IMIDAZOQUINOLINE PEGYLENE

专利摘要:
The present invention provides novel phospholipid imidazoquinolines as TLR7 and TLR8 agonists, pharmaceutical compositions, therapeutic uses and methods for their preparation.
公开号:BE1024097B1
申请号:E2016/5914
申请日:2016-12-12
公开日:2017-11-16
发明作者:Helene G. Bazin-Lee；David A. Johnson
申请人:Glaxosmithkline Biologicals Sa；
IPC主号:

专利说明:

IMIDAZOQUINOLEINES PEGYLEES Statement on Federally Funded Research
This work was funded in part by the National Institute of Allergy and Infectious Diseases (NIAID) under contract HHSN272200900036C (with Corixa Corporation operating under the name GlaxoSmithKline Biologicals SA).
Context of the invention
The present invention relates to Toll receptor agonists 7 (TLR7) and receptor type
Toll 8 (TLR8). More particularly, the present invention relates to compounds useful as agonists for TLR7 and / or TLR8, compounds useful as adjuvants, methods for making such compounds, pharmaceutical formulations comprising such compounds, and their therapeutic use. The improvement and simplification of antimicrobial vaccines and the use of synthetic and recombinant subunit antigens to improve the manufacturability and safety of vaccines have resulted in decreased potency. This has led to studies on coadministration of adjuvants with antigens to potentiate vaccine activity and low immunogenicity of synthetic and recombinant epitopes. Adjuvants are additives that enhance humoral and / or cell-mediated immune responses. However, the design of vaccine adjuvants has historically been difficult because of the complex nature of the molecular mechanisms involved in the function of the immune system. Although the addition of microbial components has long been known to enhance adaptive immune responses, it has only recently been shown that Toll-like receptors (TLRs) on cells involved in immune surveillance, such as epithelial and dendritic cells, involve many of these microbial products through so-called "pathogen-associated molecular motifs" or PAMPs. Many independent vaccine adjuvants and immunomodulators appear to interact with members of the TLR family.
Of the ten known TLRs that have been identified in humans, five are associated with the recognition of bacterial components (TLR 1, 2, 4, 5, 6) and four others (TLR 3, 7, 8, 9) appear to be restricted to cytoplasmic compartments and are involved in the detection of viral RNA (TLR 3, 7, 8) and unmethylated DNA (TLR9) (Iwasaki, A., Nat Immunol 2004, 5, 987). TLR activation regulates intracellular signaling voices and leads to gene expression through interaction with intracellular adapter molecules such as MyD88, TRIF, TIRAP, and TRAM (Akira, S. Nat Rev Immunol 2004, 4, 499, Takeda, K. Semin Immunol 2004, 16, 3). These adapter molecules can differentially regulate the expression of inflammatory cytokines / chemokines and type I interferons (IFN-α / β), which can lead to the preferential amplification of the specific humoral and cell-mediated immune responses. antigen (Zughaier, S. Infect Immun 2005, 73, 2940). Humoral immunity is the main line of defense against bacterial pathogens, while induction of cytotoxic T lymphocytes (CTLs) appears to be crucial for protective immunity in the case of viral disease and cancer.
Currently, a group of aluminum salts known as alum are the main adjuvants used in human vaccines. But alum usually only enhances humoral immunity (Th2) and is generally used intramuscularly because of local toxicity by other pathways (eg, subcutaneous or intradermal inoculation leads to granulomas) (Aguilar J. Vaccine 2007, 25, 3752). Other potential side effects of alum include increased IgE production, allergenicity, and neurotoxicity. Thus, there is a need for new safe and effective vaccine adjuvants that are able to stimulate antibody and Th1-like immune responses and that are compatible with the different routes of administration and antigen formulations.
In the case of TLR7 and TLR8 activation, a few different classes of small molecule mimetics have been identified for natural viral RNAs (rich in U and / or G). These include certain antiviral compounds related to oxidized guanosine metabolites (oxoguanosines), which interact primarily with TLR7 (Heil, F. Eur J Immunol 2003, 33, 2987, Hemmi, 2002) and adenine derivatives which involve TLR7 and / or TLR8. The immunostimulatory capacity of these compounds has been attributed to the TLR / MyD88-dependent signaling pathways and the production of cytokines, including IL-6 and type I interferons (particularly interferon a) and type II. Activation of TLR7 and TLR8 leads to the upregulation of costimulatory molecules (e.g., CD-40, CD-80, CD-86) and MHC class I and II molecules on dendritic cells (DCs). DCs are the main cells of the immune system involved in the uptake and presentation of antigens to T cells. Plasmacytoid dendritic cells (pCDs), which preferentially express TLR7, are professional α-interferon producing cells; while myeloid dendritic cells (mCD) express TLR8. Activation of TLR8 on mCD leads to preferential production of proinflammatory cytokines such as IL-12, TNF-α, and IFN-γ and cell-mediated immunity (CMI).
