br s, 1H); 13C NMR (125 MHz, (CD3)2SO, 70° C.) δ 21.1, 22.1, 29.1, 35.7, 47.8, 53.6, 55.8, 56.7, 60.4, 66.9 (2C), 125.5, 126.1, 126.4, 126.5, 127.4-128.4 (11C), 136.3, 136.9, 137.9, 156.7 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C31H34N3O4, 512.25438. found 512.25427.
ECO01-010-C dibenzyl 3-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 197 mg, 34%, colorless paste;
1H NMR (500 MHz, (CD3)2SO, 70° C.) δ 1.86 (br s, 2H), 2.24 (br s, 2H), 2.50 (br s, 2H), 3.13 (s, 4H), 4.38 (br s, 2H), 5.12 (s, 4H), 5.93 (s, 2H), 6.60 (d, J=3.1 Hz, 1H), 6.72 (d, J=1.4 Hz, 1H), 6.75 (d, J=7.9 Hz, 1H), 7.31-7.34 (m, 1 OH); 13C NMR 0 (125 MHz, (CD3)2SO, 70° C.) δ 32.2, 35.7, 55.0, 55.9 (2C), 57.9 (2C), 66.8 (2C), 100.5, 107.9, 108.8, 121.2, 127.4-127.7 (10C), 128.2, 134.1, 136.5, 145.3, 147.2, 156.6 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C30H32N3O6 530.22856. found 530.22937.
ECO01-011-C dibenzyl 3-(2,2-diphenylethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 216 mg, 35%, white solid;
1H NMR (500 MHz, (CD3)2SO, 70° C.) δ 1.80 (s, 2H), 2.22 (br s, 2H), 3.02 (d, J=7.15 Hz, 2H), 3.14 (br s, 2H), 4.17 (t, J=4.2 Hz, 1H), 4.32 (br s, 2H), 4.98 (br s, 4H), 7.13-7.30 (m, 20H); 13C NMR (125 MHz, (CD3)2SO, 70° C.) δ 35.6, 48.0, 54.7 (2C), 55.7 (2C), 61.7, 66.7 (2C), 125.9 (2C), 127.3-128.2 (18C), 136.4 (2C), 144.1 (2C), 156.3 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C35H36N3O4, 562.27003. found 562.26874.
ECO01-012-C dibenzyl 3-(3-phenylpropyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 285 mg, 52%, colorless oil;
1H NMR (500 MHz, (CD3)2SO, 70° C.) δ 1.60 (m, 2H), 1.85 (br m, 2H), 2.12 (br s, 2H), 2.32 (br s, 2H), 2.52 (t, J=3.9 Hz, 2H), 3.07 (br s, 2H), 4.38 (br s, 2H), 5.13 (s, 4H), 7.17 (d, J=6.9 Hz, 3H), 7.25 (t, J=7.4 Hz, 2H), 7.29-7.36 (m, 10H); 13C NMR (125 MHz, (CD3)2SO, 70° C.) δ 27.9, 32.4 (2C), 35.8, 55.2 (2C), 55.9 (2C), 66.9 (2C), 125.5, 127.4-128.2 (14C), 136.4 (2C), 142.1, 156.7 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C30H34N3O4, 500.25438 found 500.25461.
ECO01-015-C dibenzyl 3-(3-methoxyphenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 318 mg, 57%, yellow paste;
1H NMR (500 MHz, (CD3)2SO, 70° C.) δ 1.86 (s, 2H), 2.23 (br s, 2H), 2.56 (s, 4H), 3.15 (s, 2H), 3.74 (s, 3H), 4.38 (s, 2H), 5.13 (s, 4H), 6.75 (s, 3H), 7.18 (t, J=7.4 Hz, 1H), 7.30-7.35 (m, 10H); 13C NMR (125 MHz, (CD3)2SO, 70° C.) δ 32.7, 35.7, 54.9 (2C), 55.9 (2C), 57.6 (2C), 66.8 (2C), 111.5, 114.2, 120.7, 127.4-129.1 (11C), 136.5 (2C), 141.8, 156.6 (2C), 159.4; HRMS (ESI-Orbitrap) [M+H]+ calcd for C30H33N3O5, 516.24930 found 516.24731.
ECO01-016-C dibenzyl 3-(2-methyl phenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 251 mg, 46%, white paste;
1H NMR (500 MHz, (CD3)2SO, 30° C.) δ 1.87 (br s, 2H), 2.11 (br s, 2H), 2.21 (s, 3H), 2.40 (br s, 2H), 3.08 (br s, 2H), 3.44 (br s, 2H), 4.27 (br s, 1H), 4.51 (br s, 1H), 5.13 (s, 4H), 7.10 (s, 4H), 7.28-7.40 (m, 10H); 13C NMR (125 MHz, (CD3)2SO, 30° C., two rotamers) δ 18.8 (2C), 29.6, 30.0, 35.6, 36.0, 51.8 (2C), 53.6 (2C), 55.5 (2C), 55.7 (2C), 56.4, 56.6, 66.3 (2C), 67.2 (2C), 125.8 (2C), 125.9 (2C), 126.9-129.9 (24C), 135.5 (2C), 136.2, 136.3, 136.7 (2C), 138.2 (2C), 155.2 (2C), 157.0, 157.6; HRMS (ESI-Orbitrap) [M+H]+ calcd for C30H34N3O4, 500.25438 found 500.25369.
ECO01-017-C dibenzyl 3-(3,4-dimethylphenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 291 mg, 52%, white paste;
1H NMR (500 MHz, (CD3)2SO, 30° C.) δ 1.86 (br s, 2H), 2.05 (br s, 1H), 2.16 (br s, 6H), 2.33 (br s, 1H), 2.42 (br s, 4H), 3.03 (br s, 1H), 3.41 (br s, 1H), 4.25 (br s, 1H), 4.50 (br s, 1H), 5.03-5.15 (m, 4H), 6.85 (d, J=7.6 Hz, 1H), 6.90 (s, 1H), 7.00 (br s, 1H), 7.27-7.40 (br m, 10H); 13C NMR (125 MHz, (CD3)2SO, 30° C., two rotamers) δ 18.9 (2C), 19.3 (2C), 31.9, 32.0, 35.6, 36.0, 51.8 (2C), 53.7 (2C), 55.7 (2C), 56.5 (2C), 58.0 (2C), 66.2 (2C), 67.2 (2C), 125.7-129.6 (24C), 133.3 (2C), 135.8 (2C), 136.2 (2C), 136.3 (2C), 136.8 (2C), 137.3 (2C), 155.1 (2C), 156.9, 157.6; HRMS (ESI-Orbitrap) [M+H]+ calcd for C31H36N3O4, 514.27003 found 514.26886.
ECO01-018-C dibenzyl 3-(4-(methylsulfonyl)phenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 349 mg, 57%, colorless paste;
1H NMR (500 MHz, (CD3)2SO, 30° C.) δ 1.86 (br s, 2H), 2.06 (br d, J=11.5 Hz, 1H), 2.35 (br d, J=11.5 Hz, 1H), 2.51 (s, 1H), 2.63 (br s, 3H), 3.07 (br d, J=10.1 Hz, 2H), 3.16 (s, 3H), 4.26 (br s, 1H), 4.51 (br s, 1H), 5.12 (s, 4H), 7.33 (br s, 10H), 7.44 (d, J=7.9 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H); 13C NMR (125 MHz, (CD3)2SO, 30° C., two rotamers) δ 31.9, 32.0, 35.5, 35.9, 43.6 (2C), 51.8 (2C), 53.8 (2C), 55.6 (2C), 56.5 (2C), 57.1 (2C), 66.2 (2C), 67.2 (2C), 126.9-129.5 (26C), 136.2 (2C), 136.3 (2C), 136.7 (2C), 138.4 (2C), 146.6 (2C), 155.1 (2C), 156.8, 157.7; HRMS (ESI-Orbitrap) [M+H]+ calcd for C30H34N3O6S, 564.21628 found 564.21625.
ECO01-019-C dibenzyl 3-(2-phenoxyphenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 291 mg, 48%, yellow oil;
1H NMR (500 MHz, (CD3)2SO, 60° C.) δ 1.81 (br s, 2H), 2.19 (br s, 2H), 2.57 (br s, 2H), 2.60 (br s, 2H), 3.00 (br s, 2H), 4.33 (br s, 2H), 5.08 (br s, 4H), 6.85 (d, J=8.0 Hz, 1H), 6.90 (d, J=8.0 Hz, 2H), 7.05-7.11 (m, 2H), 7.19 (t, J=7.55 Hz, 2H), 7.20-7.28 (m, 12H); 13C NMR (125 MHz, (CD3)2SO, 60° C.) δ 26.7, 35.6, 51.9, 55.0, 55.8 (2C), 56.4, 66.8 (2C), 117.3, 119.4 (2C), 122.6 (2C), 124.1, 126.6-127.9 (10C), 128.2, 129.9, 130.8, 131.5, 136.4 (2C), 153.9, 156.9 (2C), 157.5; HRMS (ESI-Orbitrap) [M+H]+ calcd for C35H36N3O5, 578.26495 found 578.26416.
ECO01-020-C dibenzyl 3-phenyl-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 205 mg, 41%, white solid;
1H NMR (500 MHz, (CD3)2SO, 60° C.) δ 1.99-2.15 (m, 2H), 2.90 (br s, 2H), 3.81 (br s, 2H), 4.62 (br s, 2H), 5.15 (br s, 4H), 6.74-6.77 (m, 3H), 7.17-7.32 (m, 12H); 13C NMR (125 MHz, (CD3)2SO, 60° C.) δ 34.0, 50.5 (2C), 55.3 (2C), 67.0 (2C), 113.4 (2C), 117.9, 126.6-128.9 (12C), 136.2 (2C), 149.7, 156.3 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C27H28N3O4, 458.2074 found 458.2070.
ECO01-021-C dibenzyl 3-(4-(trifluoromethyl)phenyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 168 mg, 30%, yellow oil;
1H NMR (500 MHz, (CD3)2SO, 60° C.) δ 2.03-2.06 (m, 1H), 2.14-2.16 (m, 1H), 3.03 (br s, 2H), 3.89 (br s, 2H), 4.66 (br s, 2H), 5.15 (br m, 4H), 6.84 (br s, 2H), 7.17-7.32 (br m, 10H), 7.46 (d, J=8.7 Hz, 2H); 13C NMR (125 MHz, (CD3)2SO, 60° C.) δ 33.5, 47.9, 50.3 (2C), 55.0, 67.0 (2C), 112.4 (2C), 117.3 (J=32.0 Hz), 125.5 (J=270.0 Hz), CF3 126.0 (J=3.6 Hz, 2C), 126.2-128.5 (10C), 136.2 (2C), 152.2, 156.0 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C28H27F3N3O4, 526.1948 found 526.1937.
ECO01-032-C dibenzyl 3-(benzo[d][1,3]dioxol-5-yl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 254 mg, 47%, pale brown solid;
1H NMR (500 MHz, (CD3)2SO, 60° C.) δ 1.98-2.05 (m, 2H), 2.83 (br s, 2H), 3.68 (br s, 2H), 4.57 (br s, 2H), 5.16 (br m, 4H), 5.90 (s, 2H), 6.16 (br s, 1H), 6.43 (br s, 1H), 6.73 (d, J=8.5 Hz, 1H), 7.32 (br s, 10H); 13C NMR (125 MHz, (CD3)2SO, 60° C.) δ 34.2, 49.1, 51.8, 55.4 (2C), 67.0 (2C), 97.1, 100.4, 106.2, 108.2, 127.5-128.3 (11C), 136.3, 139.9, 145.7, 148.0, 156.4 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C28H27N3O6, 502.1973 found 502.1991.
