COMPOUNDS

专利摘要:
The present invention relates to the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purin-8-one or a pharmacetically acceptable salt thereof.
公开号:BE1023340B1
申请号:E2015/5741
申请日:2015-11-13
公开日:2017-02-08
发明作者:Helene G. Bazin-Lee；Yufeng Li
申请人:Glaxosmithkline Biologicals S.A.；
IPC主号:

专利说明:

COMPONENTS Statement on Federally Funded Research
Aspects of the present invention have been obtained with the support of the United States Government in accordance with NIH HHSN272200900036C, the United States Government may have certain rights in the present invention. Cross-reference to patents or associated patent applications
This is a patent cooperation treaty application and claims the benefit of US provisional application Serial No. 62/079,027 filed November 13, 2014.
Context of the invention
The present invention relates to compounds, methods for their preparation, compositions containing them and their therapeutic use as vaccine adjuvants and in the treatment of various disorders.
The innate immune system recognizes microbes via a limited number of germplasm-encoded molecular motif recognition (PRR) receptors, which have a number of important characteristics.
Toll-like receptors (TLRs) form a family of structurally related PRRs that detect highly conserved microbial components common to a broad class of pathogens. TLRs are expressed on immune cells and, after activation, mobilize defense mechanisms aimed at eliminating invasive pathogens. Of the more than ten known TLRs that have been identified in humans, some appear to be restricted to cytoplasmic compartments and involved in the detection of non-self nucleic acids (TLRs 3, 7, 8 and 9). See, for example, Akira et al., Nat Rev Immunol 2004, 4, 499-511; O'Neill, et al., Nat Rev Immunol 2013, 13, 453-460. TLR activation regulates intracellular signaling pathways resulting in the expression of inflammatory cytokines / chemokines and type I interferons (IFNα / β), which may result in the preferential enhancement of specific humoral immune responses in a patient. antigen and cell-mediated. TLR7 and TLR8 are members of the TLR subgroup (TLRs 3, 7, 8 and 9) located in the endosomal compartment of cells. TLR7 plays a crucial role in antiviral defense by the recognition of ssRNAs (Diebold S.S. et al., Science, 2004: 303, 1529-1531, and Lund J.M. et al, PNAS, 2004: 101, 5598-5603). TLR7 has a restricted expression profile in humans and is expressed primarily by B cells and plasmacytoid dendritic cells (pDCs) and to a lesser extent by monocytes. Plasmacytoid DCs are a unique population of dendritic cells of lymphoid origin (traditionally 0.2% to 0.8% of peripheral blood mononuclear cells (PBMCs)) and are the main cells producing type I interferon by secreting high levels of interferon-alpha (IFNα) and interferon-beta (IFNP) in response to viral infections (Liu Yi, Annu Rev. Immunol., 2005: 23, 275-306).
Small molecule agonists of TLR7 have been described which can induce cytokines in animals and in men (Takeda K. et al., Annu Rev. Immunol., 2003: 21, 335-76). TLR7 agonists include imidazoquinoline compounds, such as imiquimod and resiquimod, oxoadenine analogs and also nucleoside analogs, such as loxoribine and 7-thia-8-oxoguanosine, which are known to induce interferon alpha. International Patent Application Publication Number WO 2007/034882 (PCT / JP 2006/318758; Dainippon Sumitomo Pharma Co. Ltd. / AstraZeneca Aktiebolag) discloses certain adenine compounds identified as being useful as a medicament.
Some compounds derived from adenine have been shown to induce human interferon. Compounds that induce human interferon may be useful as vaccine adjuvants, as well as in the treatment of various disorders, such as infectious diseases, asthma, cancer, inflammatory conditions and allergic diseases. It is therefore desirable to provide compounds having selectivity for TLR7 / 8 and / or TLR7 / 8 activity and relatively high cytokine induction. Summary of the invention
In a first aspect, there is provided a compound of formula (I):
in which ; R1 is butoxy or methylbutoxy; R2 is a group having the structure:
where n is an integer having a value of 5;
Het is a six-membered saturated heterocycle containing five carbon atoms and one nitrogen atom, wherein Het is bonded to the - (CH2) n- moiety on the carbon at the 4-position of the heterocycle; and R3 is hydrogen; or a pharmaceutically acceptable salt thereof.
In another aspect of the invention, R 1 is selected from 1-methylbutoxy and (15) -1-methylbutoxy.
In another aspect of the invention, R 1 is 1-methylbutoxy.
In another aspect of the invention, R 1 is (15) -1-methylbutoxy.
A further aspect of the invention is a compound of formula (I) wherein R 1 is (15) -1-methylbutoxy; R2 is a group having the structure:
where n is an integer having a value of 5;
Het is a piperidine, wherein Het is attached to the - (CH2) n- moiety on the carbon at the 4-position of the heterocycle; and
R3 is hydrogen; or a pharmaceutically acceptable salt thereof.
A further aspect of the invention is the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purine -8-one or a pharmaceutically acceptable salt thereof.
It is proposed, as a further aspect of the invention, a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy. It will be understood that when a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in therapy, it is used as an active therapeutic agent.
As a further aspect of the invention, there is provided the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro -8H-purin-8-one, or a pharmaceutically acceptable salt thereof, for use in therapy. It will be understood that when the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purin-8 -one, or a pharmaceutically acceptable salt thereof, is used in therapy, it is used as an active therapeutic agent.
There is therefore also provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of allergic diseases or other inflammatory conditions, infectious diseases or cancer.
It is therefore also proposed the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purin-8- or a pharmaceutically acceptable salt thereof, for use in the treatment of allergic diseases or other inflammatory conditions, infectious diseases or cancer.
There is therefore also provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of allergic rhinitis.
6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purin-8-one is also provided or a pharmaceutically acceptable salt thereof for use in the treatment of allergic rhinitis.
There is therefore also provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of asthma.
It is therefore also proposed the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purin-8- one, or a pharmaceutically acceptable salt thereof, for use in the treatment of asthma.
There is further provided an immunogenic composition comprising an antigen or an antigen composition and a compound of formula (I), or a pharmaceutically acceptable salt thereof.
There is further provided an immunogenic composition comprising an antigen or an antigen composition and the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt thereof.
There is further provided a vaccine composition comprising an antigen or an antigen composition and a compound of formula (I), or a pharmaceutically acceptable salt thereof.
There is further provided a vaccine composition comprising an antigen or antigen composition and the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy ] -7,9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt thereof.
There is further provided a method of treating or preventing a disease, comprising administering to a human subject suffering or likely to suffer from a disease, an immunogenic composition comprising an antigen or an antigen composition and a compound of formula (I), or a pharmaceutically acceptable salt thereof.
There is further provided a method of treating or preventing a disease, comprising administering to a human subject suffering or likely to suffer from a disease, an immunogenic composition comprising an antigen or an antigen composition and 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purin-8-one compound, or a salt thereof pharmaceutically acceptable thereof.
There is further provided a method of treating or preventing a disease, comprising administering to a human patient suffering or likely to suffer from a disease, a vaccine composition comprising an antigen or an antigen composition and a compound of formula (I), or a pharmaceutically acceptable salt thereof.
There is further provided a method of treating or preventing a disease, comprising administering to a human patient suffering or likely to suffer from a disease, a vaccine composition comprising an antigen or an antigen composition and the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt thereof.
It is furthermore proposed to use a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of an immunogenic composition comprising an antigen or an antigen composition, for the treatment or prevention of a disease.
It is furthermore proposed to use the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purine -8-one, or a pharmaceutically acceptable salt thereof, for the preparation of an immunogenic composition comprising an antigen or an antigen composition, for the treatment or prevention of a disease.
It is furthermore proposed to use a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of a vaccine composition comprising an antigen or an antigen composition, for the treatment or prevention of a disease.
It is furthermore proposed to use the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H- purin-8-one, or a pharmaceutically acceptable salt thereof, for the preparation of a vaccine composition comprising an antigen or an antigen composition for the treatment or prevention of a disease.
It is further proposed the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of allergic diseases or other inflammatory conditions, infectious diseases or cancer.
It is furthermore proposed to use the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purine -8-one, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of allergic diseases or other inflammatory diseases, infectious diseases or cancer.
It is further proposed the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of allergic rhinitis.
It is furthermore proposed to use the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H- purin-8-one, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of allergic rhinitis.
It is further proposed the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of asthma.
It is furthermore proposed to use the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H- purin-8-one, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of asthma.
There is further provided a method of treating allergic diseases or other inflammatory diseases, infectious diseases or cancer, said method comprising administering to a human subject in need of a therapeutically effective amount of a formula (I), or a pharmaceutically acceptable salt thereof.
There is further provided a method of treating allergic diseases or other inflammatory conditions, infectious diseases or cancer, said method comprising administering to a human subject in need of a therapeutically effective amount of the 6-amino compound [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt of this one.
There is further provided a method of treating allergic rhinitis, said method comprising administering to a human subject in need of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof of it.
There is further provided a method of treating allergic rhinitis, said method comprising administering to a human subject in need of a therapeutically effective amount of the compound 6-amino-9- [5- (4-piperidinyl) pentyl] 2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt thereof.
There is further provided a method of treating asthma, said method comprising administering to a human subject in need of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof of it.
There is further provided a method of treating asthma, said method comprising administering to a human subject in need of a therapeutically effective amount of the 6-amino-9- [5- (4-piperidinyl) pentyl compound 2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt thereof. The invention provides, in a further aspect, a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one other therapeutically active agent. The invention provides, in a further aspect, a combination comprising the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methyl-butyl] oxy] -7, 9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt thereof, together with at least one other therapeutically active agent.
There is further provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable diluents or carriers.
In addition, there is provided a pharmaceutical composition comprising the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H- purin-8-one, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable diluents or carriers.
There is also provided a process for preparing a pharmaceutical composition which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable diluents or carriers.
There is also provided a process for preparing a pharmaceutical composition which comprises mixing the compound 6-amino-9- [5- (4-piperidinyl) -pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable diluents or carriers.
The compounds of the invention and their salts can be prepared by the methodology described herein, which is a further aspect of the present invention.
Therefore, there is provided a process for preparing a compound of formula (I), or 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methyl compound -butyl] oxy] -7,9-dihydro-8H-purin-8-one, said process comprising deprotection of a compound of formula (II):
wherein R1 and R2 are as defined above for a compound of formula (I) and R4 is C1-C6 alkyl, and thereafter, if necessary, carrying out one or more of the following optional steps (i) removal of any necessary protecting group; (ii) the preparation of a salt of the compound thus formed.
There is further provided a process for the preparation of a compound of formula (I), or the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purin-8-one, said process comprising converting a compound of formula (II) into a further compound of formula (IIP) and then, if necessary, carrying out one or more of the following optional steps: (i) removal of any necessary protecting group; (ii) the preparation of a salt of the compound thus formed.