One class of adenine derivatives that has received a considerable amount of attention is 1H-imidazo [4,5-c] quinolines (IQ). It has been discovered that the prototype member of this class, imiquimod (R847, S-26398), is effective against genital papillomavirus infections, actinic keratosis, and basal cell carcinoma when applied topically. in the form of cream. However, imiquimod has a relatively low interferon induction activity and both oral and topical preparations are not without side effects. In fact, serious side effects have been reported in a clinical trial of hepatitis C virus (HCV) with imiquimod. The "immunological fingerprint" of TLR7 agonists has generally led to concerns about toxicity. Clinical trials with another TLR7 agonist ANA-975, an oxoguanosine derivative, have recently been suspended due to toxicity issues.
As a first-line treatment for hepatitis C virus (HCV) disease, combinations of interferons can be highly effective in reducing viral load and in some individuals in eliminating viral replication. However, many patients fail to display a sustained viral response and in these patients the viral load is not controlled. In addition, treatment with interferon injection may be associated with a number of adverse adverse effects that have been shown to affect adherence (Dudley T, O'Donnell K, Haydon G, Mutimer D. Gut., 2006 , 55 (9): 1362-3). The administration of a small molecule compound that may stimulate the innate immune response, including activation of type I interferons and other cytokines, may become an important strategy for the treatment or prevention of be human including viral infections. This type of immunomodulation strategy has the potential to identify compounds that may be useful not only in infectious diseases but also in cancer (Krieg, Curr, Oncol, Rep., 2004; 6 (2): 88-95). allergic diseases (Moisan et al., Am J Physiol Lung Cell Mol Physiol 2005; 290 (5): L987-95), other inflammatory conditions such as irritable bowel disease (Rakoff-Nahum). S., Cell 2004, 23; 118 (2): 229-41), and as vaccine adjuvants (Persing et al., Trends Microbiol., 2002; 10 (10 Suppl): S32-7).
Another member of the IQ class of TLR7 / 8 ligands and a derivative of a metabolite of imiquimod is resiquimod. Resiquimod (R-848, S-28609) also activates TLR7 in macrophages and DCs in a MyD88-dependent manner either directly or indirectly via an accessory molecule and positively regulates costimulatory molecules and MHC. I / II in the CDs. But unlike imiquimod, the more potent and toxic resiquimod is also a ligand for TLR8 signaling, which leads to the reversal of the function of CD4 + regulatory cells (Treg). Using transfected HEK293 cells, it has recently been shown that TLR7 agonists are more potent in the production of IFN-α and IFN-regulated cytokines, whereas TLR8 agonists have been more effective in the production of IFN-α and IFN-regulated cytokines. induction of proinflammatory cytokines such as TNF-α and IL-12, suggesting that activation of TLR7 may be more important for antibody responses (Th2 responses) whereas activation of TLR8 may BMI or Th1 immune responses. However, as mentioned above, many TLR7 / 8 agonists often display toxic properties, are unstable, and / or have insubstantial immunostimulatory effects. Thus, the discovery and development of safe and effective adjuvants that activate TLR7 and / or TLR8 is essential for improving the efficacy and safety of existing and new vaccines by helping to control the magnitude of disease. , the direction, and the duration of the immune response against antigens. Unlike TLR2 and TLR4, which recognize PAMPs on cell surfaces, TLR7 / 8 PAMPs are detected in endosomal / lysosomal compartments and require endosomal maturation. Cellular uptake is a prerequisite for cellular activation in natural and zenobiotic TLR7 / 8 ligands such as imiquimod and resiquimod. Thus, strategies that will increase TLR7 / 8 ligand penetration into DCs and other immune cells will enhance TLR activation and vaccine efficacy as well as enhance toxic effects.
The immunostimulatory capacity of certain antiviral / antitumor 1H-imidazo [4,5-c] quinolines (Gerster, J. F, et al., J. Med Chem 2005, 48, 3481-3491), such as imiquimod, has This has been attributed mainly to TLR7 activation in plasmacytoid and B-cell dendritic cells and induction of type I interferons (IFNα / β) and IFN-regulated cytokines (Miller, RL, Meng, T. -C Tomai, MA Drug News Perspective 2008, 21, 69-87).