ECO01-044-C dibenzyl 3-(3-methoxyphenyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 312 mg, 59%, orange oil;
1H NMR (500 MHz, (CD3)2SO, 60° C.) δ 2.02-2.09 (m, 2H), 2.90 (br s, 2H), 3.72 (s, 3H), 3.81 (br s, 2H), 4.62 (br s, 2H), 5.17 (br s, 4H), 6.30-6.38 (m, 3H), 7.10 (t, J=8.1 Hz, 1H), 7.32 (br s, 10H); 13C NMR (125 MHz, (CD3)2SO, 60° C.) δ 33.9, 48.0, 50.7, 54.7, 55.2 (2C), 67.0 (2C), 99.7, 103.5, 106.2, 127.5-128.3 (11C), 129.6, 136.2, 151.1, 156.2 (2C), 160.4; HRMS (ESI-Orbitrap) [M+H]+ calcd for C28H30N3O5, 488.2180 found 488.2184.
ECO01-045-C dibenzyl 3-(4-methoxyphenyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 335 mg, 63%, brown solid;
1H NMR (500 MHz, (CD3)2SO, 60° C., δ) 2.00-2.04 (br m, 2H), 2.80 (br s, 2H), 3.56-3.78 (m, 5H), 4.58 (br s, 2H), 5.17 (s, 4H), 6.70-6.82 (br m, 4H), 7.33 (br s, 10H); 13C NMR (125 MHz, (CD3)2SO, 60° C., δ) 34.4, 49.2, 51.7, 55.4 (3C), 67.0 (2C), 114.5 (2C), 115.5 (2C), 127.6-128.3 (10C), 136.3 (2C), 144.1, 152.5, 156.5 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C28H30N3O5, 488.2180 found 488.2196.
ECO01-046-C dibenzyl 3-(2-methoxyphenyl)-3,6,7-triazabicyclo[3.2.1]octane-67-dicarboxylate: 335 mg, 63%, brown oil;
1H NMR (500 MHz, (CD3)2SO, 57° C.) δ 1.98-2.04 (m, 2H), 2.92 (br s, 2H), 3.56-3.69 (m, 2H), 3.70 (s, 3H), 4.51 (br s, 2H), 5.17 (br s, 4H), 6.86-6.92 (m, 3H), 6.98 (t, J=8.6 Hz, 1H), 7.29-7.32 (m, 10H); 13C NMR (125 MHz, (CD3)2SO, 57° C.) δ 35.3, 50.6, 52.9, 55.8 (3C), 66.9 (2C), 112.9, 120.4, 121.0, 123.0, 127.2-128.2 (10C), 136.4 (2C), 139.9, 153.0, 156.4 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C28H30N3O5, 488.2180 found 488.2189.
ECO01-048-C dibenzyl 3-(naphthalen-2-ylmethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 430 mg, 76%, white solid;
1H NMR (500 MHz, (CD3)2SO, 57° C.) δ 1.86 (br s, 2H), 2.23 (br s, 2H), 3.01 (br s, 2H), 3.92 (br s, 2H), 4.32 (br s, 2H), 5.01 (s, 4H), 7.27-7.50 (br m, 14H), 7.81 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.9 Hz, 1H), 8.14 (br s, 1H); 13C NMR (125 MHz, (CD3)2SO, 57° C.) δ 35.8, 50.6, 52.8 (2C), 55.6 (2C), 58.6, 66.7 (2C), 124.8, 125.5, 125.9, 127.2-128.2 (14C), 131.5, 133.4, 133.7, 136.1, 156.3 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C32H32N3O4, 522.2387 found 522.2397.
ECO01-049-C dibenzyl 3-(3-(phenylcarbamoyl)phenyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 368 mg, 59%, white solid;
1H NMR (500 MHz, (CD3)2SO, 57° C.) δ 2.05-2.13 (m, 2H), 2.99 (br s, 2H), 3.96-4.30 (br s, 2H), 4.66 (br s, 2H), 5.17 (br s, 4H), 6.94-7.36 br m, 17H), 7.78 (d, J=7.9 Hz, 2H), 10.04 (s, 1H, NH); 13C NMR (125 MHz, (CD3)2SO, 57° C.) δ 33.9, 48.1, 50.4, 55.1 (2C), 67.1 (2C), 112.2, 116.2, 117.0, 120.3 (2C), 123.6, 127.6-128.9 (14C), 135.8, 136.2, 139.2, 149.7, 156.1 (2C), 165.9; HRMS (ESI-Orbitrap) [M+H]+ calcd for C34H33N4O5, 577.2445 found 577.2462.
ECO01-052-C dibenzyl 3-(3-(phenylcarbamoyl)phenyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 186 mg, 58%, white solid;
1H NMR (500 MHz, (CD3)2SO, 57° C.) δ 1.30 (t, J=7.0 Hz, 3H), 1.86 (br s, 2H), 2.20 (br s, 2H), 3.19 (s, 6H), 3.98 (q, J=6.9 Hz, 2H), 4.36 (br s, 2H), 5.12 (s, 4H), 6.80 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.5 Hz, 2H), 7.30-7.35 (m, 10H); 13C NMR (125 MHz, (CD3)2SO, 57° C.) δ 14.6, 31.6, 35.7, 54.8, 55.8 (2C), 56.4, 58.0, 62.9, 66.8 (2C), 114.4 (2C), 127.6-128.3 (10C), 129.5 (2C), 132.0 (2C), 136.5 (2C), 156.7 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C31H36N3O5, 530.2649 found 530.2643.
ECO01-053-C dibenzyl 3-(4-(azepane-1-carbonyl)phenyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 301 mg, 56%, white solid;
1H NMR (500 MHz, (CD3)2SO, 57° C.) δ 1.56 (br s, 4H), 1.66 (br s, 4H), 2.04 (br s, 1H), 2.10 (br s, 1H), 2.96 (br s, 1H), 3.48 (br s, 5H), 3.74-4.33 (br m, 2H), 4.68 (br s, 2H), 5.17 (br s, 4H), 6.60 (br s, 1H), 6.74 (br s, 1H), 7.10-7.34 (br m, 12H); 13C NMR (125 MHz, (CD3)2SO, 57° C.) δ 26.6, 28.0, 32.3, 34.1, 47.6, 50.4, 55.1 (2C), 60.2, 61.3, 62.5, 66.9 (2C), 112.2, 112.9, 124.2, 126.3, 126.8-128.4 (11 C), 136.3 (2C), 150.1, 156.4 (2C), 170.5; HRMS (ESI-Orbitrap) [M+H]+ calcd for C34H39N4O5, 583.2915 found 583.2913.
ECO01-054-C dibenzyl 3-(4-(p-tolyloxy)phenyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 403 mg, 66%, white solid;
1H NMR (500 MHz, (CD3)2SO, 57° C.) δ 2.05 (br s, 2H), 2.30 (br s, 3H), 2.88 (br s, 2H), 3.77 (br s, 2H), 4.61 (br s, 2H), 5.20 (br s, 4H), 6.85 (br s, 6H), 7.10-7.34 (br m, 12H); 13C NMR (125 MHz, (CD3)2SO, 57° C.) δ 20.1, 34.1, 48.4, 48.9, 51.2 (2C), 55.0 (2C), 114.9 (2C), 117.3 (2C), 120.0 (2C), 127.6-128.3 (11C), 130.0, 131.4, 136.3 (2C), 146.2, 148.5, 156.0 (3C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C34H34N3O5, 562.2493 found 564.2488.
ECO02-008-C dibenzyl 3-(4-bromophenyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 514 mg, 44%, white solid;
1H NMR (500 MHz, (CD3)2SO, 60° C.) δ 1.99-2.10 (m, 2H), 2.90 (br s, 2H), 3.78 (br s, 2H), 4.62 (br s, 2H), 5.15 (br s, 4H), 6.67 (br s, 2H), 7.30 (br s, 12H); 13C NMR (125 MHz, (CD3)2SO, 60° C.) δ 33.8, 48.6, 50.3, 55.2 (2C), 59.7 (2C), 109.0, 115.2 (2C), 126.4-127.8 (10C), 128.3 (2C), 131.3, 136.2, 148.9, 156.2 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C27H27N3O4Br, 536.1190 found 536.1177.
ECO02-013-C dibenzyl 3-(4-bromophenyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 334 mg,
1H NMR (500 MHz, (CD3)2SO, 60° C.) δ 1.84 (br s, 2H), 2.21 (br s, 2H), 2.57 (br s, 4H), 3.09 (br s, 2H), 4.39 (br s, 2H), 5.14 (br s, 4H), 7.01-7.36 (m, 15H); 13C NMR (125 MHz, (CD3)2SO, 60° C.) δ 32.6, 35.7, 52.2, 54.9, 55.9 (2C), 57.8, 66.8 (2C), 125.5 (2C), 127.0-128.0 (7C), 128.2 (2C), 128.3 (2C), 128.4 (2C), 136.4, 140.3 (2C), 156.8 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C29H32N3O4, 486.2387 found 486.2390.
ECO02-014-C dibenzyl 3-(4-hydroxyphenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 161 mg, 29%, colorless oil;
1H NMR (500 MHz, (CD3)2SO, 60° C.) δ 1.83-1.85 (br m, 2H), 2.20 (br s, 2H), 2.47-2.55 (br m, 4H), 3.07 (br s, 2H), 4.37 (br s, 2H), 5.14 (br s, 4H), 6.67 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 7.34 (br s, 10H), 8.95 (s, 1H, OH); 13C NMR (125 MHz, (CD3)2SO, 60° C.) δ 31.7, 35.7, 52.2, 53.6, 55.9 (2C), 58.2, 66.8 (2C), 115.1 (2C), 127.5-128.3 (11C), 129.2 (2C), 130.3, 136.4, 155.3, 156.8 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C29H32N3O5, 502.2336 found 502.2335.
ECO02-019-C dibenzyl 3-(4-methoxyphenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 435 mg, 76%, colorless oil;
1H NMR (500 MHz, (CD3)2SO, 60° C.) δ 1.82-1.90 (m, 2H), 2.12 (br s, 2H), 2.50 (s, 4H), 3.10 (br s, 2H), 3.72 (s, 3H), 4.37 (br s, 2H), 5.13 (s, 4H), 6.82 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 7.28-7.38 (m, 10H); 13C NMR (125 MHz, (CD3)2SO, 60° C.) δ 31.6, 35.7, 52.5, 54.7, 55.0 (2C), 55.8, 66.8 (2C), 113.8 (2C), 126.6-128.3 (9C), 128.3 (2C), 129.3 (2C), 132.5, 136.4, 156.7 (2C), 157.9; HRMS (ESI-Orbitrap) [M+H]+ calcd for C30H34N3O5, 516.2493 found 516.2489.
ECO02-036-C dibenzyl 3-(3-hydroxyphenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 229 mg, 37%, white solid;
1H NMR (500 MHz, (CD3)2SO, 60° C., δ) 1.86 (br s, 2H), 2.22 (br s, 2H), 2.51 (br s, 4H), 3.20 (br s, 2H), 4.37 (br s, 2H), 5.14 (br s, 4H), 6.58-6.60 (m, 3H), 7.04 (t, J=7.9 Hz, 1H), 7.35 (br s, 10H), 9.05 (br s, 1H, OH); 13C NMR (125 MHz, (CD3)2SO, 60° C., δ) 32.6, 35.7, 52.2, 55.0, 55.8 (2C), 57.8, 66.8 (2C), 112.9, 115.4, 119.1, 127.5-129.0 (11C), 136.5 (2C), 141.5, 157.0 (2C), 157.3; HRMS (ESI-Orbitrap) [M+H]+ calcd for C29H32N3O5, 502.2336 OH found 502.2352.