In another embodiment, a compound of formula (I), or the compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2- [(1S) -1-methylbutyl] oxy] - 7,9-dihydro-8H-purin-8-one, can also be prepared by deprotection of a compound of formula (IIP):
wherein R1 is as defined above for a compound of formula (I), R4 is as defined above for a compound of formula (II), and R2P is a protected R2 group in which the protecting group is a appropriate protecting group, for example a tert-butoxycarbonyl (Boc) group or a carbobenzyloxy group, and then, if necessary, carrying out one or more of the following optional steps: (i) the removal of any protective group needed; (ii) the preparation of a salt of the compound thus formed.
The present invention covers all combinations of the embodiments and aspects described herein.
Description of the drawings
Figure 1 is a graph showing the NFKB response of (A) HEK293-hTLR7 and (B) HEK293-hTLR8 cells treated for 24 hours with oxoadenine compounds 3a-3g; (C) shows the EC50 values of hTLR7 and hTLR8 for oxoadenines 3a to 3g. The numbers surrounded by a circle on the graph indicate the length of the carbon-based linker of each compound.
Figure 2 (A) shows induction of TNFalpha in hPBMC and (B) IL-6 expression in mDC after stimulation with oxoadenine compounds 3a-3g. The experiment was performed in triplicate in hPBMCs from three different healthy donors. Numbers surrounded by a circle indicate the length of the carbon-based linker of each compound.
Figure 3 is a graph showing induction of IFNalpha in hPBMCs after stimulation with oxoadenines 3a-3g.
Figure 4 is a graph showing the NFkB response of HEK293-hTLR7 and (B) HEK293-hTLR8 cells (A) treated for 24 hours with oxoadenine compounds 3b, 3f or 3x, or imidazoquinoline CRX642.
Figure 5 is a graph depicting induction of TNFalpha from human PBMCs by stimulation with different oxoadenine compounds (3b, 3f or 3x), or rimidazoquinoline CRX642, or AGP compound CRX601.
Figure 6 is a graph showing the induction of IFN-alpha in human PBMCs by stimulation with various oxoadenine compounds (3b, 3f or 3x) or AGP CRX601 or CRX642 (imidazoquinaline).
Figure 7 shows the induction of IFNalpha in pDCs from three different donors, as measured by ICS (intracellular cytokine staining), by stimulation with different oxoadenines (3b, 3f or 3x), at different assays.
Figure 8A is a graph showing the induction of IL-12p70 in human PBMCs by different oxoadenines (3b, 3f or 3x) or AGP CRX601 (TLR4 agonist) or CRX642 (imidazoquinaline). Figure 8B is a graph showing the induction of IL-12p70 in human PBMCs by different oxoadenines (3b, 3f or 3x) in combination with CRX601 (TLR4 agonist), or CRX642 (imidazoquinine) in combination with CRX601.
Figure 9 is Scheme I showing the synthesis of oxoadenine compound 3x, a compound of formula (I).
Detailed description of the invention
The synthesis of oxoadenine compounds substituted at the C9 position with a piperidinylalkyl moiety, and containing butoxy or C2-methylbutoxy is described herein. In vitro evaluation with HEK293 cells transfected with human TLR7 or human TLR8, and with human PBMCs, showed that selectivity for / activity on hTLR7 / 8 and cytokine induction could be modulated by varying the length of the carbon-based linker. In addition, it has been determined that introduction of a methyl group on the first carbon of C2 butoxy (to obtain a methylbutoxy) affects both the activity of TLR7 and TLR8.
Oligonucleotide agonists of TLR7 and TLR9, and TLR7 purine-based small molecule agonists, have been described which can induce interferon alpha from these cell types in animals and humans (Takeda K. et al., Annu Rev. Immunol., 2003: 21, 335-76). TLR7 agonists include imidazoquinoline compounds, such as imiquimod and resiquimod, oxoadenine analogs and also nucleoside analogues, such as loxoribine and 7-thia-8-oxoguanosine, which are known to induce interferon alpha. International Patent Application Publication Number WO 2007/034882 (PCT / JP 2006/318758; Dainippon Sumitomo Pharma Co. Ltd. / AstraZeneca Aktiebolag) discloses certain adenine compounds identified as being useful as a medicament.
Certain adenine-derived compounds described in WO 2010/018134 (PCT / EP 2009/060 267) have been shown to induce human interferon and may have an improved profile (as compared to some other known inducers of human interferon), for example better therapeutic activity, and may be more selective for IFNG than tumor necrosis factor alpha (TNFD). For example, some compounds are 1000 times more selective for induction of IFND than for induction of TNFD. Compounds that induce human interferon may be useful as vaccine adjuvants. Compounds that induce human interferon may be useful in the treatment of various disorders, including infectious diseases, cancer, inflammatory conditions and allergic diseases. Compounds that induce human interferon may be useful in the treatment of allergic rhinitis or asthma.
The present invention is described in terms known and understood by those skilled in the art. For convenience, some terms are defined below in this document. However, the fact that certain terms are defined should not be considered to be an indication that the defined terms are used in a manner inconsistent with ordinary meanings, or alternatively that any term that is undefined is undetermined or not used in ordinary and accepted service. On the contrary, all terms used herein are meant to describe the invention, so that one skilled in the art can appreciate the scope of the present invention. The following definitions are intended to clarify, but not limit, defined terms.
The term "alkyl" refers to both the straight chain and branched chain aliphatic isomers of the corresponding alkyl containing up to eight carbon atoms, for example up to six carbon atoms, or up to four atoms. of carbon, or up to two carbon atoms, or a carbon atom. Such references to the term "alkyl" are also applicable when an alkyl group is part of another group, for example an alkylamino or alkoxy group. Examples of such alkyl groups and alkyl group-containing groups are C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkylamino and C 1 -C 6 alkoxy.
The term "heterocycle" or "heterocyclyl" refers to saturated monocyclic heterocyclic aliphatic rings containing five carbon atoms and at least one heteroatom, said heteroatom being nitrogen, oxygen or sulfur. These heterocyclic rings include piperidine or piperidinyl, the ring containing five carbon atoms and nitrogen as a heteroatom.
As used herein with respect to the compounds of formula I, the term "carbon-based linker" refers to the - (CH 2) n- moiety, and may be otherwise referred to as "alkyl-based linker". ". Therefore, a "five carbon" linker is - (CH2) 5-.
Throughout this specification, the generally accepted purine skeleton atomization system is used:
The following list provides the definitions of certain abbreviations used in this document. The list is not exhaustive ; the meaning of the abbreviations not defined below will be readily apparent to those skilled in the art. DCM dichloromethane DMF N, N-dimethylformamide DMSO dimethylsulfoxide ELISA enzyme immunoassay
EtOAc ethyl acetate H hour HCl hydrochloric acid
Et3N triethylamine L liter LCSM liquid chromatography-mass spectrometry
Mins minute SM mass spectrometry
NFKB nuclear factor kappa B NMR nuclear magnetic resonance NMRss nuclear magnetic resonance solid state PBMC peripheral blood mononuclear cells PBS physiological phosphate buffered saline PRR molecular pattern recognition receptor TA room temperature
Removed solvent removal under reduced pressure TFA trifluoroacetic acid TLR receptor type Toll TA room temperature
It is understood that the references herein to the compounds of the invention mean a compound of formula (I) in free base form or in salt form, for example a pharmaceutically acceptable salt.
The salts of the compounds of formula (I) include pharmaceutically acceptable salts and salts which may not be pharmaceutically acceptable but which may be useful in the preparation of compounds of formula (I) and pharmaceutically acceptable salts thereof. The salts may be derived from certain inorganic or organic acids, or certain inorganic or organic bases. The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).
Examples of salts are pharmaceutically acceptable salts. Pharmaceutically acceptable salts include acid addition salts and base addition salts. For an overview of suitable salts, see Berge et al., J. Pharm. Sci., 66: 1-19 (1977).
Examples of pharmaceutically acceptable acid addition salts of a compound of formula (I) include the hydrobromide, hydrochloride, sulfate, p-toluenesulfonate, methanesulfonate, naphthalenesulfonate and phenylsulfonate salts.
Examples of pharmaceutically acceptable base salts include alkali metal salts, such as sodium and potassium salts, and alkaline earth metal salts, such as calcium and magnesium salts.
The salts can be formed using techniques well known in the art, for example by precipitation in a solution followed by filtration, or by evaporation of the solvent. Generally, a pharmaceutically acceptable acid addition salt may be formed by reacting a compound of formula (I) with a suitable strong acid (such as hydrobromic, hydrochloric, sulfuric, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid) optionally in a suitable solvent, such as an organic solvent, to give the salt which is usually isolated, for example by crystallization and filtration.
It will be understood that many organic compounds can form complexes with the solvents in which they are reacted or with which they are precipitated or crystallized. These complexes are called "solvated". For example, a complex with water is called "hydrate". Solvents having high boiling points and / or solvents having a strong tendency to form hydrogen bonds, such as water, ethanol, isopropyl alcohol and N-methyl pyrrolidinone, can be used to form solvates. Methods for identifying solvates include, but are not limited to, NMR and microanalysis. The compounds and salts of the invention may exist in solvated and unsolvated forms. As used herein, the term "solvated" includes solvates of both a free base form compound and any salt thereof.
Some of the compounds of the invention may contain chiral atoms and / or multiple bonds, and may therefore exist in one or more stereoisomeric forms. The present invention encompasses all stereoisomers of the compounds of the invention, including optical isomers, whether they are individual stereoisomers or mixtures thereof, including racemic modifications. Any stereoisomer may contain less than 10% by weight, for example less than 5% by weight, or less than 0.5% by weight, of any other stereoisomer. For example, any optical isomer may contain less than 10% by weight, for example less than 5% by weight, or less than 0.5% by weight, of its antipode.
Some of the compounds of the invention may exist in tautomeric forms. It is to be understood that the present invention encompasses all the tautomers of the compounds of the invention, whether they be individual tautomers or mixtures thereof, whether explicitly stated herein or not in the present formulas.
The compounds of the invention may be in crystalline or amorphous form. In addition, some of the crystalline forms of the compounds of the invention may exist as polymorphs, all of which are within the scope of the present invention. The most thermodynamically stable polymorphic form or forms of the compounds of the invention are of particular interest.
The polymorphic forms of the compounds of the invention can be characterized and differentiated using a number of standard analytical techniques such as, but not limited to, X-ray powder diffraction (XRPD), infrared spectroscopy ( IR), RAMAN spectroscopy, differential scanning calorimetry (DSC) analysis, thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (SSNR).
It will be understood from the foregoing that the hydrates, isomers and polymorphic forms of the compounds of formula (I) and their salts are included within the scope of the invention.