TLR7 / 8 agonists in which an imidazoquinoline is conjugated to a phospho- or phosphonolipid have enhanced immune responses. It has been suggested that these agonists may enhance immune responses through direct interaction of these compounds with endosomal TLR7 and / or TLR7 / 8 and / or an interaction of an active metabolite after enzymatic action (WO 2010/04850 ). Summary of the invention
As a first aspect, the present invention provides compounds of formula (I):
in which
R 1 is selected from H, C 1 -C 5 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkoxy, C 3 -C 5 cycloalkyl-C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl-alkyl C 1 -C 5 -amino, C 1 -C 6 cycloalkyl, -C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl-amino and alkoxy C 1 -C 6 -alkoxy C 1 -C 5; C 1 to C 6 alkyl, C 1 to C 6 alkylamino, C 1 to C 6 alkoxy, C 1 to C 5 cycloalkyl C 1 to C 6 alkyl, C 3 to C 5 cycloalkyl to C 5 to C 5 alkyl groups. amino, C 1 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 5 alkoxy-C 1 -C 5 alkyl-amino or C 1 -C 4 alkoxy, -C1-alkoxy ,. being branched or unbranched and optionally substituted at their end by a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl, or male moiety; Z is selected from C2 to C6 alkyl and C2 to C6 alkenyl, C2 to C6 alkyl and C2 to C6 alkenyl unsubstituted or substituted at the end with a - (O-C2-C6alkyl) group; C6) i to 6- / X represents 0 or S; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R2 represents H or a linear or branched, optionally unsaturated C4 to C24 alkyl group or a linear or branched, optionally unsaturated C4 to C24 acyl group; R3 represents a linear or branched, optionally unsaturated C4 to C24 alkyl group, or a linear or branched, optionally unsaturated C4 to C24 acyl group.
In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I). The composition may further comprise a pharmaceutically acceptable carrier or diluent.
In a third aspect, the present invention provides a method for the treatment of a TLR7- and / or TLR7 / 8-mediated condition in a subject in need thereof. The method comprises administering to a subject a therapeutically effective amount of a compound of formula (I).
In a fourth aspect, the present invention provides a method for treating a hepatitis C virus infection in a subject in need thereof. The method comprises administering to a subject a therapeutically effective amount of a compound of formula (I).
In a fifth aspect, the present invention provides a method for the treatment of basal cell carcinoma in a subject in need thereof. The method comprises administering to a subject a therapeutically effective amount of a compound of formula (I).
In a sixth aspect, the present invention provides a method for the treatment of actinic keratosis in a subject in need thereof. The method comprises administering to a subject a therapeutically effective amount of a compound of formula (I).
In a seventh aspect, the present invention provides a method for treating a genital papillomavirus infection in a subject in need thereof. The method comprises administering to a subject a therapeutically effective amount of a compound of formula (I).
In an eighth aspect, the present invention provides a method for using a compound of formula (I) as a vaccine adjuvant.
In a ninth aspect, the present invention provides a process for preparing a compound of formula (I). This process comprises the following steps: a) the reaction of a compound of formula (III)
(III) with a compound of formula (V)
wherein PG represents a suitable protecting group for hydroxyl group protection, including but not limited to cyanoethyl, methyl, ethyl, benzyl and allyl to prepare a compound of formula (VI)
in which R represents
all other variables are as defined above for formula (I); b) the reaction of a compound of formula (VI) with a compound of formula (VII)
(VII) for preparing a compound of formula (IX)
(IX) wherein R represents
R 'represents
wherein PG represents a suitable protecting group for hydroxyl group protection, including but not limited to cyanoethyl, methyl, ethyl, benzyl and allyl groups; all other variables are as defined above for formula (I); c) oxidizing a compound of formula (IX) and removing the hydroxy-protecting group to obtain a compound of formula (I); d) optionally converting the compound of formula (I) into a pharmaceutically acceptable salt thereof; e) the optional conversion of the compound of formula (I) into a compound of formula (I) different.
In a tenth aspect, the present invention provides another method for preparing a compound of formula (I). This process comprises the following steps: a) the reaction of a compound of formula (VII)
with an H-phosphonate compound of formula (X)
wherein all other variables are as described above for formula (I) for preparing a compound of formula (I); b) optionally converting the compound of formula (I) into one of its pharmaceutically acceptable salts; c) optionally converting the compound of formula (I) into a compound of formula (I) different.