ECO02-020-C dibenzyl 3-(4-phenylbutyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 473 mg, 85%, colorless oil;
1H NMR (500 MHz, (CD3)2SO, 60° C.) δ 1.33 (m 2H), 1.54 (m, 2H), 1.80-1.84 (m, 2H), 2.20 (br s, 2H), 2.31 (br s, 2H), 2.51-2.56 (m, 2H), 2.99 (br s, 2H), 4.35 (br s, 2H), 5.12 (br s, 4H), 5.71 (s, 4H), 7.14-7.27 (m, 15H); 13C NMR (125 MHz, (CD3)2SO, 60° C.) δ 25.7, 28.1, 35.0, 35.8, 52.5, 54.7, 55.8 (3C), 66.8 (2C), 125.3 (2C), 125.5-128.2 (14C), 136.4, 142.4, 156.8 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C31H35N3O4, 514.2700 found 514.2700.
ECO02-047-C dibenzyl 3-(3-fluorophenethyl)-3,6,7-trazabicyclo[3.2.1]octane-6,7-dicarboxylate: 360 mg, 66%, colorless oil;
1H NMR (500 MHz, (CD3)2SO, 57° C.) δ 1.86 (br s, 2H), 2.22 (br s, 2H), 2.58 (br s, 4H), 3.08 (br s, 2H), 4.37 (br s, 2H), 5.12 (br s, 4H), 6.97-6.99 (m, 3H), 7.25-7.40 (m, 11H); 13C NMR (125 MHz, (CD3)2SO, 57° C.) δ 32.1, 35.7, 52.2, 54.1, 55.8 (2C), 57.3, 66.8 (2C), 112.4 (J=20.8 Hz), 115.1 (J=20.8 Hz), 124.5 (J=2.7 Hz), 126.4-129.9 (11C), 136.5 (2C), 143.2 (J=7.5 Hz), 156.7 (2C), 162.2 (J=243.3 Hz); HRMS (ESI-Orbitrap) [M+H]+ calcd for C29H31N3O4F, 504.2293 found 504.2289.
ECO02-048-C dibenzyl 3-(2-cyclohexylethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 246 mg, 46%, colorless oil;
1H NMR (500 MHz, (CD3)2SO, 57° C.) δ 0.83-0.85 (m, 2H), 1.15-1.21 (m, 6H), 1.60-1.62 (m, 5H), 1.83 (br s, 2H), 2.10 (br s, 2H), 2.31 (br s, 2H), 3.02 (br s, 2H), 4.35 (br s, 2H), 5.08-5.18 (m, 4H), 7.34 (br s, 10H); 13C NMR (125 MHz, (CD3)2SO, 57° C.) δ 25.6 (2C), 26.1, 32.8 (2C), 33.6, 34.7, 35.8, 52.3, 53.8, 54.1, 55.8 (2C), 66.8 (2C), 126.4-128.3 (10C), 136.4 (2C), 156.7 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C29H38N3O4, 492.2857 found 492.2849.
ECO02-076-C dibenzyl 3-(4-benzamidophenyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 436 mg, 69%, pale yellow solid;
1H NMR (500 MHz, (CD3)2SO, 57° C.) δ 2.01-2.07 (m, 2H), 2.88 (br s, 2H), 3.81 (br s, 2H), 4.62 (br s, 2H), 4.90-5.19 (m, 4H), 6.75 (br s, 2H), 7.34 (br s, 10H), 7.52-7.62 (m, 5H), 7.98 (d, J=7.0 Hz, 2H), 9.93 (s, 1H); 13C NMR (125 MHz, (CD3)2SO, 57° C.) δ 34.1, 48.5, 50.9, 55.3 (2C), 67.1 (2C), 113.5 (2C), 121.8 (2C), 127.5-131.1 (16C), 135.3, 136.3 (2C), 146.3, 156.2 (2C), 164.9; HRMS (ESI-Orbitrap) [M+H]+ calcd for C34H33N4O5, 577.2445 found 577.2435.
Hydrogenolysis of Bicyclic Hydrazines Using Flow Hydrogenation
ECO01-026-C
Hydrogenation on H-Cube:
ECO01-015-C (100 mg, 0.194 mmol) was solubilised in MeOH (77 mL), c=0.0025 M. 3 Runs at 35° C., 30 Bars at 1 mL/min. After evaporation, purification Chromatography on silica gel (CH2Cl2 to CH2Cl2/MeOH/NH4OH 90/9/1) afforded ECO01-026-C2 (13 mg, 27%), colorless paste.
ECO01-026-C2 1-(3-methoxyphenethyl)piperidine-3,5-diamine: 13 mg, 27%, yellow paste;
1H NMR (500 MHz, CD3OD, 27° C.) δ 0.87 (q, J=11.7 Hz, 1H), 1.72 (t, J=10.4 Hz, 2H), 2.00-2.04 (m, 1H), 2.53-2.57 (m, 2H), 2.67-2.70 (m, 2H), 2.79-2.82 (m, 2H), 2.92 (dd, J=10.4 Hz, J=3.8 Hz, 2H), 3.67 (s, 3H), 6.64-6.69 (m, 3H), 7.07 (t, J=5.33 Hz, 1H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 34.1, 42.5, 48.1 (2C), 55.6, 61.1, 61.3 (2C), 112.5, 115.5, 122.0, 130.4, 142.9, 161.3; HRMS (ESI-Orbitrap) [M+H]+ calcd for C14H24N3O, 250.1914 found 250.1910.
ECO01-025-C2 piperidine-3,5-diamine: 3 mg, yellow oil
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.15 (q, J=12.0 Hz, 1H), 2.10-2.13 (m, 1H), 2.13 (t, J=10.4 Hz, 2H), 2.82-2.87 (m, 2H), 2.98 (ddd, J=12.3 Hz, J=4.09 Hz, J=1.57 Hz, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 39.8 (2C), 49.2, 51.7 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C5H14N3, 116.1182 found 116.1183.
ECO01-028-C 1-(2-methylphenethyl)piperidine-3,5-diamine: 13 mg, 28%, white paste;
1H NMR (500 MHz, CD3OD, 27° C.) δ 0.99 (q, J=11.5 Hz, 1H), 1.82 (t, J=10.4 Hz, 2H), 2.17 (d, J=10.8 Hz, 1H), 2.34 (s, 3H), 2.57-2.62 (m, 2H), 2.84-2.87 (m, 2H), 2.93-2.95 (m, 2H), 3.08-3.10 (m, 2H), 7.10-7.15 (m, 4H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 19.3, 31.2, 42.8, 48.1 (2C), 59.9, 61.5 (2C), 127.2, 127.4, 130.3, 131.3, 137.0, 139.1; HRMS (ESI-Orbitrap) [M+H]+ calcd for C14H24N3, 234.1965 found 234.1961.
ECO01-029-C 1-(4-methylphenethyl)piperidine-3,5-diamine: 17 mg, 36%, white paste;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.16 (q, J=10.8 Hz, 1H), 1.99 (t, J=10.2 Hz, 2H), 2.17 (d, J=12.8 Hz, 1H), 2.34 (s, 3H), 2.70 (t, J=8.7 Hz, 2H), 2.81 (t, J=8.8 Hz, 2H), 3.05-3.07 (m, 4H), 7.10-7.15 (m, 4H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 21.1, 33.6, 40.2, 47.9 (2C), 60.1 (2C), 61.1, 129.6 (2C), 130.1 (2C), 136.7, 138.1; HRMS (ESI-Orbitrap) [M+H]+ calcd for C14H24N3, 234.1965 found 234.1956.
ECO01-030-C 1-(3-methylphenethyl)piperidine-3,5-diamine: 12 mg, 26%, colorless paste;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.14 (q, J=10.9 Hz, 1H), 1.99 (t, J=9.4 Hz, 2H), 2.11 (d, J=12.3 Hz, 1H), 2.30 (s, 3H), 2.65-2.68 (m, 2H), 2.76-2.77 cm, 2H), 3.00-3.02 (m, 4H), 6.98-7.03 (m, 3H), 7.14 (t, J=7.5 Hz, 1H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 21.4, 33.9, 39.8, 47.9 (2C), 60.1 (2C), 61.1, 126.8, 127.9, 129.4, 130.4, 139.1, 141.2; HRMS (ESI-Orbitrap) [M+H]+ calcd for C14H24N3, 234.1965 found 234.1957.
ECO01-031-C 1-(2-methoxyphenethyl)piperidine-3,5-diamine: 18 mg, 37%, white solid;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.27 (q, J=11.0 Hz, 1H), 2.08 (t, J=9.0 Hz, 2H), 2.17 (d, J=11.8 Hz, 1H), 2.65 (t, J=8.7 Hz, 2H), 2.82 (t, J=8.8 Hz, 2H), 3.03 (d, J=10.5 Hz, 2H), 3.10 (t, J=9.6 Hz, 2H), 3.82 (s, 3H), 6.85 (t, J=7.1 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 7.12 (t, J=7.3 Hz, 1H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 28.5, 38.4, 47.8, 55.8, 59.1, 59.2 (3C), 111.5, 121.5, 128.7, 129.1, 131.2, 158.9. HRMS (ESI-Orbitrap) [M+H]+ calcd for C14H24N3O, 250.1914 found 250.1903.
ECO01-033-C 1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-3,5-diamine: 27 mg, 54%, pale brown solid;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.05 (q, J=11.2 Hz, 1H), 1.87-1.89 (m, 2H), 2.12 (d, J=11.4 Hz, 1H), 2.60-2.63 (m, 2H), 2.73-2.75 (m, 2H), 2.93-3.01 (m, 4H), 5.88 (s, 2H), 6.67-6.72 (m, 3H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 24.2, 33.7, 41.2, 47.9, 60.7 (2C), 61.2, 102.0, 109.1, 110.0, 122.5, 135.0, 147.3, 149.0; HRMS (ESI-Orbitrap) [M+H]+ calcd for C14H22N3O2, 264.1707 found 264.1695.
ECO01-035-C 1-(3-phenylpropyl)piperidine-3,5-diamine: 22 mg, 48%, brown paste;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.18 (q, J=10.2 Hz, 1H), 1.82 (m, 2H), 1.86 (br s, 1H), 2.13 (d, J=12.2 Hz, 2H), 2.44-2.49 (m, 2H), 2.66 (t, J=7.6 Hz, 2H), 2.92 (d, J=10.4 Hz, 2H), 3.05-3.08 (m, 2H), 7.15-7.21 (m, 3H), 7.25-7.28 (m, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 22.5, 28.0, 33.0, 46.5 (2C), 56.9, 58.3 (2C), 125.4 (2C), 127.9 (2C), 141.8 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C14H24N3, 234.1965 found 234.1969.
ECO01-037-C 1-phenylpiperidine-3,5-diamine: 17 mg, 40%, colorless paste;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.34-1.39 (m, 1H), 2.29-2.32 (m, 1H), 2.68 (t, J=10.8 Hz, 2H), 3.01-3.22 (m, 2H), 3.74-3.77 (m, 2H), 6.94 (t, J=7.3 Hz, 1H), 7.08 (d, J=8.5 Hz, 2H), 7.31-7.34 (m, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 38.4, 46.5 (2C), 55.6 (2C), 116.9 (2C), 120.0, 128.7 (2C), 150.8; HRMS (ESI-Orbitrap) [M+H]+ calcd for C11H18N3, 192.1495 found 192.1501.
ECO01-039-C 1-(4-(methylsulfonyl)phenethyl)piperidine-3,5-diamine: 14 mg, 26%, white paste;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.10 (q, J=11.2 Hz, 1H), 1.94-1.99 (m, 2H), 2.16 (d, J=12.2 Hz, 1H), 2.74-2.77 (m, 2H), 2.99 (t, J=7.6 Hz, 4H), 3.04 (d, J=10.5 Hz, 2H), 3.14 (s, 3H), 7.55 (d, J=8.2 Hz, 2H), 792 (d, J=8.2 Hz, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 32.4, 39.9, 43.0, 46.6 (2C), 58.7, 59.3 (2C), 127.0 (2C), 129.4 (2C), 138.4, 146.9; HRMS (ESI-Orbitrap) [M+H]+ calcd for C14H24N3O2S, 298.1584 found 298.1573.