Examples of conditions wherein the compounds of formula (I) and pharmaceutically acceptable salts thereof have potentially beneficial effects include allergic diseases and other inflammatory conditions (e.g. allergic rhinitis and asthma). ), infectious diseases and cancer. The compounds of formula (I) and the pharmaceutically acceptable salts thereof can also be potentially used as vaccine adjuvants.
As modulators of the immune response, the compounds of formula (I) and the pharmaceutically acceptable salts thereof may also be useful as a therapeutic agent, either alone or in combination with other compounds, in the treatment and / or or the prevention of immunity-mediated diseases such as, but not limited to, inflammatory or allergic diseases, such as asthma, allergic rhinitis and rhinoconjunctivitis, food allergy, pulmonary hypersensitivity reactions, eosinophilic pneumonia, delayed hypersensitivity disorders, atherosclerosis, pancreatitis, gastritis, colitis, osteoarthritis, psoriasis, sarcoidosis, pulmonary fibrosis, respiratory distress syndrome, bronchiolitis, bronchopneumopathy chronic obstructive, sinusitis, cystic fibrosis, actinic keratosis, cutaneous dysplasia, chronic urticaria, eczema and all types of dermatitis.
As used herein, the term "prevention" (or "prophylaxis") refers to the administration or use of a compound or composition in a subject before the subject develops. a particular disease, to reduce the risk in the subject of developing the disease or reduce the severity of the disease if the subject develops it. Therefore, although prevention or prophylaxis can not prevent the development of a disease in each treated subject, the occurrence or severity of the disease in a group of treated subjects will be improved compared to a control group untreated subjects.
The compounds of formula (I) or the pharmaceutically acceptable salts thereof may also be useful in the treatment and / or prevention of reactions against respiratory infections such as, but not limited to, viral exacerbations of the respiratory tract. and tonsillitis. The compounds may also be useful in the treatment and / or prevention of autoimmune diseases such as, but not limited to, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, Sjoegren syndrome, ankylosing spondylitis, scleroderma, dermatomyositis, diabetes, transplant rejection, including graft-versus-host disease, inflammatory bowel diseases such as, but not limited to, Crohn's disease and rectocolitis hemorrhagic.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof may also be useful in the treatment of infectious diseases such as, but not limited to, those caused by hepatitis viruses (e.g. hepatitis B virus, hepatitis C virus), human immunodeficiency virus, papillomavirus, herpesvirus, respiratory viruses (eg, influenzaviruses, respiratory syncytial virus, rhinovirus, metapneumovirus parainfluenzavirus, SARS) and West Nile virus. The compounds of formula (I) and the pharmaceutically acceptable salts thereof may also be useful in the treatment of microbial infections caused by, for example, bacteria, fungi or protozoa. These include, but are not limited to, tuberculosis, bacterial pneumonia, aspergillosis, histoplasmosis, candidiasis, pneumocystosis, leprosy, chlamydia, cryptococcal disease, cryptosporidiosis, toxoplasmosis, leishmaniasis, malaria and trypanosomiasis.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof may also be useful in the treatment of various cancers, in particular the treatment of cancers which are known to be susceptible to immunotherapy and including but not limited to limit, kidney cancer, lung cancer, breast cancer, colorectal cancer, bladder cancer, melanoma, leukemia, lymphoma and ovarian cancer.
A "subject" as used herein includes mammalian subjects, and includes non-primate mammalian subjects, primate subjects, and human subjects. As used herein, the therapy or treatment of a disease refers to an action that can improve the symptoms of the disease and / or prolong the expected life expectancy or disease-free survival of the disease. a subject suffering from the disease. References in this document to treatment or therapy may, depending on the condition, be prophylactic to reduce the risk of a subject contracting or developing a disease.
As mentioned herein, compounds of formula (I) and pharmaceutically acceptable salts thereof may be useful as a therapeutic agent.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof may be formulated for administration by any convenient route.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof can be formulated, for example, for oral, topical, inhalation, intranasal, oral, parenteral (e.g., intravenous, subcutaneous, intradermal or intramuscular) or rectally. In one aspect, the compounds of formula (I) and pharmaceutically acceptable salts thereof are formulated for oral administration. In a further aspect, the compounds of formula (I) and pharmaceutically acceptable salts thereof are formulated for topical administration, for example intranasal or inhalation administration.
Tablets and capsules for oral administration may contain conventional excipients, such as binding agents, for example syrup, gum arabic, gelatin, sorbitol, gum tragacanth, starch mucilage, cellulose or cellulose. polyvinylpyrrolidone; fillers, for example lactose, microcrystalline cellulose, sugar, corn starch, calcium phosphate or sorbitol; lubricants, for example magnesium stearate, stearic acid, talc, polyethylene glycol or silica; sliders, for example potato starch, croscarmellose sodium or sodium starch glycolate; or wetting agents, such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art.
Oral liquid preparations may be in the form of, for example, suspensions, solutions, aqueous or oily emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxymethylcellulose, carboxymethylcellulose, stearate gel aluminum or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or gum arabic; non-aqueous vehicles (which may include edible oils), for example, sweet almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavoring agents, colorants and / or sweeteners (eg, mannitol) as appropriate.
Formulations for intranasal administration include aqueous formulations administered into the nose by drops or by a pressurized pump. Suitable formulations contain water as a diluent or carrier for this purpose. The compositions for administration into the lung or nose may contain one or more excipients, for example one or more suspending agents, one or more preservatives, one or more surfactants, one or more tonicity adjusting agents, a or more cosolvents, and may include components for adjusting the pH of the composition, for example a buffer system. In addition, the composition may contain other excipients, such as antioxidants, for example sodium metabisulfite, and taste-masking agents. The compositions may also be administered in the nose or other regions of the respiratory tract by nebulization.
The intranasal compositions may allow the compound (s) of formula (I) or the pharmaceutically acceptable salts thereof to be delivered to all areas of the nasal cavities (the target tissue) and further may allow the compound (s) of formula (I) or the pharmaceutically acceptable salt (s) thereof to remain in contact with the target tissue for longer periods of time. An appropriate dosing regimen for intranasal compositions would be that the patient inhales slowly through the nose after cleaning the nasal cavity. During inhalation, the composition may be administered in one nostril, while the other is manually compressed. This procedure can then be repeated for the other nostril. Traditionally, one or two sprays per nostril may be administered by the above procedure one, two or three times a day, ideally once a day. The intranasal compositions suitable for once-daily administration are of particular interest.
The suspending agent (s), if included, will usually be present in an amount of 0.1% to 5% (w / w), such as 1.5% to 2.4% (w / w). weight), based on the total weight of the composition. Examples of pharmaceutically acceptable suspending agents include, but are not limited to, AVICEL® (microcrystalline cellulose and sodium carboxymethylcellulose), sodium carboxymethylcellulose, veegum, gum tragacanth, bentonite, methylcellulose, xanthic gum, carbopol and polyethylene glycols.
The compositions for administration into the lung or nose may contain one or more excipients and may be protected against contamination and microbial or fungal growth by the inclusion of one or more preservatives. Examples of pharmaceutically acceptable antimicrobial agents or preservatives include, but are not limited to, quaternary ammonium compounds (e.g., benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, uralkonium and myristylpicolinium chloride), mercury agents (eg, phenylmercuric nitrate, phenylmercuric acetate and thimerosal), alcoholic agents (eg, chlorobutanol, phenylethyl alcohol and benzyl alcohol) antibacterial esters (eg, para-hydroxybenzoic acid esters), chelating agents such as edetate disodium (EDTA) and other antimicrobial agents such as chlorhexidine, chlorocresol, sorbic acid and its salts (like potassium sorbate) and polymyxin. Examples of pharmaceutically acceptable antifungal or preservative agents include, but are not limited to, sodium benzoate, sorbic acid, sodium propionate, methylparaben, ethylparaben, propylparaben and butylparaben. The preservative (s), if included, may be present in an amount of from 0.001% to 1% (w / w), such as 0.015% to 0.5% (w / w), based on weight. total of the composition.
The compositions (for example, in which at least one compound is in suspension) may comprise one or more surfactants whose function is to facilitate the dissolution of the drug particles in the aqueous phase of the composition. For example, the amount of surfactant used is an amount that will not cause foaming during mixing. Examples of pharmaceutically acceptable surfactants include fatty alcohols, esters and ethers, such as polyoxyethylene (20) sorbitan monooleate (Polysorbate 80), macrogol ethers and poloxamers. The surfactant may be present in an amount between about 0.01% to 10% (w / w), such as 0.01% to 0.75% (w / w), for example about 0.5 % (w / w), based on the total weight of the composition.
One or more tonicity adjusting agents may be included to achieve tonicity with body fluids, for example fluids in the nasal cavity, thereby reducing irritation. Examples of pharmaceutically acceptable tonicity adjusting agents include, but are not limited to, sodium chloride, dextrose, xylitol, calcium chloride, glucose, glycerin and sorbitol. A tonicity adjusting agent, if present, may be included in an amount of 0.1% to 10% (w / w), such as 4.5% to 5.5% (w / w). weight), for example about 5.0% (w / w), based on the total weight of the composition.
The compositions of the invention may be buffered by the addition of suitable buffering agents, such as sodium citrate, citric acid, trometamol, phosphates such as disodium phosphate (eg, dodecahydrate, heptahydrate forms). , dihydrate and anhydrous), or sodium phosphate and mixtures thereof.
A buffering agent, if present, may be included in an amount of from 0.1% to 5% (w / w), for example from 1% to 3% (w / w) based on weight. total of the composition.
Examples of taste masking agents include sucralose, sucrose, saccharin or a salt thereof, fructose, dextrose, glycerol, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, menthol, eucalyptus oil, camphor, a natural flavoring agent, an artificial flavoring agent and their combinations .
One or more cosolvents may be included to facilitate solubilization of the drug compound (s) and / or other excipients. Examples of pharmaceutically acceptable cosolvents include, but are not limited to, propylene glycol, dipropylene glycol, ethylene glycol, glycerol, ethanol, polyethylene glycols (e.g., PEG300 or PEG400) and methanol . In one embodiment, the cosolvent is propylene glycol.
The cosolvent (s), if present, may be included in an amount of 0.05% to 30% (w / w), such as 1% to 25% (w / w), for example, 1% to 10% (w / w) based on the total weight of the composition.
The compositions for administration by inhalation comprise aqueous, organic or aqueous / organic mixtures, dry powder or crystalline compositions administered into the respiratory tract by a pressurized pump or an inhaler, for example dry powder inhalers with a reservoir, single dose dry powder, previously measured multidose dry powder inhalers, nasal inhalers or inhalers, nebulizers or aerosol insufflators under pressure. Suitable compositions contain water as a diluent or carrier for this purpose and may be provided with conventional excipients such as buffering agents, tonicity modifiers and the like. Aqueous compositions may also be administered into the nose and other regions of the respiratory tract by nebulization. These compositions can be aqueous solutions or suspensions or aerosols delivered from pressurized packagings, such as a metered dose inhaler, using a suitable liquefied propellant.