In another aspect, the present invention provides a compound of formula (I) for use in therapy, the present invention also provides a compound of formula (I) for use in the treatment of a disease-mediated condition. TLR7 and / or TDR8 in a subject; a compound of formula (I) for use in the treatment of hepatitis C virus infection in a subject; a compound of formula (I) for use in the treatment of basal cell carcinoma in a subject; a compound of formula (I) for use in the treatment of actinic keratosis in a subject; a compound of formula (I) for use in treating a genital papillomavirus infection in a subject; and a compound of formula (I) for use as a vaccine adjuvant.
In another aspect, the present invention provides the use of a compound of formula (I) for the preparation of a medicament for the treatment of a condition mediated by the activity of TLR7 and / or TLR8 in a subject; the use of a compound of formula (I) for the preparation of a medicament for the treatment of a hepatitis C virus infection; the use of a compound of formula (I) for the preparation of a medicament for the treatment of basal cell carcinoma; the use of a compound of formula (I) for the preparation of a medicament for the treatment of actinic keratosis in a subject; the use of a compound of formula (I) for the preparation of a medicament for the treatment of a genital papillomavirus infection in a subject; and the use of a compound of formula (I) as a vaccine adjuvant for the preparation of adjuvanted vaccines.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of a condition mediated by the activity of TLR7 and / or TLR8. Other aspects of the present invention are described in the description of particular embodiments, examples, and claims that follow.
Brief description of the drawings
Figure 1: NFkB response of (A) HEK293-hTLR7 and (B) HEK293-hTLR8 cells treated for 24 hours with PEGylated analogs. Downstream signaling of hTLR7 / 8 receptors was monitored using NFkB-mediated SEAP secretion. The activity profile of each compound was quantified by measuring the SEAP activity in the culture supernatant of HEK293 cells.
Figure 2: induction of TNF-α from hCMSP by PEGylated imidazoquinolines.
Figure 3: induction of IFN-α from hCMSP by PEGylated imidazoquinolines.
Detailed Description of the Preferred Embodiments
As used herein, "a compound of the invention" or "a compound of formula (I)" means a compound of formula (I) or a pharmaceutically acceptable or solvated salt thereof.
The present invention provides compounds of formula (I):
in which
R1 is selected from H, C1 to C6 alkyl, C1 to C6 alkylamino, C1 to C6 alkoxy, C3 to C6 cycloalkyl, C1 to C6 alkyl, C3 to C6 cycloalkyl, C1 to C6 alkyl, amino, C3-C6 cycloalkyl-C1-C6 alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl-amino and C1-C6 alkoxy-C1-alkoxy at C6; C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, C3-C6cycloalkyl-C1-C6alkyl, C3-C6cycloalkyl-C1-C6alkylamino, cycloalkyl C3-C6-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl-amino or C1-C6-alkoxy-C1-C6 alkoxy branched or unbranched and optionally substituted at their end by a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl, or maleimido group; Z is selected from C2 to C6 alkyl and C2 to C6 alkenyl, C2 to C6 alkyl and C2 to C6 alkenyl unsubstituted or substituted at the end with a - (O-C2-C6alkyl) group; C6) 1-6; X is 0 or S; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R2 represents H or a linear or branched, optionally unsaturated C4 to C24 alkyl group or a linear or branched, optionally unsaturated C4 to C24 acyl group; R3 represents a linear or branched, optionally unsaturated C4 to C24 alkyl group, or a linear or branched, optionally unsaturated C4 to C24 acyl group.
In one embodiment of the invention, R 1 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkylamino and C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkyl, C6-amino and C1-C6 alkoxy being branched or unbranched and optionally substituted at their end by a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl, or maleimido group.
In a preferred embodiment, R 1 is C 1 -C 6 alkyl, for example, C 1 -C 4 alkyl, such as butyl, particularly n-butyl.
In another preferred embodiment, Z is (C2-C6) alkyl, wherein (C2-C6) alkyl is unsubstituted or substituted at the end with a - (C2-C6) O-alkyl group. In such an embodiment, Z represents an unsubstituted C 2 -C 6 alkyl group. In a preferred embodiment, Z represents a (CH 2) 2 group.
In another preferred embodiment, X represents 0.
In another embodiment of the invention, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
In another embodiment of the invention, n is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
In another embodiment of the invention, n is 3, 4, 5, 6, 7, 8, or 9.