ECO01-042-C 1-(benzo[d][1,3]dioxol-yl)piperidine-3,5-diamine: 10.6 mg, 22%, colorless oil;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.17 (q, J=8.4 Hz, 1H), 2.20-2.23 (m, 1H), 2.48 (t, J=7.1 Hz, 2H), 3.05-3.10 (m, 2H), 3.50-3.52 (m, 2H), 5.91 (s, 2H), 6.45-6.49 (m, 1H), 6.65-6.67 (m, 1H), 6.73-6.77 (m, 1H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 31.7, 40.1, 46.7 (2C), 58.1, 100.5, 100.7, 107.5, 109.8, 142.0, 146.9, 148.2; HRMS (ESI-Orbitrap) [M+H]+ calcd for C12H18N3O2, 236.1394 found 236.1386.
ECO01-055-C 1-(3-methoxyphenyl)piperidine-3,5-diamine: 12 mg, 26%, white paste;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.19 (q, J=11.3 Hz, 1H), 2.20-2.23 (m, 1H), 2.50 (t, J=7.3 Hz, 2H), 3.02-3.07 (m, 2H), 3.69 (dd, J=11.8, 5.3 Hz, 2H), 3.78 (s, 3H), 6.45 (dd, J=8.0, 3.4 Hz, 1H), 6.53-6.55 (m, 1H), 6.60 (dd, J=8.2, 3.5 Hz, 1H), 7.15 (t, J=8.2 Hz, 1H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 41.7, 47.9 (2C), 55.7, 57.6 (2C), 104.4, 106.2, 110.8, 130.9, 153.6, 162.1; HRMS (ESI-Orbitrap) [M+H]+ calcd for C12H20N3O, 222.1601 found 222.1595.
ECO01-056-C 1-(4-methoxyphenyl)piperidine-3,5-diamine: 21 mg, 46%, brown solid;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.13 (q, J=11.3 Hz, 1H), 2.17-2.21 (m, 1H), 2.39 (t, J=10.7 Hz, 2H), 3.03-3.07 (m, 2H), 3.50 (dd, J=11.0, 5.1 Hz, 2H), 3.76 (s, 3H), 6.84 (d, J=9.1 Hz, 2H), 6.97 (d, J=9.1 Hz, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 42.2, 48.5 (2C), 56.2, 59.9 (2C), 115.7 (2C), 120.8 (2C), 146.9, 156.1; HRMS (ESI-Orbitrap) [M+H]+ calcd for C12H20N3O, 222.1601 found 222.1592.
ECO02-003-C 3-(3,5-diaminopiperidin-1-yl)-N-phenylbenzamide: 15 mg, 28%, colorless oil;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.20 (q, J=11.5 Hz, 1H), 2.23 (m, 1H), 2.54 (t, J=7.4 Hz, 2H), 3.01-3.06 (m, 2H), 3.83 (dd, J=11.7, 5.3 Hz, 2H), 7.17 (t, J=7.4 Hz, 1H), 7.20-7.24 (m, 1H), 7.36-7.40 (m, 4H), 7.52 (s, 1H), 7.69 (d, J=7.9 Hz, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 42.5, 47.9 (2C), 57.4 (2C), 116.6, 119.5, 121.0, 122.5 (2C), 125.7, 129.8 (2C), 130.5, 137.2, 139.8, 152.4, 169.4; HRMS (ESI-Orbitrap) [M+H]+ calcd for C18H23N4O, 311.1866 found 311.1857.
ECO02-005-C 1-(4-ethoxyphenethyl)piperidine-3,5-diamine: 15 mg, 38%, white paste;
1H NMR (500 MHz, CD3OD, 27° C.) δ 0.97 (q, J=11.8 Hz, 1H), 1.37 (t, J=7.0 Hz, 3H), 1.81 (t, J=10.4 Hz, 2H), 2.13 (d, J=12.5 Hz, 1H), 2.60-2.64 (m, 2H), 2.75-2.78 (m, 2H), 2.90-2.94 (m, 2H), 3.03 (dd, J=11.0, 5.2 Hz, 2H), 4.00 (t, J=7.0 Hz, 2H), 6.83 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 13.7, 31.7, 40.3, 46.5, 59.5, 59.9, 63.0, 114.1 (2C), 129.1 (2C), 131.7, 157.4; HRMS (ESI-Orbitrap) [M+H]+ calcd for C15H26N3O, 264.2070 found 264.2059.
ECO02-007-C azepan-1-yl(4-(3,5-diaminopiperidin-1-yl)phenyl)methanone: 15 mg, 28%, colorless oil;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.17 (q, J=11.7 Hz, 1H), 1.55 (td, J=12.6, 7.5 Hz, 1H), 1.65 (br s, 6H), 1.86 (br s, 2H), 2.23 (td, J=12.5, 8.0 Hz, 1H), 2.50 (t, J=7.5 Hz, 2H), 2.94-2.99 (m, 2H), 3.23-3.34 (m, 1H), 3.54 (br s, 2H), 3.60 (d, J=5.3 Hz, 2H), 3.89 (dd, J=12.1, 4.0 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 25.9, 26.8, 27.5, 29.0, 32.3, 41.6, 46.2, 46.3, 55.4, 62.2, 62.5, 114.8 (2C), 126.2, 127.8 (2C), 151.5, 172.6; HRMS (ESI-Orbitrap) [M+H]+ calcd for C18H29N4O, 317.2336 found 317.2324.
ECO02-025-C 1-(4-methoxyphenethyl)piperidine-3,5-diamine: 16 mg, 25%, colorless paste;
1H NMR (500 MHz, CD3OD, 27° C.) δ 0.97 (q, J=11.5 Hz, 1H), 1.79 (t, J=10.5 Hz, 2H), 2.10-2.14 (m, 1H), 2.59-2.62 (m, 2H), 2.74-2.77 (m, 2H), 2.86-2.93 (m, 2H), 3.03 (dd, J=10.9, 4.7 Hz, 2H), 3.65 (s, 3H), 6.84 (d, J=8.6 Hz, 2H), 7.11 (d, J=8.6 Hz, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 33.2, 42.8, 48.1 (2C), 55.7 (2C), 61.4, 61.5, 115.0 (2C), 130.6 (2C), 133.2, 159.6.
ECO02-026-C 1-(4-phenylbutyl)piperidine-3,5-diamine: 12 mg, 25%, white paste;
1H NMR (500 MHz, CD3OD, 27° C.) δ 0.97 (q, J=11.4 Hz, 1H), 1.53-1.56 (m, 2H), 1.63-1.75 (m, 4H), 2.11-2.14 (m, 1H), 2.42-2.46 (m, 2H), 2.66 (t, J=7.4 Hz, 2H), 2.88-2.96 (m, 3H), 7.16-7.20 (m, 3H), 7.23-7.28 (m, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 25.6, 29.0, 35.2, 40.9 (2C), 46.5, 57.8, 59.9 (2C), 125.3, 127.9 (2C), 128.0 (2C), 142.2.
ECO02-027-C 1-phenethylpiperidine-3,5-diamine: 12 mg, 27%, colorless oil;
1H NMR (500 MHz, CD3OD, 27° C.) δ 0.94 (q, J=11.6 Hz, 1H), 1.77 (t, J=10.6 Hz, 2H), 2.11-2.17 (m, 1H), 2.64-2.67 (m, 2H), 2.82-2.91 (m, 4H), 3.04-3.08 (m, 2H), 7.17-7.23 (m, 3H), 7.25-7.30 (m, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 32.6, 42.0, 46.6 (2C), 59.8, 60.4 (2C), 125.7, 128.0 (2C), 128.2 (2C), 139.9.
ECO02-028-C 4-(2-(3,5-diaminopiperidin-1-yl)ethyl)phenol: 9.5 mg, 22%, colorless oil;
1H NMR (500 MHz, CD3OD, 27° C.) δ 0.96 (q, J=11.6 Hz, 1H), 1.77 (t, J=10.6 Hz, 2H), 2.13-2.16 (m, 1H), 2.60-2.64 (m, 2H), 2.72-2.75 (m, 2H), 2.87-2.92 (m, 2H), 3.03-3.07 (m, 2H), 6.71 (d, J=8.5 Hz, 2H), 7.04 (d, J=8.5 Hz, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 31.6, 41.6, 46.6 (2C), 60.2 (3C), 114.8 (2C), 129.1 (2C), 130.5, 155.3.
ECO02-029-C 1-(4′-methoxy-[1,1′-biphenyl]-4-yl)piperidine-3,5-diamine4-(2-((3S,5R)-3,5-diaminopiperidin-1-yl)ethyl)phenol: 9 mg, 17%, off-white paste;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.27 (q, J=11.2 Hz, 1H), 2.24-2.27 (m, 1H), 2.58 (dd, J=11.4, 10.3 Hz, 2H), 3.10-3.13 (m, 2H), 3.75 (dd, J=11.5, 5.1 Hz, 2H), 3.85 (s, 3H), 6.98 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 7.51 (t, J=8.5 Hz, 4H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 39.8, 46.5 (2C), 54.4, 56.0 (2C), 113.8 (2C), 116.9 (2C), 126.7 (2C), 126.9 (2C), 132.4, 133.2, 149.6, 158.7.
ECO02-030-C 1-(3,5-diaminopiperidin-1-yl)-2-(3-methoxyphenyl)ethanone: 13 mg, 26%, colorless paste;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.10 (q, J=11.6 Hz, 1H), 2.12-2.15 (m, 1H), 2.28 (dd, J=12.5, 10.9 Hz, 1H), 2.47-2.53 (m, 1H), 2.60-2.71 (m, 2H), 3.78 (s, 2H), 3.80 (s, 3H), 3.98-4.01 (m, 1H), 4.57-4.60 (m, 1H), 6.84-6.87 (m, 3H), 7.24-7.27 (m, 1H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 40.1, 41.7, 45.6, 47.1, 48.8, 52.8, 54.2, 112.0, 114.0, 120.6, 129.4, 136.3, 160.1, 170.7.
ECO02-031-C 1-(3,5-diaminopiperidin-1-yl)-2-(3-methoxyphenyl)ethanone: 7.5 mg, 15%, colorless oil;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.10 (q, J=12.2 Hz, 1H), 2.08-2.15 (m, 1H), 2.23-2.24 (m, 1H), 2.42-2.48 (m, 1H), 2.60-2.68 (m, 2H), 3.74 (br s, 2H), 3.80 (s, 3H), 3.99-4.02 (m, 1H), 4.57-4.59 (m, 1H), 6.90 (d, J=8.1 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 39.2, 41.8, 46.4, 47.1, 48.8, 52.7, 54.2, 113.8 (2C), 126.8, 129.3 (2C), 158.7, 171.2.
ECO03-002-C N-(4-(3,5-diaminopiperidin-1-yl)phenyl)benzamide: 9 mg, 17% colorless oil;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.09 (q, J=11.4 Hz, 1H), 2.20-2.23 (m, 1H), 2.40 (t, J=11.0 Hz, 2H), 2.96-3.03 (m, 2H), 3.69-3.73 (m, 2H), 7.01 (d, J=9.0 Hz, 2H), 7.51 (t, J=7.5 Hz, 2H), 7.56-7.58 (m, 3H), 7.93 (d, J=7.3 Hz, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 41.5, 46.6 (2C), 56.9 (2C), 116.7 (2C), 122.3 (2C), 127.1 (2C), 128.2 (2C), NH 130.7, 131.3, 134.9, 148.1, 167.2; HRMS (ESI-Orbitrap) [M+H]+ calcd for C18H23N4O, 311.1866 found 311.1864.