Compositions for topical administration in the nose (e.g., for the treatment of rhinitis) or in the lung include pressurized aerosol compositions and aqueous compositions delivered into the nasal cavities by a pressurized pump. Compositions which are not pressurized and which are suitable for topical administration into the nasal cavity are of particular interest. Suitable compositions contain water as a diluent or carrier for this purpose. Aqueous compositions for administration to the lung or nose may be provided with conventional excipients such as buffering agents, tonicity modifiers and the like. Aqueous compositions may also be administered into the nose by nebulization.
A fluid dispenser can traditionally be used to deliver a fluid composition to the nasal cavities. The fluid composition may be aqueous or non-aqueous, but generally aqueous. Such a fluid dispenser may have a dispensing nozzle or a dispensing orifice through which a dose of the fluid composition is dispensed upon applying a user applied force to a fluid dispenser pump mechanism. . Such fluid dispensers are generally provided with a reservoir containing multiple doses of the fluid composition, the doses being dispensed upon sequential actuation of the pump. The nozzle or dispensing orifice may be adapted to be inserted into the nostrils of the user to spray the fluid composition into the nasal cavity. A fluid dispenser of the aforementioned type is described and illustrated in International Patent Application Publication Number WO 2005/044 354 (Glaxo Group Limited). In one embodiment, the fluid dispenser is of the general type illustrated in Figures 30 to 40 of WO 2005/044354.
Aqueous compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be delivered by a pump as described in International Patent Application Publication Number WO 2007/138 084 (Glaxo Group Limited), for example, as described with reference to Figs. 22 to 46 of this document, or as described in WO 2011/098451 (Glaxo Group Limited, GB 0 723 418.0), for example as described with reference to Figs. 32 of this document. The pump may be actuated by an actuator as described in Figures 1 to 6 of WO 2011/098451.
Dry powder compositions for topical administration in the lung by inhalation may be presented, for example, in capsules or cartridges for example of gelatin, or in blister packs composed of, for example, a laminated aluminum sheet, for use in an inhaler or insufflator. The powder mixing compositions generally contain a mixture of powders for inhalation of the compound of formula (I) or a pharmaceutically acceptable salt thereof and an appropriate base powder (carrier substance / diluent / excipient), such as mono-, di- or polysaccharides (eg lactose or starch). The dry powder compositions may also comprise, in addition to the drug and the carrier, an additional excipient (for example, a ternary agent such as a sugar ester, for example cellobiose octoacetate, calcium stearate or stearate magnesium).
In one embodiment, a composition suitable for administration by inhalation may be incorporated into a plurality of dose sealed containers disposed on one or more drug packages mounted within a suitable inhalation device. The containers may be opened by rupture, peeling or otherwise one at a time and the doses of the dry powdery composition may be administered by inhalation to a mouthpiece of the inhalation device, as is known in the art. . The drug package may take a variety of forms, for example a disc shape or an elongated strip. Representative inhalation devices are the DISKHALER ™ and DISKUS ™ devices marketed by GlaxoSmithKline.
An inhalable dry powder composition may also be provided as a bulk tank in an inhalation device, the device then being provided with a metering mechanism for measuring a dose of the composition from the reservoir to a channel in which the dose can be inhaled by a patient via a mouthpiece of the device. Examples of such devices marketed are TURBUHALER ™ (AstraZeneca), TWISTHALER ™ (Schering) and CLICKHALER ™ (Innovata.)
Another method of administering an inhalable dry powder composition is to introduce doses of the composition into capsules (one dose per capsule) which are then loaded into an inhalation device, typically by the patient upon request. The device includes means for opening by rupture, piercing or otherwise the capsule so that the dose can be entrained into the patient's lungs when inhaling through the mouthpiece. Examples of such commercially available devices include ROTAHALER ™ (GlaxoSmithKline) and HANDIHALER ™ (Boehringer Ingelheim.)
The pressurized aerosol compositions suitable for inhalation may be either a suspension or a solution and may contain a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable propellant, such as a fluorocarbon or a chlorofluorocarbon containing hydrogen or mixtures thereof, especially hydrofluoroalkanes, especially 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro n-propane or a mixture thereof. The aerosol composition may optionally contain additional composition excipients well known in the art, such as surfactants, for example oleic acid, lecithin or an oligolactic acid or a derivative thereof, e.g. as described in WO 94/21 229 and WO 98/34596 (Minnesota Mining and Manufacturing Company) and cosolvents, for example ethanol. The pressurized compositions will generally be retained in a box (eg, an aluminum can) closed with a valve (e.g., a metering valve) and installed in an actuator with a mouthpiece.
Ointments, creams and gels can be formulated, for example, with an aqueous or oily base with the addition of a suitable thickening and / or gelling agent and / or solvents. Such bases may therefore include, for example, water and / or an oil, such as paraffin oil, or a vegetable oil, such as peanut oil or castor oil, or solvent, such as polyethylene glycol. Thickening agents and gelling agents that can be used depending on the nature of the base include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols, lanolin, beeswax, carboxypolymethylene and the like. cellulosic derivatives, and / or glyceryl monostearate and / or nonionic emulsifying agents.
The lotions may be formulated with an aqueous or oily base and will generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.
Powders for external application may be formed using any suitable powder base, for example talc, lactose or starch. The drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilizing agents, suspending agents or preservatives.
The compounds of formula (I) and pharmaceutically acceptable salts thereof may, for example, be formulated for transdermal administration by a transdermal patch composition or other devices (eg, pressurized gas devices) which release the active component into the skin.
For oral administration, the compositions may be in the form of tablets or tablets formulated in a conventional manner.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof may also be formulated as suppositories containing, for example, conventional suppository bases, such as cocoa butter or other glycerides.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof may also be formulated for parenteral administration by bolus injection or continuous infusion and may be in a single dose form, for example in the form of ampoules, vials , small volume infusions or pre-filled syringes, or in multi-dose containers with added preservative. The compositions may be in the form of solutions, suspensions or emulsions in aqueous or non-aqueous vehicles, and may contain formulating agents, such as antioxidants, buffers, antimicrobial agents and / or adjusting agents. tonicity. Alternatively, the active ingredient may be in the form of a powder for rehydration with a suitable vehicle, for example sterile pyrogen-free water, prior to use. The dry solid presentation can be prepared by introducing sterile sterile powder into sterile individual containers or by introducing a sterile sterile solution into each container and freeze drying.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof can also be formulated with vaccines as adjuvants. Such compositions may contain one or more antibodies or antibody fragments or an antigenic component such as, but not limited to, live or dead protein, DNA, bacteria and / or viruses or viral particles, together with with one or more components having adjuvant activity such as, but not limited to, aluminum salts, oil and water emulsions, heat shock proteins, lipid A preparations, and derivatives, glycolipids, other TLR agonists such as CpG DNA or similar agents, cytokines such as granulocyte-macrophage colony stimulating factor (GM-CSF) or interleukin-12 (IL-1). 12) or similar agents.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof can be used alone or in combination with other therapeutic agents. The compounds of formula (I) and the pharmaceutically acceptable salts thereof and the other pharmaceutically active agent (s) may be administered together or separately and, when administered separately, the administration may take place simultaneously or sequentially, in a any order. The amounts of the compound (s) of formula (I) or the pharmaceutically acceptable salt (s) thereof and of the other pharmaceutically active agent (s) and the relative times of administration will be selected in order to achieve the combined therapeutic effect. longed for. Administration of a combination of a compound of formula (I) and a pharmaceutically acceptable salt thereof with other treatment agents may be carried out in combination by concomitant administration in a unit pharmaceutical composition containing both compounds, or in separate pharmaceutical compositions each containing one of the compounds. Alternatively, the combination can be administered separately in a sequential manner in which a treatment agent is administered first and then the second agent or vice versa. Such sequential administration can be approximated in time or distant in time.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof may be used in combination with one or more agents useful in the prevention or treatment of viral infections. Examples of such agents include, but are not limited to, polymerase inhibitors such as those described in WO 2004/037818-A1, as well as those described in WO 2004/037818 and WO 2006/045. 613; JTK-003, JTK-019, NM-283, HCV-796, R-803, RI728, RI626, as well as those described in WO 2006/018725, WO 2004/074 270, WO 2003/095 441, US 2005/0 176 701, WO 2006/020 082, WO 2005/080388, WO 2004/064 925, WO 2004/065367, WO 2003/007 945, WO 02/04 425, WO 2005/014 543, WO 2003 / 000 254, EP 1 065 213, WO 01/47 883, WO 2002/057 287, WO 2002/057 245 and the like; replication inhibitors such as acyclovir, famciclovir, ganciclovir, cidofovir, lamivudine and similar agents; protease inhibitors such as HIV protease inhibitors: saquinavir, ritonavir, indinavir, nelfmavir, amprenavir, fosamprenavir, brecanavir, atazanavir, tipranavir, palinavir, lasinavir, and HCV protease inhibitors: BILN2061, VX-950, SCH503034; and similar agents; nucleoside and nucleotide reverse transcriptase inhibitors such as: zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidin, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine and similar agents; non-nucleoside reverse transcriptase inhibitors (including an agent having an antioxidant activity such as immuneocal, oltipraz, etc.) such as: nevirapine, delavirdine, efavirenz, loviride, immunocalocal, Foltipraz, capravirine, TMC-278, TMC-125, Fetavirin and similar agents; entry inhibitors such as Fenfuvirtide (T-20), T-1249, PRO-542, PRO-140, TNX-355, BMS-806, 5-Helix and the like; integrase inhibitors such as L-870, 180 and similar agents; budding inhibitors such as PA-344 and PA-457, and the like; chemokine receptor inhibitors such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK-427,857), TAK449, as well as those described in WO 02/74,769, WO 2004/054 974 , WO 2004/055 012, WO 2004/055 010, WO 2004/055 016, WO 2004/055 011 and WO 2004/054 581, and the like; neuraminidase inhibitors such as CS-8958, zanamivir, Foseltamivir, peramivir and the like; ion channel blockers such as amantadine or rimantadine and similar agents; and interfering RNA and antisense oligonucleotides such as FISIS-14803 and the like; antiviral agents of undetermined action mechanism, for example those described in WO 2005/105,761, WO 2003/085 375 and WO 2006/122011, ribavirin and similar agents. The compounds of formula (I) and the pharmaceutically acceptable salts thereof may also be used in combination with one or more other agents which may be useful in the prevention or treatment of viral infections, for example immunotherapies (e.g. interferon or other cytokines / chemokines, cytokine / chemokine receptor modulators, cytokine agonists or antagonists and the like); and therapeutic vaccines, antifibrogens, anti-inflammatory agents such as corticosteroids, or nonsteroidal anti-inflammatory drugs (NSAIDs) and the like.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof can be used in combination with one or more other agents which may be useful in the prevention or treatment of allergic diseases, inflammatory diseases, autoimmune diseases for example: antigen immunotherapy, antihistamines, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), bronchodilators (eg, beta 2 agonists, adrenergic agonists, anticholinergic agents, theophylline), methotrexate, modulators leukotrienes and the like; monoclonal antibody therapy such as anti-immunoglobulin E (IgE), anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; receptor therapies, for example, entanercept and similar agents; non-antigen-specific immunotherapies (eg, interferon or other cytokines / chemokines, cytokine / chemokine receptor modulators, cytokine agonists or antagonists, TLR agonists and the like).