In another preferred embodiment, n is selected from 3, 6 and 9.
In another preferred embodiment, n is selected from 3 and 6.
In another preferred embodiment of the invention, n is 3.
In another preferred embodiment of the invention, n is 6.
In another preferred embodiment of the invention, n is 9.
In another embodiment of the invention, R2 represents a linear or branched, optionally unsaturated C4-C24 acyl group, for example a saturated linear chain C4 to C24 acyl group, particularly C10 to C20, as a acyl group
Cl6 ·
In another embodiment of the invention, R3 represents a linear or branched, optionally unsaturated, C4-C24 acyl group, for example a saturated linear chain C4 to C24 acyl group, particularly C10 to C20, such as acyl group
Cl6 ·
In one embodiment, R2 and R3 are the same. In an alternative embodiment, R2 and R3 are different.
In another preferred embodiment of the invention, R2 represents an unbranched C16 acyl group (palmitoyl, COCi5H3i).
In another preferred embodiment of the invention, R3 represents an unbranched C16 acyl group (palmitoyl, COCi5H3i).
In another preferred embodiment of the invention, R2 is H and R3 is n-C15H3iCO.
In a preferred embodiment of the invention, R 1 is C 1 -C 6 alkyl; Z is C 2 -C 6 alkyl, C 2 -C 6 alkyl unsubstituted or substituted at the end with - (O-C 2 -C 6) alkyl at 6 ~; X is 0; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; R2 represents a linear or branched, optionally unsaturated C4-C24 acyl group; and R3 represents a linear or branched, optionally unsaturated C4-C24 acyl group.
In another preferred embodiment of the invention, R 1 is C 1 -C 6 alkyl; Z is C2-C6 alkenyl; X represents O; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; R2 represents an unsaturated linear chain C4-C24 acyl group; and R3 represents an unsaturated linear chain C4-C24 acyl group.
In another preferred embodiment of the invention, R4 = n-butyl; Z represents a group (CH2) 2; n is selected from 3, 6 and 9; R2 is C16 acyl and R3 is acyl.
Cl6 ♦
Specific examples of particular compounds of the present invention are selected from the group consisting of: 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-ethyleneglycol-phospho) ethyl] -2-n -butyl-1H-imidazo [4,5-c] quinoline; 4-Amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-triethyleneglycol-phospho) ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinoline; 4-Amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-hexaethyleneglycol-phospho) ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinoline; 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-nonaethyleneglycol-phospho) ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinoline; and their pharmaceutically acceptable salts.
A preferred compound of the invention is 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-triethyleneglycolphospho) ethyl] -2-n -butyl-1H-imidazo [4, 5-c] quinoline; or a pharmaceutically acceptable salt thereof. In a particular embodiment, 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-triethyleneglycol-phospho) ethyl] -2-n-butyl-1H-imidazo [4,5] quinoline; or a pharmaceutically acceptable salt thereof is in crystalline form. In another embodiment, 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-triethyleneglycolphospho) ethyl] -2-n-butyl-1H-imidazo [4,5] quinoline is in the form of a choline salt.
Another preferred compound of the invention is 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-hexaethylene glycol phospho) ethyl] -2-n-butyl-1H-imidazo. [4,5-c] quinoline; or a pharmaceutically acceptable salt thereof. In a particular embodiment, 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-hexaethyleneglycol-phospho) ethyl] -2-n-butyl-1H-imidazo [4, 5-c] quinoline; or a pharmaceutically acceptable salt thereof is in crystalline form. In another embodiment, 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-hexaethylene-glycol-phospho) ethyl] -2-n-butyl-1H-imidazo [4] 5-c] -quinoline is in the form of a choline salt.
Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the present invention. The present invention also covers the individual isomers of the compounds represented by the formula (I) in the form of mixtures with their isomers in which one or more chiral centers are reversed.
Suitable pharmaceutically acceptable salts according to the present invention will be readily ascertainable to those skilled in the art and will include, for example, salts prepared from organic or inorganic bases such as lithium hydroxide, sodium hydroxide, sodium hydroxide and the like. potassium hydroxide, lithium carbonate, lithium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, potassium tert-butoxide and organic bases such as such as diethylamine, lysine, arginine, choline, tris (hydroxymethyl) aminomethane (tromethamine), triethanolamine, diethanolamine, and ethanolamine.
When used in medicine, the salts of a compound of formula (I) should be pharmaceutically acceptable, but pharmaceutically unacceptable salts can be conveniently used to prepare the corresponding free base or pharmaceutically acceptable salts thereof .