Hydrogenolysis under batch conditions according to the Journal of Organic Chemistry 2013, 78, 12236-12242
ECO01-041-C 1-(2,3-dihydro-1H-inden-2-yl)piperidine-3,5-diamine: 18 mg, 77%, beige solid;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.00 (q, J=11.7 Hz, 1H), 1.82 (t, J=10.7 Hz, 2H), 2.18-2.21 (m, 1H), 2.92-2.97 (m, 4H), 3.12-3.21 (m, 4H), 3.31 (quint, J=7.9 Hz, 1H), 7.16-7.18 (m, 2H), 7.23-7.24 (m, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 37.8 (2C), 43.3, 48.0 (2C), 59.9 (2C), 67.7, 125.4 (2C), 127.7 (2C), 142.3 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C14H22N3, 232.1808 found 232.1800.
AB-77 (3S,5R)-1-(3,4-dimethoxyphenethyl)piperidine-3,5-diamine: 62 mg, 88%, colorless oil; 1H NMR (400 MHz, CDCl3, δ) 0.89 (q, J=11.7 Hz, 1H), 1.25 (br s, 4H), 1.71 (t, J=10.1 Hz, 2H), 2.17 (d, J=11.7 Hz, 1H), 2.60-2.71 (m, 2H), 2.75-2.85 (m, 2H), 2.92-3.03 (m, 2H), 3.06 (d, J=10.1 Hz, 2H), 3.90 (s, 3H), 3.91 (s, 3H), 6.77-6.85 (m, 3H); 13C NMR (100 MHz, CDCl3, δ) 33.1, 44.9, 47.6, 55.8, 55.9, 60.3, 62.3, 111.1, 111.9, 120.5, 132.8, 147.2, 148.7; HRMS (ESI-TOF) [M+H]+ calcd for C15H26N3O2 280.2025. found 280.2029.
AB-81 (S)-methyl 2-((3S,5R)-3,5-diaminopiperidin-1-yl)-3-phenylpropanoate: 39 mg, 98%, colorless oil; 1H NMR (400 MHz, CDCl3, δ) 0.85 (q, J=11.4 Hz, 1H), 1.47 (br s, 4H), 1.89 (t, J=10.3 Hz, 1H), 2.05 (t, J=10.3 Hz, 1H), 2.12 (d, J=11.4 Hz, 1H), 2.80-2.99 (m, 4H), 3.04-3.15 (m, 2H), 3.50 (dd, J=7.9 Hz, J=7.0 Hz, 1H), 3.64 (s, 3H), 7.15-7.35 (m, 5H); 13C NMR (75 MHz, CDCl3, δ) 35.6, 44.8, 47.7, 47.9, 51.1, 56.3, 61.2, 69.1, 126.4, 128.3, 129.1, 138.1, 171.7; HRMS (ESI-TOF) [M+H]+ calcd for a C15H24N3O2 278.1869. found 278.1864; [α]D20 −19.0 (c 1.0, CH3OH).
AB-84 (3S,5R)-1-(2-(5-methoxy-1H-indol-3-yl)ethyl)piperidine-3,5-diamine: 29 mg, quantitative, colorless oil; 1H NMR (400 MHz, CDCl3, δ) 0.90 (q, J=11.4 Hz, 1H), 1.30 (br s, 4H), 1.75 (t, J=10.3 Hz, 2H), 2.19 (d, J=11.4 Hz, 1H), 2.74-2.81 (m, 2H), 2.95-3.07 (m, 4H), 3.13 (dd, J=10.3 Hz, J=3.2 Hz, 2H), 3.90 (s, 3H), 6.90 (d, J=8.8 Hz, 1H), 7.04 (s, 1H), 7.08 (s, 1H), 7.30 (d, J=8.8 Hz, 1H), 8.30 (s, 1H); 13C NMR (100 MHz, CDCl3, δ) 22.9, 45.0, 47.7, 56.0, 58.9, 62.4, 100.6, 111.9, 112.1, 113.9, 122.4, 127.8, 131.4, 153.9; HRMS (ESI-TOF) [M+H]+ calcd for C16H25N4O, 289.2028. found 289.2021.
AB-86 (3S,5R)-1-(1H-indol-5-yl)piperidine-3,5-diamine: 22 mg, 79%, colorless oil; 1H NMR (300 MHz, CDCl3, δ) 0.96 (q, J=11.6 Hz, 1H), 1.39 (br s, 4H), 2.24 (d, J=11.6 Hz, 1H), 2.33 (dd, J=11.1 Hz, J=10.3 Hz, 2H), 3.12 (m, 2H), 3.60 (dd, J=11.1 Hz, J=4.4 Hz, 2H), 6.48 (br s, 1H), 6.97 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 7.17 (t, J=2.7 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 8.34 (br s, 1H); 13C NMR (75 MHz, CDCl3, δ) 44.7, 47.8, 61.3, 102.3, 108.5, 111.5, 116.4, 124.7, 128.3, 131.4, 145.6; HRMS (ESI-TOF) [M+H]+ calcd for C13H19N4 231.1610. found 231.1606.
AB-103 (3S,3′R,3″S,5R,5′S,5″R)-1′-(3,4-dimethoxyphenethyl)-[1,3′:5′,1″-terpiperidine]-3,3″,5,5″-tetraamine: 44 mg, quantitative, colorless oil; 1H NMR (500 MHz, CD3OD, δ) 1.55-1.70 (m, 3H), 2.12 (d, J=10.9 Hz, 1H), 2.45-2.56 (m, 6H), 2.60-2.69 (m, 2H), 2.95-3.11 (m, 6H), 3.15-3.26 (m, 4H), 3.30-3.37 (m, 6H), 3.82 (s, 3H), 3.86 (s, 3H), 6.84 (d, J=8.5 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.94 (s, 1H); 13C NMR (125 MHz, CD3OD, 5) 28.7, 32.3, 34.5, 48.0, 48.1, 52.8, 53.5, 55.2, 56.7, 60.0, 60.8, 113.5, 114.0, 122.2, 132.4, 149.4, 150.6; HRMS (ESI-TOF) [M+Na]+ calcd for C25H45N7O2Na, 498.3532. found 498.3526.
AB-109 F3 (R)-methyl 2-((3S,5R)-3,5-diaminopiperidin-1-yl)-3-phenylpropanoate: 13 mg, 52%, colorless oil; 1H NMR (400 MHz, CDCl3, δ) 0.85 (q, J=11.4 Hz, 1H), 1.47 (br s, 4H), 1.89 (t, J=10.3 Hz, 1H), 2.05 (t, J=10.3 Hz, 1H), 2.12 (d, J=11.4 Hz, 1H), 2.80-2.99 (m, 4H), 3.04-3.15 (m, 2H), 3.50 (dd, J=7.9 Hz, J=7.0 Hz, 1H), 3.64 (s, 3H), 7.15-7.35 (m, 5H); 13C NMR (75 MHz, CDCl3, δ) 35.6, 44.8, 47.7, 47.9, 51.1, 56.3, 61.2, 69.1, 126.4, 128.3, 129.1, 138.1, 171.7; HRMS (ESI-TOF) [M+H]+ calcd for C15H24N3O2 278.1869. found 278.1864; [α]D20=+21.1 (c=1.0, MeOH).
AB-116 (3S,5R)-1-(3,4,5-trimethoxyphenyl)piperidine-3,5-diamine: 45 mg, 88%, colorless oil; 1H NMR (300 MHz, CD3OD, δ) 1.06 (q, J=11.4 Hz, 1H), 2.20 (br d, J=11.4 Hz, 1H), 2.35 (dd, J=11.6 Hz, J=10.4 Hz, 2H), 2.95 (m, 2H), 3.65 (dd, J=11.6 Hz, J=4.3 Hz, 2H), 3.71 (s, 3H), 3.84 (s, 6H), 6.27 (s, 2H); 13C NMR (75 MHz, CD3OD, δ) 41.9, 46.8, 55.1, 57.5, 59.9, 95.0, 131.5, 148.2, 153.4; HRMS (ESI-TOF) [M+H]+ calcd for C14H24N3O3 282.1818. found 282.1815.
AB-120 N-(4-((3S,5R)-3,5-diaminopiperidin-1-yl)-2-hydroxyphenyl)benzamide: 21 mg, 95%, orange oil; 1H NMR (300 MHz, CD3OD, δ) 1.45 (q, J=11.0 Hz, 1H), 2.26 (d, J=11.0 Hz, 1H), 2.74 (dd, J=11.9 Hz, J=9.2 Hz, 2H), 3.22 (m, 2H), 3.66 (dd, J=11.9 Hz, J=2.9 Hz, 2H), 6.57 (dd, J=8.8 Hz, J=2.3 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 7.52-7.60 (m, 4H), 7.97 (d, J=8.0 Hz, 2H); 13C NMR (75 MHz, CD3OD, δ) 36.4, 46.3, 54.6, 105.1, 108.4, 118.8, 124.3, 127.2, 128.4, 131.6, 134.2, 149.5, 150.2, 167.3; HRMS (ESI-TOF) [M+H]+ calcd for C18H23N4O2 327.1821. found 327.1821.
AB-378 (3S,5R)-1-(4-methoxybenzyl)piperidine-3,5-diamine 40 mg, quantitative, colorless oil; 1H NMR (250 MHz, CD3OD, δ) 0.84 (q, J=11.6 Hz, 1H), 1.62 (t, J=10.4 Hz, 2H), 2.09 (d, J=11.6 Hz, 1H), 2.75-2.87 (m, 2H), 2.94 (dd, J=10.4 Hz, J=4.4 Hz, 2H), 3.50 (s, 2H), 3.77 (s, 3H), 6.86 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H); 13C NMR (125 MHz, CD3OD, δ) 43.3, 48.1, 55.8, 61.5, 63.0, 114.8, 130.4, 131.9, 160.6; HRMS (ESI-Orbitrap) [M+H]+ calcd for C13H22N3O, 236.1762. found 236.1756.
AB289-2 N-(6-amino-1-(3,5-diaminopiperidin-1-yl)-1-oxohexan-2-yl)-4-ethylbenzamide 1H NMR (500 MHz, (CD3)2SO, 70° C.) δ=1.27 (t, J=7.6, 3H); 1.44-1.67 (m, 2H); 1.72-1.80 (m, 2H); 1.85-1.96 (m, 3H); 2.62 (broad d, J=10.8, 1H); 2.72 (q, J=7.6, 2H); 2.70-2.78 (m, 1H); 2.97 (t, J=7.3, 2H); 3.27-3.37 (m, 2H); 3.51-3.69 (m, 1H); 4.45-4.61 (m, 1H); 4.84-4.91 (m, 1H); 4.91-5.04 (m, 1H); 7.33 (d, J=8.0, 2H); 7.80 (d, J=8.0, 2H) 13C NMR (125 MHz, (CD3)2SO, 70° C.) δ=15.8, 24.0, 28.3, 29.8, 31.8, 34.3, 40.5, 45.2, 46.2, 47.0, 49.9, 51.5, 128.7 (2C), 129.1 (2C), 132.1, 150.3, 170.6, 173.6. HRMS (ES+) m/z [M+H]+ Calcd for C20H34N5O2 376.27125. Found 376.27057.
AB289-1 N-(6-amino-1-(3,5-diaminopiperidin-1-yl)-1-oxohexan-2-yl)-4-(1-hydroxyethyl)benzamide 1H NMR (500 MHz, (CD3)2SO, 70° C.) δ=1.46 (d, J=6.4, 3H); 1.54 1.60 (2 broad s, 2H); 1.76 (broad s, 2H); 1.85-1.92 (m, 3H, H4); 2.62 (broad s, 1H); 2.70-2.78 (m, 1H); 2.97 (broad s, 2H); 3.30-3.37 (m, 2H); 3.55-3.68 (m, 1H); 4.45-4.59 m, 1H); 4.87-5.05 (m, 3H); 7.49 (d, J=8.0, 2H); 7.86 (d, J=8.0, 2H) 13C NMR (125 MHz, (CD3)2SO, 70° C.) δ=23.9, 25.6, 28.3, 31.8, 34.2, 40.5, 45.2, 46.2, 47.0, 48.9, 51.6, 70.3, 126.6 (2C), 128.7 (2C), 133.4, 152.2, 170.4, 173.6.