The compounds of formula (I) and the pharmaceutically acceptable salts thereof can be used in combination with one or more other agents which may be useful in the prevention or treatment of cancer, for example chemotherapeutic agents such as alkylating agents. , topoisomerase inhibitors, antimetabolites, antimitotic agents, kinase inhibitors and the like; monoclonal antibody therapy such as trastuzumab, gemtuzumab and the like; and hormone therapy such as tamoxifen, goserelin and the like.
The pharmaceutical compositions according to the invention may also be used alone or in combination with at least one other therapeutic agent in other therapeutic areas, for example a gastrointestinal disease. The compositions of the invention may also be used in combination with gene replacement therapy. The invention comprises, in a further aspect, a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one other therapeutically active agent.
The combinations mentioned above may conveniently be used for use in the form of a pharmaceutical composition and, therefore, pharmaceutical compositions comprising a combination as defined above together with at least one pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.
A therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof will depend on a number of factors. For example, the species, age and weight of the recipient, the precise condition requiring treatment and its severity, the nature of the composition, and the route of administration are all factors to be considered. The therapeutically effective amount will ultimately depend on the judgment of the attending physician. In any event, an effective amount of a compound of the present invention for the treatment of humans is generally in the range of 0.0001 to 100 mg / kg body weight of the recipient per day. More usually, the effective amount is in the range of 0.001 to 10 mg / kg of body weight per day. Therefore, for a 70 kg adult, an example of a real amount per day is usually 7 mg to 700 mg. For intranasal and inhalation administration, usual doses for a 70 kg adult are in the range of 1 microgram to 1 mg per day. This amount may be given in a single dose per day or in a number (such as two, three, four, five or more) of sub-doses per day so that the total daily dose is the same. An effective amount of a pharmaceutically acceptable salt of a compound of formula (I) may be determined as a proportion of the effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof per se. Similar doses are appropriate for the treatment of the other conditions cited herein.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof may also be administered at any convenient frequency, for example 1 to 7 times per week. The precise dosage regimen will, of course, depend on such factors as the therapeutic indication, the age and condition of the patient, and the particular route of administration chosen.
The pharmaceutical compositions may be in single-dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit dose may contain, by way of nonlimiting example, 0.5 mg to 1 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, depending on the condition to be treated. , the route of administration, and the age, weight, and condition of the patient. Preferred single-dose compositions are those containing a daily dose or sub-dose, as mentioned hereinabove, or an appropriate fraction thereof, of an active ingredient. Such pharmaceutical compositions may be prepared by one of the following: any of the methods well known in the art of pharmacy.
There is therefore further provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable diluents or carriers.
There is also provided a process for preparing such a pharmaceutical composition comprising mixing a compound of formula (I), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable diluents or carriers.
Throughout the description and the claims that follow, unless otherwise indicated, the term "understand", and its variations such as "includes" and "including", will be understood to imply the inclusion of an integer or a step or group of integers stipulated, but without excluding another integer or another step or another group of integers or steps.
Processes for preparing oxoadenine compounds and their salts are described in WO 2010/018134, the entire contents of which are hereby incorporated by reference. Processes for preparing compounds of formula (I) and for preparing 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9 dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt thereof, are described herein and constitute a further aspect of the present invention.
Examples
Example I: Synthesis of Oxoadenines Substituted at the 9-position
In the case of TLR7 and TLR8 activation, a small number of different classes of small molecule mimetics have been identified, including viral RNAss-type ligands rich in uridine and / or guanosine, including 1H-imidazo [4]. , 5-c] quinolones and 8-hydroxyadenines. see Heil, et al., Eur. J. Immunol. 2003, 33, 2987-2997; Hemmi, et al., Nat Immunol 2002, 5, 196-200; Lee, et al., Proceedings of the National Academy of Sciences of the United States of America 2006,103, 1828-1833; Gerster, et al., J. Med. Chem. 2005, 48, 3481-3491; Hirota, et al., J. Med. Chem. 2002, 45, 5419-5422. Various evaluations of structure-activity relationships have been performed on oxoadenines. see Isobe, et al., Bioorganic & Medicinal Chemistry 2003, 11, 3641-3647; Kurimoto, et al., Bioorganic & Medicinal Chemistry 2003, 11, 5501-5508; Kurimoto, et al., Bioorganic & Medicinal Chemistry 2004, 12, 1091-1099; Isobe, et al., J. Med. Chem. 2006, 49, 2088-2095; Jin, et al., Bioorganic & Medicinal Chemistry Letters 2006, 16, 4559-4563; Pryde, et al., R. Med. Chem. Common. 2011, 2, 185-189; Kurimoto, et al., J. Med. Chem. 2010, 53, 2964-2972. Nakamura, et al., Bioorganic & Medicinal Chemistry Letters 2013, 23, 669-672; Weterings, et al., Bioorganic & Medicinal Chemistry Letters 2009, 19, 2249-2251.
The present inventors have undertaken a structure-activity relationship study on oxoadenines substituted with non-aromatic groups at the 9-position. Previous studies have examined some 9-alkyl derivatives and have shown that the introduction of an alkyl (i-propyl) , butyl, c-pentyl, c-hexyl) at position 9 gave weak activity and decreased activity (Hirota, et al., J. Med Chem 2002, 45, 5419-5422, Isobe, et al. J. Med Chem 2006, 49, 2088-2095). The present studies have focused on the synthesis and biological evaluation of a series of seven oxoadenines of formula I:
where R1 is n-butoxy and R2 is a piperidinylalkyl moiety wherein the length of the carbon-based linker is from 0 to 6 carbons:
These compounds (3a-g) were evaluated in vitro for their selectivity for TLR7 / 8 and the induction of cytokines. Compound 3a does not contain a carbon-based linker (n = 0); 3b contains a carbon linker (n = 1); 3c contains a two-carbon linker (n = 2); 3d contains a three-carbon linker (n = 3); 3e contains a four-carbon linker (n = 4); 3f contains a five-carbon linker (n = 5) and 3g contains a six-carbon linker (n = 6).
The 9-piperidinylalkyl oxoadenines 3a-g were synthesized as shown in Scheme 1 via Common Advanced Intermediate (CAI) 6. (Tanji et al., Science 2013, 339, 1426-1429.) CAI 6 was prepared easily on a scale of several tens of grams in 6 steps and with an overall yield greater than 50% from dichloropurine 7 in commerce (Scheme 2). In Scheme 2, dichloropurine 7 was protected as the 9-tetrahydropyranyl derivative and substituted in the 6-position by treatment with 2M NH3 in isopropanol at 60 ° C to give 2-chloro adenine 8 with 86% yield. Reaction of 8 with sodium tert-butoxide in n-butanol at 100 ° C gave the functionalized adenine 9 in 85% yield. THP-protected adenine 9 was converted to CAI 6 in 3 steps and with an overall yield of 87% by bromination at the 8-position, displacement of bromine with methoxide and deprotection of THP with trifluoroacetic acid (TFA). Alkylation of CAI 6 with the various N-piperidinyl bromides protected by a tert-butyloxycarbonyl (Boc) 5b-g in the presence of potassium carbonate in dimethylformamide (DMF) and then an acidic deprotection of the groups Boc and methyl with 4N HCl in dioxane gave the desired oxoadenines 3b-g with yields of 41% to 84% (scheme 1). The alkylation of CAI 6 with bromide 5a did not work and oxoadenine 3a was instead prepared in 38% yield by Mitsunobu reaction of CAI 6 with alcohol 4a in the presence of DIAD and of PPI13 at 70 ° C, followed by deprotection in an acid medium (scheme 1).
Diagram 1
Reagents: {a} TEA, PPU ,. ## STR5 ## wherein (h) CBn · PPl ·., · CHXt ·, · TA · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · (d> 4N HCl dicxsni) MeOH.TA, 1h.
Compound 3a does not contain a carbon-based linker (n = 0); 3b contains a carbon linker (n = 1); 3c contains a two-carbon linker (n = 2); 3d contains a three-carbon linker (n = 3); 3e contains a four-carbon linker (n = 4); 3f contains a five-carbon linker (n = 5) and 3g contains a six-carbon linker (n = 6).
Figure 2: Common Intermediate 6 advanced synthesis
Reagents: pT * OH. AtO 3, C, 2h, NMR, IW. K · C, ## STR2 ## ## STR2 ## ## STR2 ## leflus. 4 li: <f) TFA. MtOK. TA K> 1
When not commercially available, bromides (5b-d, fg) were prepared with a yield of greater than 90% by bromination of the corresponding alcohols using Call Conditions (PhsP / CBrQ). 4f-g were not commercially available and were prepared in 3 steps from bromopyridine 8 by (i) cross-linking of 10 with 11f or 11g acetylenic alcohols, (ii) reduction of 12f and 12g with hydrogen in the presence of 5% of Rh / C catalyst and (iii) Boc protection of the amine group (Scheme 3).
Figure 3: synthesis of 4f and 4g alcohols
11f, n = 3 12f, n = 3, 82% 4f, n = 3. 80% 11g, n = 4 12g, n = 4, 21% 4g, n * 4, 80% Reagents: (a) {PPhjJPrfCK . Ass ΊΤ.Λ. Λ, HOnuts {t>) H Cutw V. C, H ;. O.-ΟΗ 90 O) BOC ^O, ΤΕΛ, CH, CU. YOUR. 3Ù miiwtes
Example 2 Synthesis of Oxoadenine Compound 3x
Additional oxoadenine (3x compound) of formula I was prepared, where:
wherein R 1 is (lS) -1-methylbutoxy, and wherein R 2 is a piperidinylalkyl moiety wherein the length of the carbon-based linker is 5 carbons. 3x compound:
Oxoadenines and methods of preparing oxoadenines are also described in WO 2010/018134, the contents of which are incorporated herein by reference.
The synthesis of oxoadenine 3x was performed as described in Scheme 4 (see also Figure 20) and as described below. Intermediate compounds 1, 2, 40, 41, 42 and 43 are further described in WO 2010/018134 (these intermediates are numbered in the same manner in this document and in WO 2010/018134).
Figure 4
As can be seen in Scheme 4, 4-bromopyridine hydrochloride A (2.5 g) was partitioned between 1N sodium hydroxide (20 ml) and ethyl acetate (3x). 20 ml). The organic phase was separated, dried over Na2SO4 and concentrated in vacuo. The resulting oil was dissolved in TEA (2.6M) and degassed under nitrogen. 4-pentyn-1-ol (1.1 eq) was added followed by bis (triphenylphosphine) palladium (II) chloride (0.01 eq) and copper (I) iodide (0.02 eq). ), and the reaction mixture was stirred under reflux for 20 minutes. Final treatment in aqueous medium (ethyl acetate / water) and purification by silica gel chromatography (gradient from 0% to 30% ethyl acetate in heptane) gave B with a yield of 82. %. B was dissolved in acetic acid (0.05M) and the solution was hydrogenated using the H-CUBE® continuous flow hydrogenation reactor (ThalesNano) (20% Pd (OH) 2 cartridge / C, 100 bar H2, 90 ° C, 1 mL / min).
After the hydrogenation was complete, the reaction mixture was concentrated and dried under vacuum. The resulting crude product was dissolved in CH 2 Cl 2 (0.4 M), and reacted with FUN (1.5 eq) and di-f-butyl dicarbonate (1.2 eq) at room temperature. during 30 minutes. After a final treatment in an aqueous medium (CH 2 Cl 2 / H 2 O) and purification by chromatography on silica gel (gradient from 0% to 30% ethyl acetate in heptane), C was isolated with a yield of 80%. %: 1H NMR (400 MHz, CDCl3) δ 4.06 (s, 2H), 3.64 (t, 2H), 2.66 (t, 2H), 1.541.66 (m, 5H), 1, 45 (s, 9H), 1.24-1.39 (m, 8H), 1.08 (m, 2H).
CBr4 (1.6 eq) and PPI13 (1.2 eq) were slowly added (exothermic reaction) to a solution containing C in CH2Cl2 (0.45 M) at 0 ° C. After 5 minutes, the reaction mixture was allowed to warm to room temperature, was stirred at room temperature for 45 minutes, concentrated and purified directly by silica gel chromatography (gradient from 0% to 30% acetate of ethyl in heptane) to give D in 92% yield.
K2CO3 (325 mesh, 3.0 eq) was added to a solution containing 43 in DMF (0.25 M) and the reaction mixture was sonicated several seconds to obtain a fine slurry, then allowed to stir at 60 ° C. for 1 hour. After cooling to 50 ° C, D (1.2 eq) was added and the reaction mixture was stirred overnight at 50 ° C. After cooling to ambient temperature and a final treatment under aqueous conditions (ethyl acetate / water), the resulting crude product was purified by chromatography on silica gel (0% to 10% gradient of methanol in chloroform) .
The purified product E was dissolved in methanol (0.1 M) and reacted with 4 N HCl in dioxane (6.0 eq) at room temperature for 1 hour. The reaction mixture was concentrated and dried under vacuum, and the residue was purified by silica gel chromatography (0% to 100% CHCl3 / CH3OH / H2O 90/10 / 0.5 in CHCl3 / CH3OH / H2O). 15 / 1.0) to give F with a yield of 64% (2 steps). NMR (400 MHz, CD3OD) gamma 5.14 (m, 1H), 3.81 (t, 2H), 3.36 / 3.32 (m, 4H), 2.97 (d of t, 2H), 1.92 (m, 2H), 1.75 (p, 2H), 1.72 (m, 1H), 1.57 (m, 2H) 1.51.3 (m, 14H), 0.95 ( t, 3H); ES TOF positive-MS calculated for [M + H] + 391.28222, found 391.0843.
Example 3 - Preparation of the intermediates shown in Scheme 4
Intermediate compounds 1, 2, 40, 41, 42 and 43 (see Figure 4 and Figure 20) are further described in WO 2010/018134; these intermediates are numbered in the same manner in this document and in WO 2010/018 134. The LCSM A-D systems are as described in WO 2010/018 134.
Intermediate 1: 2,6-dichloro-9-tetrahydro-277-pvran-2-yl-9H-purine
To 2,6-dichloropurine (25.0 g) (available, for example, from Aldrich, UK) was added ethyl acetate (260 ml) followed by p-toluenesultonic acid (0.253 g). . The mixture was heated to 50 ° C and then 3,4-dihydro-2H-pyran (16.8 g) was added. The reaction mixture was then heated at 50 ° C for 4 hours. The reaction mixture was evaporated in vacuo to give 2,6-dichloro-9- (tetrahydro-2H-pyran-2-yl) -9 / 7-purine as a yellow solid (36.9 g). boy Wut). NMR * H (CDCl3): δ 8.35 (1H, s), 5.77 (1H, dd), 4.20 (1H, m), 3.79 (1H, m), 2.20-1, 65 (6H, m).
Intermediate 2: 2-chloro-9- (tetrahydro-2H-pvran-2-yl) -9H-purin-6-amine
2,6-Dichloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (36.9 g) was heated with 2 M ammonia in isopropanol (250 g). ml) at 50 ° C for 5 hours. After standing at room temperature overnight, additional 2M ammonia in isopropanol (100 mL) was added to dissolve the resulting cake and the reaction mixture was heated for an additional 9 hours until the reaction was complete. be completed. To the reaction mixture was added water (70 ml) and the yellow solid was removed by filtration. The solid was washed with isopropyl alcohol / water (5/1 (v / v), 60 ml) and then air dried under suction to give a first batch. The filtrate was filtered again after standing overnight to isolate the precipitate and both solids were dried under vacuum. The first batch was pure and the second batch contained a very small amount of impurity (wide signal isolated at 3.5 ppm absent from the first batch) but otherwise identical. First batch of a solid (28.4 g), second batch of solid (3.42 g). 1 H NMR (CDCl 3): 8.01 (1 s), 5.98 (2H, brs), 5.70 (1 dd), 4.16 (1), 3.78 (1H, m). , 2.15-1.60 (frH, m overlap).
Intermediate 2 (alternative method): 2-chloro-9- (2H-tetrahydro-7-p-yr) -9H-purin-6-amine
To a solution containing 2,6-dichloropurine (25 g) (available, for example, from Aldrich, UK) in anhydrous ethyl acetate (200 ml) was added p-toluenesulfonic acid monohydrate (235 g). mg). The reaction was heated to 50 ° C and 3,4-dihydro-27β-pyran (18.1 ml) was added all at once. The reaction was stirred at 50 ° C for 1 hour and the solvent was removed under reduced pressure. This gave a yellow solid. A suspension of this solid (~ 36 g) in 2.0 M ammonia in isopropanol (460 ml) was heated under nitrogen at 60 ° C for 4 hours with an attached condenser. The reaction was poured into water (50 ml) and allowed to cool overnight. The precipitate was filtered and rotary-dried (60 ° C) for 30 minutes to give 2-chloro-9- (tetrahydro-2H-pyran-2-yl) -9 // - purine -6-amine as an off-white solid, 31 g (93%, 2 steps). MS calculated for (C10H12C1N5O) + = 254, 256 MS found (electrospray): (M) + = 254, 256 (3/1) NMR! H ((CD3) 2SO): δ = 0.83 (s), 7, 82 (2H, s), 5.55 (1¾ dd), 4.00 (1¾ m), 3.69 (1¾ m), 2.21 (¾ m), 1.95 (2H, m), 1, 74 (m), 1.56 (2H, m).
Intermediate 40: 2 - {[(1S, 1-Methylbutynoxy) -9-tetrahydro-2H-pvran-2-yl) -9H-purin-6-amine
Method A
Sodium t-butoxide (48.5 g, 505 mmol) was added portionwise to (5) -2-pentanol (185 mL) (available, for example, from Julich Chiral Solutions, Germany) with stirring at room temperature. until homogeneous (note: the reaction is exothermic). 2-Chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine (32 g, 126 mmol) was added and the reaction mixture was heated to 70 °. C for 72 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate (500 ml) and water (500 ml).
The organic phase was washed with saturated sodium chloride solution (100 ml), dried (MgSCL), filtered and evaporated. The residue was triturated with ether and the solid was filtered. The precipitate was washed again with ether and the filtrates were combined and evaporated. The crude material (about 30 g) was dissolved in the DMSO / methanol mixture (1/1) and purified by reversed phase column chromatography (Cis) (330 g) using a gradient of 25% to 65%. of acetonitrile (+ 0.1% TFA) -water (+ 0.1% TFA) with 8 column volumes, the fractions were immediately neutralized with a saturated aqueous solution of sodium carbonate. The appropriate fractions were combined and partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The organic phase was dried by passing through a hydrophobic sinter, filtered and evaporated to give 2 - {[(1S) -1-methylbutyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -97 / -purin-6-amine as a pale cream foam (14.97 g). LCSM (System B): Islet = 2.21 minutes; MH + 306
Method B:
Sodium t-butoxide (206 g, 2.144 mol) was added to (5) -2-pentanol (720 ml, 6.58 mol) (available, for example, from Julich Chiral Solutions, Germany) in a flask. round bottom of 2 liters. The mixture was stirred at 50 ° C until complete dissolution of t-butoxide. 2-Fluoro-9- (tetrahydro-27β-pyran-2-yl) -9,7-purin-6-amine (130 g, 548 mmol) was then added in portions over a period of 5 minutes.