AB287-F1 1-((3S,5R)-3,5-diaminopiperidin-1-yl)-2-(3,4-dimethoxyphenyl)ethanone: 16 mg, 76%, colorless oil; 1H NMR (500 MHz, CD3OD, δ) 1.43 (q, J=11.8 Hz, 1H), 2.21 (d, J=11.8 Hz, 1H), 2.80-2.87 (m, 2H), 2.95-3.10 (m, 2H), 3.76 (d, J=4.9 Hz, 2H), 3.81 (s, 3H), 3.82 (s, 3H), 3.99 (d, J=13.5 Hz, 1H), 4.41 (d, J=13.5 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H), 6.84 (s, 1H), 6.86 (d, J=8.2 Hz, 1H); 13C NMR (125 MHz, CD3OD, δ) 38.2, 41.0, 47.0, 47.5, 48.0, 52.4, 56.7, 113.4, 114.0, 122.5, 128.9, 149.8, 150.9, 173.2; HRMS (ESI-Orbitrap) [M+H]+ calcd for C15H24N3O3 294.1817. found 294.1815.
Synthesis of RA20
2-Bromo-1-tricyclo[8.2.2.24,7]hexadeca-1 (13),4,6,10(14),11,15-hexaen-5-yl-ethanone (150 mg, 0.45 mmol) and NaN3 (31 mg, 0.47 mmol) were stirred at room temperature in H2O/acetone (1:2; 4.5 mL) for 3 h. (4-tert-Butoxycarbonylamino-2-prop-2-ynyloxy-cyclopentyl)-carbamic acid tert-butyl ester (135 mg, 0.38 mmol) in acetone (1.5 mL) was then added, followed by the addition of sodium ascorbate (1 M, 0.19 mL) and CuSO4 (1 M, 0.19 mL). The resultant mixture was then stirred at room temperature until complete consumption of the alkyne and was monitored by TLC. After addition of water the product was extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo. The crude product was purified flash chromatography on silica gel (cyclohexane:AcOEt 50:50) to give 203 mg (83%) of the product.
1H NMR (400 MHz, CDCl3): 1.44 (19H, bs), 1.87 (1H, bs), 2.04 (1H, bs), 2.55 (1H, m), 2.85 (1H, m), 2.99-3.08 (2H, m), 3.12-3.25 (4H, m), 3.85 (1H, m), 3.93 (1H, s), 3.97 (1H, s), 4.08 (1H, bs), 4.77 (2H, m, H-6), 5.29 (1H, d, 17.6, H-9), 5.85 (1H, d, 17.6, H-9), 6.38 (1H, d, 7.8), 6.43 (1H, d, 7.8), 6.51 (1H, d, 7.8), 6.55 (1H, d, 7.8), 6.59 (1H, d, 7.8), 6.74 (1H, d, 7.8), 7.02 (1H, s), 7.75 (1H, s, H-8).
13C NMR (75 MHz, CDCl3): 28.5 (6) (CH3), 34.8 (CH2), 35.1 (2)(CH2), 35.9 (CH2), 37.2 (2)(CH2), 49.2 (CH), 55.8 (CH), 56.3 (CH2), 62.8 (CH2) 79.2 (2)(C), 83.5 (CH), 124.6 (CH), 131.2 (CH), 132.2 (CH), 132.9 (CH), 133.0 (CH), 133.1 (CH), 134.3 (C), 136.9 (CH), 137.8 (CH), 139.3 (C),140.1 (C), 140.4 (C), 142.7 (C), 145.7 (C), 155.5 (2)(C), 192.1 (C).
MS (ES): 646 (MH+), 688 (MNa+).
A solution of the Boc-protected triazole derivative in AcOEt (173 mg, 0.26 mmol) was cooled in an ice-bath and HCl (g) was bubbled inside until the formation of a white precipitate (few minutes). The solution was then filtered and rinsed with AcOEt and DCM to obtain 130 mg (96%) of RA 20 hydrochloride.
1H NMR (300 MHz, CD3OD): 1.86 (1H, m), 2.27 (2H, t, 7.6), 2.68 (1H, dt), 2.92 (1H, m), 3.04-3.28 (6H, m), 3.65 (1H, m), 3.89 (2H, m), 4.35 (1H, m), 4.76 (1H, d, 12.2), 4.84 (1H, d, 12.2), 5.70 (1H, d, 17.8, H-9), 6.16 (1H, d, 17.8, H-9), 6.46 (1H, d, 7.8), 6.55-6.63 (3H, m), 6.79 (1H, d, 7.8), 6.86 (1H, d, 7.8), 7.29 (1H, s), 8.16 (1H, s, H-8).
13C NMR (75 MHz, CD3OD): 32.7 (CH2), 34.0 (CH2), 34.2 (CH2), 34.5 (CH2), 34.6 (CH2), 35.5 (CH2), 47.4 (CH), 55.1 (CH), 58.1 (CH2), 61.5 (CH2), 80.4 (CH), 83.5 (CH), 128.5 (CH), 131.0 (CH), 132.1 (CH), 132.8 (CH), 133.2 (CH), 133.7 (CH), 133.9 (C), 136.8 (CH), 137.9 (CH), 139.6 (C), 139.8 (C), 140.8 (C), 142.6 (C), 191.5 (C).
MS (ES): 446 (MH+), 468 (MNa+).
PDA25 1-(3,4-dimethoxybenzyl)piperidine-3,5-diamine 1H NMR (500 MHz, CD3OD) 5=1.55 (q, J=11.9, 1H, H4); 2.13 (t, J=11.0, 2H); 2.49 (d, J=11.9, 1H); 3.21 (dd, J=11.0, J=4.3, 2H; 3.45-3.47 (m, 2H); 3.68 (s, 2H); 3.77-3.85 (m, 6H); 6.88-6.95 (m, 3H) 13C NMR (125 MHz, CD3OD) δ=32.4, 45.8 (2C); 53.9 (2C), 55.0, 55.1, 61.0, 111.5, 112.6, 121.6, 128.8, 148.9, 149.3. HRMS (APCI+-Orbitrap) [M+H]+ calcd for C14H24N3O2 266.18685. Found 266.18570.
AB541 1-(adamantan-1-yl)piperidine-3,5-diamine 1H NMR (500 MHz, CD3OD) δ=0.86 (q, J5=11.4); 1.62-1.78 (m, 12H); 1.81 (d, J=10.5, 2H); 2.04-2.15 (m, 4H); 2.71-2.82 (m, 2H); 3.19 (dd, J=10.5, J=4.3, 2H); 13C NMR (125 MHz, CD3OD) δ=31.4 (3C), 38.0, 39.6 (6C), 44.1, 48.9 (2C), 53.5, 55.7. HRMS (ESI-Orbitrap) [M+H]+ calcd for C15H58N3 250.22832. Found 250.22810.
AB542 1-isopropylpiperidine-3,5-diamine 1H NMR (500 MHz, CD3OD) δ=0.88 (q, J=11.6, 1 H); 1.07 1.08 (2s, 2X3H); 1.83 (t, J=10.7, 2H); 2.07-2.16 (m, 1H); 2.73-2.86 (m, 3H); 2.91 (dd, J=10.7, J=4.1, 2H) 13C NMR (125 MHz, CD3OD) 5=18.4 (2C), 43.3, 48.5 (2C), 55.8 (C7), 57.2 (2C)
Acylation of Bicyclic Hydrzine
ECO02-018-C dibenzyl 3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate (350 mg, 0.918 mmol) was solubilized in dry CH2Cl2 (5 mL) and in dry DMF (0.2 mL). methoxyphenylacetic acid (168 mg, 1.01 mmol), triethylamine (0.87 ml, 6.43 mmol) and EDC (264 mg, 1.38 mmol) were added. Mixture was stirred at RT under Ar overnight. The reaction was monitored by TLC until disappearance of the initial product. The solution was quenched with NaHCO3, extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and evaporated. Flash chromatography (Cyclohexane to Cyclohexane/Ethyl acetate 4/6) afforded ECO02-018-C (178 mg, 37%), colorless oil.
ECO02-018-C dibenzyl 3-(2-(3 methoxyphenyl)acetyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 178 mg, 37%, colorless oil;
1H NMR (500 MHz, (CD3)2SO, 60° C.) δ 1.95-1.97 (m, 1H), 2.09 (d, J=11.6 Hz, 1H), 2.86 (br s, 1H), 3.20 (s, 1H), 3.48 (br s, 1H), 3.58 (br s, 1H), 3.72 (s, 3H), 4.08 (br s, 1H), 4.50 (br s 3H), 5.11 (s, 4H), 6.70-6.73 (m, 2H), 6.79 (dd, J=7.8, 3.3 Hz, 1H), 7.18 (t, J=7.8 Hz, 1H), 7.35 (br s, 10H); 13C NMR (125 MHz, (CD3)2SO, 60° C.) δ 35.0, 40.6, 46.5, 49.9, 55.5 (2C), 55.9, 68.2 (2C), 112.9, 115.8, 122.2, 128.4-130.1 (12C), 137.0, 137.7, 156.8 (2C), 160.2, 171.6; HRMS (ESI-Orbitrap) [M+H]+ calcd for C30H32N3O6, 530.2286 found 530.2283.
ECO02-021-C dibenzyl 3-(2-(4-methoxyphenyl)acetyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 167 mg, 34%, colorless oil;
1H NMR (500 MHz, (CD3)2SO, 60° C.) δ 1.94-1.98 (m, 1H), 2.08 (d, J=11.5 Hz, 1H), 2.84 (br s, 1H), 3.20-3.25 (m, 1H), 3.44 (br s, 1H), 3.53 (br s, 1H), 3.72 (s, 3H), 4.06 (br s, 1H), 4.50 (br s 3H), 5.11 (s, 4H), 6.84 (d, J=8.2 Hz, 2H), 7.06 (d, J=8.2 Hz, 2H), 7.35 (br s, 10H); 13C NMR (125 MHz, (CD3)2SO, 60° C.) δ 34.0, 38.8, 45.7, 48.6, 54.5 (2C), 55.1, 67.2 (2C), 113.7 (2C), 127.2-128.3 (12C), 130.2, 136.1 (2C), 156.0 (2C), 158.0, 171.0; HRMS (ESI-Orbitrap) [M+H]+ calcd for C30H32N3O6, 530.2286 found 530.2278.
Suzuki Coupling of Bicyclic Hydrazines
ECO02-008-C (414 mg, 0.774 mmol), was solubilized in DMF (4 mL) and water (1.2 mL). 4-methoxyphenylboronic acid (141 mg, 0.929 mmol), K2CO3 (374 mg, 2.71 mmol), and Pd(Ph3)4 (44.7 mg, 0.0387 mmol) were added under Ar. Mixture was stirred at 90° C., overnight under Ar. The reaction was monitored by TLC until disappearance of the initial product. The solution was quenched with NaHCO3, extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and evaporated. Flash chromatography (Cyclohexane to Cyclohexane/Ethyl acetate 7/3) afforded ECO02-023-C (273 mg, 48%), white solid.
ECO02-023-C dibenzyl 3-(4′-methoxy-[1,1′-biphenyl]-4-yl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 273 mg, 48%, white solid;
1H NMR (500 MHz, (CD3)2SO, 60° C.) δ 2.01-2.05 (m, 1H), 2.08-2.12 (m, 1H), 2.91 (br s, 2H), 3.79 (s, 3H), 3.84 (br s, 2H), 4.63 (br s 2H), 5.11-5.19 (s, 4H), 6.76-6.79 (m, 2H), 6.99 (d, J=8.8 Hz, 2H), 7.32 (br s, 10H), 7.79 (d, J=8.7 Hz, 2H), 7.51 (d, J=7.9 Hz, 2H); 13C NMR (125 MHz, (CD3)2SO, 60° C.) δ 34.0, 48.4, 50.5, 55.2 (3C), 67.0 (2C), 113.7, 114.4, 126.6-128.3 (16C), 129.6, 131.4, 132.8, 136.2, 148.9, 156.2 (2C), 158.2; HRMS (ESI-Orbitrap) [M+H]+ calcd for C34H34N3O5, 564.2493 found 564.2480.