After 3 hours, LCMS analysis showed the total consumption of the starting compound and the mixture was poured into ice / water (3 L) and then extracted with methyl t-butyl ether. This resulted in the formation of an emulsion and the mixture was filtered through celite and the organic phase was separated. The aqueous phase was then treated with solid NaCl and then re-extracted with methyl t-butyl ether. The organic extracts were combined and washed with brine, dried over magnesium sulphate, filtered and evaporated to give 2 - {[(1S) -1-methylbuty]] oxy} -9- (tetrahydro-2H) - pyran-2-yl) -9,7-purin-6-amine as a light brown gum (158.59 g). LCMS (system D): islet = 2.65 minutes; MH + 306
Intermediate 41: 8-bromo-2- (r (15) -1-methylbutyloxy) -9- (tetrahydro-2H-pyran-2-yl) -9H-purin-6-amine
N-bromosuccinimide (12.16 g, 68.3 mmol) was added portionwise over a period of 5 minutes to a stirred solution of 2 - {[(1S) -1-methylbutyl] oxy} -9- (tetrahydro). -27β-pyran-2-yl) -9H-purin-6-amine (14.9 g, 48.8 mmol) in chloroform (80 ml) at a temperature below 5 ° C under a nitrogen atmosphere . The reaction mixture was stirred at a temperature below 5 ° C for 5 hours, then washed with saturated sodium hydrogen carbonate solution (80 ml) and then with water (80 ml). The foam was dissolved in DCM (50ml) and washed with water (50ml) then brine (50ml). The combined aqueous phases were washed with DCM (50 ml). The combined organic phases were dried through a hydrophobic sinter, and the solvent was removed in vacuo to give 8-bromo-2 - {[(15) -1-methylbutyl] oxy} -9- (tetrahydro-2H). pyran-2-yl) -9H-purin-6-amine as an orange foam (18.5 g). LCMS (System D): tRi-ri = 3.06 minutes; MH + 384/386
Intermediate 42: 2- (Γ (153-1-Methyl) butyloxy) -8- (methoxy) -9- (tetrahydro-2H-pvran-2-yl) -9H-purin-6-amine
8-Bromo-2 - {[(15) -1-methylbutyl] oxy} -9- (tetrahydro-2H-pyran-2-yl) -9,7-purin-6-amine (7.1 g 18.48 mmol) was dissolved in anhydrous methanol (70 ml) and a solution of sodium methoxide (25%) in methanol (8 ml) was added dropwise under a nitrogen atmosphere. The solution was refluxed at 90 ° C for 4 hours under a nitrogen atmosphere. Additional sodium methoxide in methanol (25% solution, 3 ml) was added and the reaction was allowed to stir at 60 ° C for an additional 16 hours. An additional portion of sodium methoxide in methanol (25% solution, 5 mL) was added and the reaction was allowed to stir at 90 ° C for an additional 7 hours. The solvent was removed using a rotary evaporator and the crude product was partitioned between EtOAc (75 mL) and saturated ammonium chloride solution (75 mL). The organic phase was washed with brine (75 ml). The solvent was removed by rotary evaporation to give 2 - {[(15) -1-methylbutyl] oxy} -8- (methyloxy) -9- (tetrahydro-2H-pyran-2-yl). ) -9 // - purin-6-amine as a pale orange foam (6 g). LCSM (system D): t = 3.08 minutes; MH + 336
Intermediate 43: 2-1 [Π 5V1-methylbutyl-loxvi-8-methyloxy) -9H-purin-6-amine trifluoroacetate
2- {[(1S) -1-methylbutyl] oxy} -8- (methyloxy) -9- (tetrahydro-277-pyran-2-yl) -97H -purin-6-amine (6 g, 17 g); 89 mmol) was dissolved in methanol (50 ml). Trifluoroacetic acid (20.67 ml, 268 mmol) was added dropwise, and the mixture was stirred at 2 ° C for 72 hours under a nitrogen atmosphere. The solvent was removed in vacuo, and the resulting solid was washed with ethyl acetate and filtered. The filtrate was extracted from its solvent and the residue was washed with ethyl acetate. The combined solid residues were dried in a vacuum oven for 2 hours to give 2 - {[(15) -1-methyl-butyl] oxy} -8- (methyloxy) -9H-purin-6-amine trifluoroacetate. in the form of an off-white solid (5.3 g). LCMS (System C): = 0.76 min; MH + 252
The preparation of additional compounds useful as an intermediate in the production of oxoadenines, as well as the preparation of additional oxoadenine compounds, are described in WO 2010/018134, the entire contents of which are incorporated herein by way of reference.
Example 4: Assay for Induction of Interferon-alpha Using Cryopreserved Peripheral Human Blood Mononuclear Cells (PBMC)
The following method was used to test the in vitro biological activity of the oxadenine compounds.
Preparation of compounds
The compounds were dissolved in DMSO. Serial 2-fold dilutions with DMSO were prepared and 0.25 EI was introduced into Greiner polypropylene plates of 384 transparent wells.
Preparation of PBMCs
Blood samples up to 200 ml were collected from healthy human donors. Whole blood at a volume of 25 ml was spread over 15 ml of Ficoll gradient in Leucosep tubes, and centrifuged at 1000 g for 20 minutes. Cells in the plasma / histopaque interface band were carefully removed and washed twice with PBS (centrifuged at 400 g for 5 minutes for collection). The final pellet was resuspended in freezing medium (90% heat-inactivated serum, 10% DMSO) at a cell concentration of 4 x 10 7 cells / ml. The resuspended cells were then cryopreserved (frozen) using a controlled rate freezer and stored at -140 ° C for up to 4 months.
Incubation and assay for interferon-alpha
Immediately prior to testing, cryopreserved (frozen) PBMC vials were thawed rapidly in a water bath at 37 ° C. A 1/10 dilution of the cells in trypan blue was prepared and counted. The PBMCs were then diluted in growth medium [RPMI 1640 containing 10% fetal calf serum (invitrogen), penicillin + streptavidin (Gibco, catalog number 25030024, 1:50), 2mM L-glutamine, and 1000 units / ml of recombinant human IFN-gamma (Preprotech, catalog number 300-02)] at a density of 1 x 10 6 cells / ml, and 50 μl / well introduced into the wells (polypropylene plates) containing either 0.25 μl of DMSO, a compound tested in 0.25 μl of DMSO. A high final concentration of the compound was generally 50 μΜ or 5 μΜ (to obtain a curve fit for highly active compounds). Plates were incubated for 24 hours at 37 ° C under 5% CO2.
A multiple isoform immunoassay was used to quantify IFN-alpha in PBMC supernatants. A rabbit polyclonal antibody to human IFN-alpha (catalog number 31101, Stratech Scientific) was diluted 1: 10000 in assay buffer (RPMI 1640 containing 10% fetal calf serum, Invitrogen) and 20 μl were added to each well of a small monospot MSD (Meso-Scale Discovery, Gaithersburg, MD, USA) plate of GAR (coated with goat anti-rabbit antibody). The wafer was incubated for 1 hour at room temperature with vigorous stirring. After three washes with PBS, 20 μl of cell supernatant was added to each well of the plate. The plate was then incubated for 1 hour at room temperature with vigorous stirring. A pair of monoclonal antibodies against IFN-alpha (catalog numbers 21100 and 21112, Stratech Scientific) was labeled with SULFO-TAG (TM) (MSD), diluted 1/1000 in the assay buffer, and 20 μl were added to each well of the plate. The plate was incubated again for 1 hour at room temperature with vigorous stirring. After three washes with PBS, 30 μl of T x2 buffer (MSD) was added to each well and the plate was read on a Sector 6000 MSD plate reader.
The data were normalized to internal plaque controls, i.e., 1 μM resiquimod (n = 16) and DMSO (n = 16). The pCE50 values were obtained by a 4-parameter curve adjustment with IRLS (iterative reweighted least squares) in the ActivityBase software, from 11 points obtained with serial dilution by two of the tested compounds.
Example 5 Test for Induction of Interferon-alpha and TNF-alpha Using Fresh Human Human Peripheral Blood Mononuclear Cells (PBMC)
Preparation of compounds
The compounds were dissolved in 2% glycerol in water to obtain working concentrations starting at 10 μΜ, diluted serially to 0.00013 μΜ by 5 fold dilutions. This compound preparation was added to 96-well flat bottom plates with a volume of 10 μΐ. An additional 10 μΐ of medium was added to these wells, or another compound preparation if co-stimulation was considered.
Preparation of PBMCs
Blood samples from human donors were collected in 60 cc heparinized syringes and divided into 20 ml aliquots in 50 ml conical culture tubes. Aliquots of whole blood were then diluted with 15 ml of PBS and then plated on 15 ml of HISTOPAQUE (TM). Samples were centrifuged at 800 g for 30 minutes continuously and the buffy coat interface was carefully removed. The collected cells were centrifuged at 1500 rpm for 5 minutes and the pellet resuspended in 10 ml of PBS. Cells were pooled and washed twice more with PBS to remove all HISTOPAQUE (TM) samples. After the final wash, the combined cells were introduced into 20 ml of complete medium (RPMI 1640 supplemented with 10% v / v of heat inactivated fetal bovine serum (FBS), 100 U / ml penicillin G, 100 μg streptomycin / ml, 10 mM L-glutamine), counted using an automatic countess cell counter (Invitrogen, Life Technologies) and diluted to give a final concentration of 2.8x106 / ml. This cell suspension was added to the culture plate containing the compound preparations (see above), at a volume of 180 μΐ, to obtain a total volume in the well of 200 μΐ.
Incubation and assays for interferon-alpha and TNF-alpha
After 24 hours of incubation (37 ° C, 95% air, 5% CO2), the supernatants were carefully removed and tested for cytokine / chemokine induction using multiplex kits (FLUOROKINE ™). multiplex kits available at R & D
Systems [bio-techne], Minneapolis, MN) and VERIKINE (TM) ELISA Kit for Human IFNa (Pestka Biomedical Laboratories, Inc., Piscataway, NJ).
Example 6: Allerein-mediated cytokine assay using fresh human peripheral blood mononuclear cells (PBMC) from atopic volunteers
An assay based on co-culture of peripheral blood mononuclear cells (PBMC) from atopic human donors with an allergen and tested compounds was developed. After a 5-6 day culture, various cytokines were assayed in the cell supernatants.
Preparation of compounds
The compounds were dissolved in DMSO and then serially diluted in growth medium (RPMI 1640 medium supplemented with 100 U / ml penicillin G, 100 μg / ml streptomycin, 10 mM L-glutamine) to give 4x the required concentration range in the presence of 0.04% DMSO. Each compound was tested in triplicate at all concentrations.
Preparation of PBMCs
Defibrinated human blood from a volunteer known to be allergic to timothy was centrifuged at 2500 rpm for 15 minutes. The upper serum phase was collected and inactivated by heating at 56 ° C for 30 minutes (autologous serum HI). The lower cell phase was resuspended in 50 ml of PBS (+ Ca + Mg), 25 ml of diluted blood was plated on 20 ml of LYMPHOPREP (TM) in 50 ml tubes, and then centrifuged at 2500 rpm. / minute for 20 minutes at RT. Serum / LYMPHOPREP (TM) interface was carefully removed. The collected cells were washed with PBS and resuspended at 4x 10 6 / ml in growth medium with HI autologous serum. PBMCs were introduced at 0.4 x 106 cells / well in 96-well flat-bottomed plates in the presence of 10 μg / ml timothy grass antigen (Alk-Abello, Denmark) and compounds tested in appropriate concentrations in a total volume of 200 μl.
Incubation and cytokine dosing
Plates were incubated at 37 ° C under 5% CO2 for up to 6 days. The cell medium from each well was collected and stored at -20 ° C prior to analysis. The cytokines and chemokines in the supernatants were detected using MESO SCALE DISCOVER Y ™ spot plates for human TH1 / Th2 cytokines.
Example 7: TLR7 / 8 activity of oxoadenines 3a-3g The activity of oxoadenines 3a-g on human TLR7 / 8 (h) was evaluated by a reporter gene assay using HEK293 cells stably transfected with hTLR7 or hTLR8, and with the reporter NFkB SEAP (secreted embryonic alkaline phosphatase).