Acetylation of Bicyclic Hydrazine
ECO02-045-C dibenzyl 3-(3-acetoxyphenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 105 mg, quant., transparent oil;
1H NMR (500 MHz, (CD3)2SO, 60° C., δ) 1.60 (br s, 2H), 2.25 (br s, 5H), 2.57 (br s, 2H), 3.07 (br s, 2H), 3.20 (br s, 2H), 4.37 (br s, 2H), 5.13 (br s, 4H), 6.92 (br s, 2H), 7.04 (br s, 1H), 7.34 (br s, 11H); 13C NMR (125 MHz, (CD3)2SO, 60° C., δ) 20.8, 28.9, 35.7, 52.1, 54.7, 55.8 (2C), 57.4, 66.8 (2C), 119.2, 121.6, 125.8, 127.5-129.1 (11C), 136.4 (2C), 141.9, 150.6, 156.8 (2C), 168.9; HRMS (ESI-Orbitrap) [M+H]+ calcd for C31H34N3O6, 544.2442 found 544.2440.
Reductive Amination of Protected Diaminopiperidines
ECO02-056-C
ECO02-051-C (65 mg, 0.206 mmol) was solubilized in MeOH (1.5 mL) and DCM (1.5 mL). Freshly distilled benzaldehyde (328 mg, 0.309 mmol) and MgSO4 (tip of spatula) were added. Mixture was stirred 1 h under Ar at RT. NaBH(OAc)3 (131 mg, 0.618 mmol), was added and mixture was stirred 1 h. NaBH(OAc)3 (87 mg, 0.412 mmol) was added and mixture was stirred overnight under Ar at RT. The reaction was monitored by TLC (not completed reaction). The solution was quenched with water, extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and evaporated. Flash chromatography (CH2Cl2 to CH2Cl2/MeOH/NH4OH 90/9/1) afforded ECO02-056-C (31 mg, 40%), white solid.
ECO02-056-C di-tert-butyl (1-benzylpiperidine-3,5-diyl)dicarbamate: 31 mg, 44%, white solid;
1H NMR (500 MHz, CD3OD, 27° C.) δ 0.98 (q, J=12.0 Hz, 1H), 1.30 (br s, 18H), 1.63 (br s, 2H), 1.91-1.96 (m, 1H), 2.82-2.86 (m, 2H), 3.45-3.49 (m, 4H), 7.10-7.17 (m, 1H), 7.21 (br s, 4H); 13C NMR (125 MHz, CD3OD, 27° C., δ) 28.7 (6C), 38.2, 47.7 (2C), 58.9 (2C), 63.4, 80.0 (2C), 128.4, 129.4 (2C), 130.4 (2C), 138.8, 157.6 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C22H36N3O4, 406.2700 found 406.2706.
ECO02-058-C di-tert-butyl (1-(furan-2-ylmethyl)piperidine-3,5-diyl)dicarbamate: 41 mg, 51%, pale yellow solid;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.07 (q, J=11.8 Hz, 1H), 1.43 (br s, 18H), 1.74-1.83 (m, 2H), 2.03 (br s, 1H), 2.93-2.99 (m, 2H), 3.56-3.66 (m, 4H), 6.27-6.30 (m, 1H), 6.36-6.39 (m, 1H), 7.46 (s, 1H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 27.3 (6C), 36.4, 46.2 (2C), 53.4, 56.9 (2C), 78.6 (2C), 108.8, 109.8, 142.1, 151.0, 156.1 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C20H34N3O5, 396.2488 found 396.2493.
ECO02-059-C di-tert-butyl (1-(4-(pyrrolidin-1-yl)benzyl)piperidine-3,5-diyl)dicarbamate: 41 mg, 55%, off-white solid;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.07 (q, J=11.8 Hz, 1H), 1.42 (br s, 18H), 1.71 (br s, 2H), 1.97-2.08 (m, 5H), 2.90-2.99 (m, 2H), 3.23-3.28 (m, 4H), 3.46 (br s, 2H), 3.61 (br s, 2H), 6.55 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 24.9 (2C), 27.3 (6C), 36.8, 46.2 (2C), 48.1, 48.2, 57.1 (2C), 61.6, 78.6 (2C), 111.2 (2C), 123.1, 130.1 (2C), 147.7, 156.1 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C26H43N4O4, 475.3279 found 475.3278.
ECO02-060-C di-tert-butyl (1-((6-methoxy-1-methyl-1H-indol-3-yl)methyl)piperidine-3,5-diyl)dicarbamate: 25 mg, 32%, white solid;
1H NMR (500 MHz, CDCl3, 27° C.) δ 1.42 (br s, 18H), 1.98 (br s, 2H), 2.20 (br s, 2H), 2.76 (br s, 2H), 3.56-3.79 (m, 7H), 3.89 (s, 3H), 4.67 (br s, 2H, NH), 6.76 (d, J=2.2 Hz, 2H), 6.79 (d, J=2.2 Hz, 1H), 6.80 (d, J=2.2 Hz, 1H), 6.85 (br s, 1H), 7.55 (d, J=8.9 Hz, 1H); 13C NMR (125 MHz, CDCl3, 27° C.) δ 28.3 (6C), 32.7, 46.2 (2C), 53.1, 55.8, 57.8 (3C), 79.2 (2C), 92.9, 109.1, 110.5, 120.2, 122.7, 127.2, 137.8, 155.1 (2C), 156.5; HRMS (ESI-Orbitrap) [M+H]+ calcd for C26H41N4O5, 489.3071 found 489.3077.
ECO02-062-C di-tert-butyl 1-(4-(dimethylamino)benzyl)piperidine-3,5-diyl)dicarbamate: 26 mg, 28%, white solid;
1H NMR (500 MHz, CDCl3, 27° C.) δ 1.20-1.45 (m, 18H), 1.67 (br s, 1H), 2.01 (br s, 3H), 2.70 (br s, 2H), 2.91 (s, 6H), 3.45 (br s, 2H), 3.72 (br s, 2H), 4.60 (br s, 2H, NH), 6.67 (d, J=8.3 Hz, 2H), 7.12 (d, J=8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3, 27° C.) δ 28.4 (6C), 36.2, 40.7 (2C), 46.2 (2C), 57.7 (2C), 61.8, 79.3 (2C), 112.5 (2C), 125.2, 130.0 (2C), 150.0, 155.0 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C24H41N4O4, 449.3122 found 449.3127.
Deprotection of Diaminopiperidines
ECO02-056-C (31 mg, 0.074 mmol) was solubilized in HCl 4M/Dioxane (1 mL). Mixture was stirred under Ar, 0.5 h at RT. Evaporation of the solvents crude gives ECO02-063-C (28 mg, quant.), white solid._ECO02-064-C and ECO02-065-C were purified by preparative HPLC using a C18 Hypersil column (elution gradient H2O/MeCN 80/20 to 20/80).
ECO02-063-C 1-benzylpiperidine-3,5-diamine trihydrochloride: 28 mg, quant., white solid;
1H NMR (500 MHz, CD3OD, 27° C.) δ 2.02 (q, J=12.1 Hz, 1H), 2.66 (d, J=11.7 Hz, 1H), 3.26 (t, J=11.7 Hz, 2H), 3.67 (d, J=4.6 Hz, 2H), 3.85-3.90 (m, 2H), 4.55 (s, 2H), 7.51-7.52 (m, 3H), 7.68-7.69 (m, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 30.4, 43.4 (2C), 51.0 (2C), 60.8, 128.9 (2C), 129.9 (2C), 131.1 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C12H20N3, 206.1652 found 206.1658.
ECO02-064-C 1-(3,5-dimethoxybenzyl)piperidine-3,5-diamine: 21 mg, 95%, white solid;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.56 (q, J=11.8 Hz, 1H), 2.11 (t, J=10.9 Hz, 2H), 2.52 (d, J=11.6 Hz, 1H), 3.18-3.22 (m, 2H), 3.40-3.45 m, 2H), 3.65 (s, 2H), 3.78 (s, 6H), 6.40-6.43 (m, 1H), 6.53-6.54 (m, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 34.0, 47.5 (2C), 55.7 (2C), 55.8 (2C), 62.9, 110.4, 108.1 (2C), 140.5, 162.6 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C14H24N3O2, 266.1863 found 266.1862.
ECO02-068-C 1-(isoquinolin-5-ylmethyl)piperidine-3,5-diamine trihydrochloride: 6 mg, 83%, yellow paste;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.63 (q, J=11.8 Hz, 1H), 2.34 (t, J=10.5 Hz, 1H), 2.52 (d, J=11.7 Hz, 2H), 3.26-3.29 (m, 2H), 3.44-3.46 (m, 2H), 4.33 (s, 2H), 8.06 (t, J=8.2, 7.2 Hz, 1H), 8.28 (d, J=7.1 Hz, 1H), 8.52 (d, J=8.3 Hz, 1H), 8.66 (d, J=6.7 Hz, 1H), 8.90 (d, J=6.6 Hz, 1H), 9.84 (s, 1H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 32.3, 45.8 (2C), 54.0 (2C), 58.0, 123.1, 128.3, 130.5, 130.6, 131.0, 132.0, 138.0, 138.3, 147.2; HRMS (ESI-Orbitrap) [M+H]+ calcd for C15H21N4, 257.1765 found 257.1761.
ECO02-069-C 1-(4-(dimethylamino)benzyl)piperidine-3,5-diamine H2N NH2 trihydrochloride: 20 mg, quant., beige solid;
1H NMR (500 MHz, D2O, 27° C.) δ 1.86 (q, J=12.1 Hz, 1H), 2.67-2.70 (m, 1H), 2.92 (t, J=11.7 Hz, 2H), 3.36 (s, 6H), 3.63 (s, 6H), 3.65-3.69 (m, 2H), 3.72-3.77 (m, 2H), 4.39 (s, 2H), 7.76 (s, 4H); 13C NMR (125 MHz, D2O, 27° C.) δ 43.2 (2C), 43.7, 46.4 (2C), 60.3 (2C), 62.9, 120.5 (2C), 129.2 (2C), 132.9, 143.0; HRMS (ESI-Orbitrap) [M+H]+ calcd for C14H25N4, 249.2078 found 249.2074.
ECO03-001-B 1-(phenylsulfonyl)piperidine-3,5-diamine: 43 mg, quant., colorless oil;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.67 (q, J=11.9 Hz, 1H), 2.49 (t, J=11.3 Hz, 2H), 2.57 (d, J=11.8 Hz), 3.52-3.55 (m, 2H), 4.15-4.19 (m, 2H), 7.67-7.71 (m, 2H), 7.76 (t, J=7.4 Hz, 1H), 7.87 (d, J=7.5 Hz, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 31.8, 45.6 (2C), 46.9 (2C), 127.2 (2C), 128.4 (2C), 133.5, 136.1; HRMS (ESI-Orbitrap) [M+H]+ calcd for C11H18N3O2S, 366.2023 found 366.2020.
Acylation of Diaminopiperidines
ECO01-026-C2 (100 mg, 0.401 mmol) was solubilized in acetic anhydride (2.30 mL). Anhydrous pyridine (0.30 mL) and DMAP (2.4 mg, 0.020 mmol) were added. Mixture was stirred under Ar, 3 h at RT. The reaction was monitored by TLC until disappearance of the initial product. In an ice bath, the solution was quenched with NaHCO3, extracted with Ethyl Acetate. The organic layer was dried over MgSO4, filtered and evaporated. Flash chromatography (CH2Cl2 to CH2Cl2/MeOH/NH4OH 90/9/1) afforded ECO02-072-C (26 mg, 19%), white solid.
ECO02-072-C N,N′-(1-(3-methoxyphenethyl)piperidine-3,5-diyl)diacetamide: 26 mg, 19%, white solid;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.21 (q, J=10.5 Hz, 1H), 1.86 (t, J=10.7 Hz, 2H), 1.94 (s, 6H), 2.11-2.13 (m, 1H), 2.66-2.69 (m, 2H), 2.77-2.80 (m, 2H), 3.11 (dd, J=10.5, 4.0 Hz, 2H), 3.79 (s, 3H), 3.93-3.99 (m, 2H), 6.75 (dd, J=8.1, 2.6 Hz, 1H), 6.79-6.80 (m, 2H), 7.18 (t, J=8.1 Hz, 1H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 21.2 (2C), 32.8, 35.8, 45.2 (2C), 54.2, 57.0 (2C), 59.4, 111.2, 114.0, 120.7, 129.0, 141.5, 159.9, 171.3 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C18H28N3O3, 334.2125 found 334.2125.
Sulfonylation of Diaminopiperidines
ECO02-072-C (100 mg, 0.401 mmol) was solubilized in anhydrous CH2Cl2 (1 mL). Anhydrous pyridine (36 μL, 0.441 mmol) was added. At 0° C., methane sulfonyl chloride (68 μL, 0.882 mmol) was added. Mixture was stirred 10 min at 0° C. and at RT for 7 h under Ar. The reaction was monitored by TLC until disappearance of the initial product. Mixture was quenched with water and NaOH 3M, extracted with CH2Cl2. The organic layer was washed with a saturated aqueous solution of NaCl, dried over MgSO4, filtered and evaporated. Flash chromatography (CH2Cl2 to CH2Cl2/MeOH/NH4OH 90/9/1) afforded mono-substituted compound ECO02-073-C (5.5 mg) as a yellow oil. The aqueous layer was adjusted at pH=7 with HCl 3M and extracted with Ethyl Acetate. The organic layer was washed with NaCl sat, dried over MgSO4, filtered and evaporated. Crude product was obtained to give ECO02-073-B2 (84 mg, 52%), white solid.
ECO02-073-C rac-cis-N-(5-amino-1-(3-methoxyphenethyl)piperidin-3-yl) methanesulfonamide: 5.5 mg, yellow oil;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.11 (q, J=11.8 Hz, 1H), 1.78 (t, J=10.6 Hz, 1H), 1.90 (t, J=10.7 Hz, 1H), 2.21-2.24 (m, 1H), 2.67-2.69 (m, 2H), 2.79-2.80 (m, 2H), 2.90-2.94 (m, 1H), 2.97 (s, 3H), 3.04-3.08 (m, 1H), 3.15-3.19 (m, 1H), 3.41-3.46 (m, 1H), 3.79 (s, 3H), 6.75-6.81 (m, 3H), 7.19 (t, J=8.0 Hz, 1H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 34.1, 41.4, 41.5, 48.1, 50.5, 55.6, 60.3, 60.8, 61.2, 112.6, 115.4, 122.1, 130.5, 142.9, 161.3; HRMS (ESI-Orbitrap) [M+H]+ calcd for C15H26N3O3S, 328.1689 found 328.1688.
ECO02-073-B2 N,N′-(1-(3-methoxyphenethyl)piperidine-3,5-diyl)dimethanesulfonamide: 84 mg, 52%, white solid;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.23 (q, J=12.2 Hz, 1H), 1.90 (t, J=10.8 Hz, 2H), 2.31-2.33 (m, 1H), 2.69-2.72 (m, 2H), 2.79-2.82 (m, 2H), 2.99 (s, 6H), 3.14-3.18 (m, 2H), 3.43-3.48 (m, 2H), 3.79 (s, 3H), 6.75-6.77 (m, 1H), 6.80-6.82 (m, 2H), 7.19 (t, J=8.1 Hz, 1H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 32.8, 38.7, 40.0 (2C), 50.5 (2C), 54.2, 58.5 (2C), 59.1, 111.3, 114.0, 120.7, 129.0, 141.5, 160.0; HRMS (ESI-Orbitrap) [M+H]+ calcd for C16H28N3O5S2, 406.1465 found 406.1466.
Carbamoylation of Diaminopiperidines
ECO01-026-C2 (100 mg, 0.401 mmol) was solubilized in anhydrous pyridine (0.8 mL). At 0° C., methyl chloroformate was added (94 μL, 1.2 mmol). Mixture was stirred 10 min at 0° C. and at RT for 4 h under Ar. The reaction was monitored by TLC until disappearance of the initial product. Mixture was quenched with water, extracted with CH2Cl2. The organic layer with a saturated aqueous solution of NaCl, dried over MgSO4, filtered and evaporated. Flash chromatography (Cyclohexane to Ethyl Acetate) afforded ECO02-074-C (87 mg, 59%), white solid.
ECO02-074-C dimethyl (1-(3-methoxyphenethyl)piperidine-3,5-diyl)dicarbamate: 87 mg, 59%, white solid;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.19 (q, J=11.8 Hz, 1H), 1.84 (t, J=10.7 Hz, 2H), 2.12-2.14 (m, 1H), 2.66-2.68 (m, 2H), 2.77-2.79 (m, 2H), 3.09-3.11 (m, 2H), 3.60-3.72 m, 8H), 3.79 (s, 3H), 6.75-6.77 (m, 1H), 6.79-6.80 (m, 2H), 7.19 (t, J=8.1 Hz, 1H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 34.2, 37.9, 48.2 (2C), 52.4 (2C), 55.6, 58.9 (2C), 60.9, 112.6, 115.4, 122.1, 130.4, 142.9, 158.8, 161.3 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C18H28N3O5, 366.2023 found 366.2020.
Monocarbamoylation of Diaminopiperidines
ECO01-026-C2 (100 mg, 0.401 mmol), was solubilized in THF (4 mL) and NaOH 1M (4 mL). Boc2O (219 mg, 1.00 mmol) was added. Mixture was stirred 2 h under Ar at RT. The reaction was monitored by TLC until disappearance of the initial product. THF was evaporated. Mixture was extracted with Ethyl Acetate. The organic layer with a saturated aqueous solution of NaCl, dried over MgSO4, filtered and evaporated. Crude product was purified on SiO2 (CH2Cl2 to CH2Cl2/MeOH/NH4OH 90/9/1) afforded ECO02-078-C (24 mg), colorless oil.
ECO02-078-C tert-butyl 5-amino-1-(3-methoxyphenethyl)piperidin-3-yl)carbamate: 24 mg, byproduct, colorless oil;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.07 (q, J=11.8 Hz, 1H), 1.46 (s, 9H), 1.82 (td, J=10.5, 4.8 Hz, 2H), 2.13-2.17 (m, 1H), 2.66-2.69 (m, 2H), 2.78-2.81 (m, 2H), 2.93-2.99 (m, 1H), 3.05-3.11 (m, 2H), 3.62-365 (m, 1H), 3.79 (s, 3H), 6.75-6.80 (m, 3H), 7.19 (t, J=8.1 Hz, 1H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 28.8 (3C), 34.1, 39.9, 47.6, 48.1, 55.6, 58.9, 60.7, 60.9, 80.2, 112.6, 115.5, 122.1, 130.4, 142.9, 157.7, 161.3; HRMS (ESI-Orbitrap) [M+H]+ calcd for C19H32N3O3, 350.2438 found 350.2439.
Sulfonylation of Protected Diaminopiperidines
ECO02-051-C (79 mg, 0.251 mmol) was suspended in CH2Cl2 (5 mL) and anhydrous pyridine (22 μL, 0.276 mmol). At 0° C., benzenesulfonylchloride (35 μL, 0.276 mmol) was added. Mixture was stirred overnight under Ar at RT. At 0° C., benzenesulfonylchloride (35 μL, 0.276 mmol) was added and mixture was stirred 6 h under Ar at RT. Water and NaOH 2M were added. The aqueous layer extracted with Ethyl Acetate. The organic layer with a saturated aqueous solution of NaCl, dried over MgSO4, filtered and evaporated. Flash chromatography (Cyclohexane to Cyclohexane/Ethyl Acetate 5/5) afforded ECO02-081-C (60 mg, 52%), white solid.
ECO02-081-C di-tert-butyl (1-(phenylsulfonyl)piperidine-3,5-diyl)dicarbamate: 60 mg, 52%, white solid;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.11 (q, J=12.1 Hz, 1H), 1.46 (s, 18H), 1.98-2.02 (m, 3H), 3.57 (br s, 2H), 3.80-3.90 (m, 2H), 7.62-7.65 (m, 2H), 7.65-7.70 (m, 1H), 7.83 (d, J=7.3 Hz, 2H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 27.2 (6C), 35.8; 46.0 (2C), 49.5 (2C), 79.0 (2C), 127.2 (2C), 129.0 (2C), 132.8, 136.8, 156.0 (2C)
Preparation of ECO03-03-C
ECO01-026-C2 (100 mg, 0.401 mmol) was solubilized in THF (4 mL) and NaOH 1M (4 mL). Boc2O (394 mg, 1.80 mmol) was added. Mixture was stirred 2 h under Ar at RT. The reaction was monitored by TLC until disappearance of the initial product. THF was evaporated. Mixture was extracted with Ethyl Acetate. The organic layer with a saturated aqueous solution of NaCl, dried over MgSO4, filtered and evaporated. Flash chromatography (Cyclohexane to Cyclohexane/Ethyl Acetate 6/4) afforded ECO003-03-C (110 mg, 61%).
ECO03-03-C di-tert-butyl (1-(3-methoxyphenethyl)piperidine-3,5-diyl)dicarbamate: 110 mg, 61%, white solid;
1H NMR (500 MHz, CD3OD, 27° C.) δ 1.14 (q, J=11.8 Hz, 1H), 1.45 (s, 18H), 1.82 (t, J=10.6 Hz, 2H), 2.03-2.11 (m, 1H), 2.64-2.67 (m, 2H), 2.77-2.81 (m, 2H), 3.04-3.09 (m, 2H), 3.62-3.65 (m, 2H), 3.79 (s, 3H), 6.73-6.77 (m, 1H), 6.79-6.81 (m, 2H), 7.18 (t, J=8.1 Hz, 1H); 13C NMR (125 MHz, CD3OD, 27° C.) δ 28.8 (6C), 34.2, 38.0, 47.7 (2C), 55.6, 59.0 (2C), 60.9, 80.1 (2C), 112.6, 115.4, 122.1, 130.4, 143.0, 157.7, 161.3 (2C); HRMS (ESI-Orbitrap) [M+H]+ calcd for C24H40N3O5, 450.2962 found 450.2949.
Preparation of ECO02-045-C
ECO02-045-C dibenzyl 3-(3-acetoxyphenethyl)-3,6,7-triazabicyclo[3.2.1]octane-6,7-dicarboxylate: 105 mg, quant., transparent oil;
1H NMR (500 MHz, (CD3)2SO, 60° C., δ) 1.60 (br s, 2H), 2.25 (br s, 5H), 2.57 (br s, 2H), 3.07 (br s, 2H), 3.20 (br s, 2H), 4.37 (br s, 2H), 5.13 (br s, 4H), 6.92 (br s, 2H), 7.04 (br s, 1H), 7.34 (br s, 11H); 13C NMR (125 MHz, (CD3)2SO, 60° C., δ) 20.8, 28.9, 35.7, 52.1, 54.7, 55.8 (2C), 57.4, 66.8 (2C), 119.2, 121.6, 125.8, 127.5-129.1 (11C), 136.4 (2C), 141.9, 150.6, 156.8 (2C), 168.9; HRMS (ESI-Orbitrap) [M+H]+ calcd for C31H34N3O6, 544.2442 found 544.2440.
| Number | Date | Country | Kind |
|---|---|---|---|
| 14305808.9 | May 2014 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2015/062046 | 5/29/2015 | WO | 00 |