HEK293 cells expressing human TLR7 or TLR8, and the NFkB-sensitive SEAP reporter gene, were obtained from InivoGen (San Diego, CA). These cells were maintained in culture medium containing Dulbecco's modified Eagle's medium (DMEM) (Invitrogen, Grand Island, NY), 10% fetal bovine serum (FBS) (Sigma, St. Louis, Missouri) and a selection antibiotics (Invitrogen and InvivoGen). Stably transfected HEK293 cells were introduced into 96-well flat-bottom culture plates at 1E5 / well and stimulated for 24 hours with a dose range of aqueous formulations of the compounds starting from 200 μΜ, diluted in half. series up to 0.012 μΜ with 2-fold dilutions (unless the formulation conditions ensured lower starting concentrations). Culture supernatants were collected and tested for activation of NFkB using the colorimetric detection kit of SEAP QUANTI-BLUE (an InvivoGen trademark). The assay measured the production of NFkB-mediated SEAP after specific activation of TLR7 or TLR8. The specificity for hTLR7 and hTLR8 and the activity (EC50) of oxoadenines 3a-g are shown in FIGS. 1A-C.
It should be noted that the HEK assay is not optimal for evaluating TLR7, as TLR7 signals pass through both NFkB (leading to the induction of inflammatory cytokines) and IRF7 ( leading to induction of IFN) and the HEK system measures only the NFkB side of the TLR7 signaling. Oxoadenine 3a was not active on hTLR7 or hTLR8, but the other oxoadenines 3b-g were all active. Although increasing the length of the linker beyond 1 carbon increases the power of hTLR7, no linear correlation between the length of the carbon-based linker and the power of hTLR7 was observed in this assay. The 5-carbon oxoadenine 3f was the most potent hTLR7 agonist of the series (see Figure IC), while the 1B oxoadenine 3b was the most potent agonist of hTLR8 in the series, the power of hTLR8 decreases significantly with longer carbon-based linkers.
The loss of hTLR8 activity observed after stimulation with higher doses of oxoadenin 3e-g suggests possible cell toxicity in HEK293-hTLR8 cells. Aqua fixable LIVE / DEAD (TM) staining was used to evaluate potential cell death following stimulation of HEK293-hTLR8 with oxoadenines 3e-g. Significant cellular toxicity was observed at higher doses of oxoadenines 3e-g (data not shown). This cellular toxicity was not observed after 24 hours of stimulation with the shorter carbon-based oxoadenines 3b-d (data not shown). Induction of cytokines in human peripheral blood mononuclear cells (hPBMC) after 24 hours of stimulation with oxoadenines 3e-g was then assessed using cytokine ELISA and intracellular cytokine staining (ICS). The induction of TNFD is shown in Figure 2A. A clear increase in TNFD secretion with increasing length of the carbon chain is observed, with maximum secretion of TNFD being observed for the five-carbon linker. ICS has also been used to examine the activation status and cytokine contributions of distinct cellular subsets. A similar pattern was observed with myeloid dendritic cells (mDC) compared with induction of IL-6 (Figure 2B), TNFD and IFN CD. Taken together, these data strongly suggest an increase in cytokines proinflammatory when the carbon-based linker increases up to five carbons. The 6-carbon oxoadenine with 6 carbons induces less TNFD than 3f but more than Foxcharen 3 with 4-carbon linkers. Induction of IFND from hPBMCs after stimulation with oxoadenines 3a-g was also evaluated. Given the nonlinear relationship observed between the length of the carbon-based linkers and the DE50 values for hTLR7 obtained with the oxoadenines 3a-g in the HEK293 system (which indicates the NFDB side of the TLR7 signaling), we have expected that the induction of IFND from hPBMC is more representative of the activity of these compounds on hTLR7. A unique profile for IFND expression was observed for compounds 3a-g (Figure 3).
Each of the compounds 3a-g had a peak-to-base bell-shaped dose-response curve within a 100 CM dose range, except oxoadenine 3a which was inactive. Oxoadenines with increasing length of carbon-based linker were more potent IFNC1 inducers, as indicated by the lower dose required to achieve maximum IFND response, but higher concentrations of oxoadenines were associated at a decrease in dose response for IFNCL At the same time, TNFD levels in the same cell culture supernatants increased in a dose-dependent manner. pDC is the major cell type responsible for more than 90% of IFN secretion, thus suppressing the TLR7-IRF7 signaling pathway through a regulatory feedback loop to restrict the importance of IFNDBu activation of cell-specific activation-induced cell death (AICD) could be responsible for the unique cytokine profile observed in this study.
To evaluate these hypotheses, hPBMCs were stimulated with various doses of 3b (1-carbon linker) or 3f (5-carbon linker) and the cells were evaluated for apoptosis induced by annexin-dependent staining. V. 3f was associated with a dose-dependent increase in annexin-V staining in pDCs but not in mDCs. In contrast, only the highest dose of 3b (10 mM) was associated with annexin-V positive cells in both the pDC and mDC subsets. This observed apoptosis specific for a cell type is correlated with the dose-dependent induction curves of IFND and TNFD.
To further confirm the effect of pDC apoptosis upon induction of IFND, co-stimulation with equimolar amounts of 3b and 3f was evaluated in hPBMCs. As expected, the combination of a high dose (-0.3 CM) of 3f and 3b reduces the IFND peak compared to 3b alone, while the combination of a lower dose of 3f and 3b ( -0.003 DM) does not modify the maximum response of the IFND by 3f alone (data not shown). Overall, these results demonstrate that increasing the length of the carbon-based linker from 1 to 5 carbons increases the induction power of IFNO from pDCs, but also reduces the dose threshold for apoptosis while leaving the induction of TNFD from mDC largely unaltered.
In summary, the structure-activity relationship of seven oxoadenines (3a-3g) substituted at the 9-position with a piperidinyl alkyl moiety was studied. At a minimum, a 1-carbon linker was required for the activation of hTLR7 and hTLR8. 5-carbon oxoadenine is the most potent hTLR7 agonist, while the 1-carbon linker is the most potent hTLR8 agonist of the series. The induction of proinflammatory cytokines and IFND in hPBMC increases with increasing carbon chain length of up to 5 carbons, with 5-carbon oxoadenine being the most potent cytokine inducer. These results indicate that it is possible to modulate the activity of hTLR7 / 8 and the induction of cytokines with the oxoadenine series containing non-aromatic groups on N-9 through a minor structural change.
Example 8 Specificity for TLR7 and TLR8 and Power of Compound 3x
The 3x compound is shown to have better TLR7 potency and TLR7 agonist activity compared to the other oxoadenines studied.
Compared with oxoadenine 3b, the power of 3f and 3x on TLR7 is 50 and 100 respectively higher (FIG. 4A), and their activity is lower on TLR8 (FIG. 4B). The influence of the C2 substituent can be observed by comparing 3f and 3x: the introduction of a (S) -methyl group on the first carbon of the C2 butoxy chain increases the activity on both TLR7 and TLR8 .
When evaluated for cytokine induction in hPBMCs, the 3f and 3x compounds exhibit high potency (lower DE50) and TNF-alpha response (Fig. 5). The same result is observed for the other proinflammatory cytokines (data not shown).
As expected on the basis of the low EDso for TLR7 observed in the HEK293 assay for the 3f and 3x compounds, the two oxoadenines induce IFN-alpha at very low doses (of the order of ~ lnM) (FIG. 6).
Figure 7 shows induction of IFN-alpha by oxoadenines, as measured by ICS. The cytokine induction was analyzed as a percentage of total live pDC cells for IFN-alpha. The doses used were 360 picomolar, 11 nanomolar, 330 nanomolar and 10 micromolar.
Previously observed with the other oxoadenines (see WO 2010/018134), the synergism with AGP CRX601 for IL12-p70 was relatively low compared to the imidazoquinoline compound CRX642 (see WO 2010/048 520; PCT / US 2009/061 867, US 8,624,029) in combination with CRX601. However, 3x and 3f showed synergism with CRX601 over a wide dose range (Figures 8A and 8B).
Table 2 summarizes the data mentioned above. Pay attention to the 3x compound for its low DE50 for TLR7 and the relatively high induction of IFN-alpha and IL-12p70.
Table 2
* at **** ; from lowest to highest level of cytokine induction;

权利要求:
Claims (12)
[1]
1. Compound of formula (I):

in which ; R 1 is 1-methylbutoxy or (1S) -1-methylbutoxy; R2 is a group having the structure:

where n is an integer having a value of five; Het is a six-membered saturated heterocycle containing five carbon atoms and one nitrogen atom, wherein Het is bonded to the - (CH2) n- moiety on the carbon at the 4-position of the heterocycle; and R3 is hydrogen; or a pharmaceutically acceptable salt thereof.
[2]
2. A compound of formula (I), wherein R1 is (1S) -1-methylbutoxy; R2 is a group having the structure:

where n is an integer having a value of 5; Het is a piperidine, wherein Het is attached to the - (CH2) n- moiety on the carbon at the 4-position of the heterocycle; and R3 is hydrogen; or a pharmaceutically acceptable salt thereof.
[3]
3. Compound 6-amino-9- [5- (4-piperidinyl) pentyl] -2 - [(1S) -1-methylbutyl] oxy] -7,9-dihydro-8H-purin-8-one or pharmaceutically acceptable salt acceptable of it.
[4]
4. A compound as defined in any one of claims 1 to 3 for use in the treatment of allergic diseases or other inflammatory conditions.
[5]
5. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 3, and one or more pharmaceutically acceptable diluents or carriers.
[6]
An immunogenic composition comprising a compound as defined in any one of claims 1 to 3, and an antigen or antigen composition.
[7]
7. Use of a compound as defined in any one of claims 1 to 3 for the preparation of an immunogenic composition comprising an antigen or an antigen composition for the treatment or prevention of a disease.
[8]
8. Use of a compound as defined in any one of claims 1 to 3, for the preparation of a medicament for the treatment of allergic diseases or other inflammatory diseases, infectious diseases or cancer.
[9]
9. Use of a compound as defined in any one of claims 1 to 3 for the preparation of a medicament for the treatment of allergic rhinitis or asthma.
[10]
A composition comprising a compound as defined in any one of claims 1 to 3, and further comprising a component selected from: (a) at least one other therapeutically effective agent, (b) a pharmaceutically acceptable diluent, and c) a pharmaceutically acceptable carrier.
[11]
11. A composition comprising a compound as defined in any one of claims 1 to 3 for use in therapy.
[12]
12. Use of a compound as defined in any one of claims 1 to 3 for the preparation of a medicament for use in therapy.

类似技术:

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法律状态:
2021-08-11| MM| Lapsed because of non-payment of the annual fee|Effective date: 20201130 |

优先权:

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申请号 | 申请日 | 专利标题

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US201462079027P| true| 2014-11-13|2014-11-13|

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US62/079,027|2014-11-13|

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