As used herein, the term "solvated" refers to a crystalline form containing the compound of formula (I) or a pharmaceutically acceptable salt thereof and a stoichiometric or non-stoichiometric amount of a solvent. Solvents, for example, include water (thereby producing hydrates), methanol, ethanol, or acetic acid. Hereinafter, the reference to a compound of formula (I) is to any physical form of this compound, unless a particular form, salt or solvate thereof is specified.
Processes for preparing the pharmaceutically acceptable salts of the compounds of formula (I) are conventional in the art. See, for example, Burger's Medicinal Chemistry and Drug Discovery 5th Edition, Vol 1: Principles And Practice.
The compounds of the invention of formula (I) 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 included 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 traditional analytical techniques including, but not limited to, X-ray powder diffraction (XRPD), infrared spectroscopy ( IR), Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (NMRes).
It will be understood from the foregoing that are included within the scope of the invention the hydrates, isomers and polymorphic forms of the compounds of formula (I) and their salts.
As will be apparent to those skilled in the art, in the processes described below for the preparation of compounds of formula (I), certain intermediates may be in the form of pharmaceutically acceptable salts of the compound. These terms as applied to any intermediate used in the process for the preparation of the compounds of formula (I) have the same meanings as those noted above for the compounds of formula (I). The processes for preparing the pharmaceutically acceptable salts of these intermediates are known in the art and are analogous to the process for preparing the pharmaceutically acceptable salts of the compounds of formula (I).
In one embodiment, the compounds of formula (I) are TLR7 and / or TLR8 agonists. As used herein, the term "agonist" refers to a compound that exhibits TLR7 and / or TLR8 activity in the HEK 293 cell assay described below and / or induces IFN-α and / or TNF-α in the cytokine induction test described below.
The compounds of formula (I) are useful in therapy in subjects such as mammals, and particularly humans. In particular, the compounds of formula (I) are useful in the treatment of a condition mediated by the activity of TLR7 and / or TLR8 in a subject such as a mammal, particularly a human being. As used herein, the term "treatment" includes preventing the onset of symptoms of the condition or illness in the subject, preventing the recurrence of the symptoms of the condition or disease in the subject , the delay in the recurrence of symptoms of the disease condition in the subject, the decrease in the severity or frequency of the external symptoms of the disease or disease in the subject, the slowing down or elimination of the progression of the condition and the partial or complete elimination of the symptoms of the disease or condition in the subject.
The compounds of the invention induce interferon-α, TNF-α, IL-12 and other immunostimulatory cytokines. The amplitude of cytokine induction is modulated by the length of the PEGylated radical. These compounds may possess an improved activity-toxicity profile compared to known cytokine inducers when used as adjuvants for vaccine antigens in the therapeutic or prophylactic treatment of infectious diseases and cancer.
Conditions that may be mediated by the activity of TLR7 and / or TLR8 and / or IFN-α include, but are not limited to, inflammation, including but not limited to, inflammatory or allergic diseases such as asthma, allergic rhinitis, lung diseases hypersensitivity, eosinophilic pneumonia, delayed hypersensitivity, atherosclerosis, pancreatitis, gastritis, osteoarthritis, psoriasis, sarcoidosis , pulmonary fibrosis, respiratory distress syndrome, bronchiolitis, chronic obstructive pulmonary disease, sinusitis, cystic fibrosis, and dermatitis; autoimmune diseases including, but not limited to, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, Sjögren's disease, ankylosing spondylitis, scleroderma, diabetes, graft rejection, including graft-versus-host disease, inflammatory bowel diseases including, but not limited to, Crohn's disease and ulcerative colitis; infectious diseases including, but not limited to, those caused by hepatitis viruses (eg, hepatitis B virus, hepatitis C virus), human immunodeficiency virus , papillomaviruses, herpesviruses, respiratory viruses (eg, influenza viruses, respiratory syncytial virus, rhinoviruses, metapneumoviruses, parainfluenza viruses, SARS), and West Nile virus; microbial infections caused by, for example, bacteria, fungi, or protozoa including, but not limited to, tuberculosis, bacterial pneumonia, aspergillosis, histoplasmosis, candidiasis, pneumocystosis, leprosy, chlamydia, cryptococcal disease, cryptosporidiosis, toxoplasmosis, leishmaniasis, malaria, and trypanosomiasis; various cancers, in particular the treatment of cancers that are known to respond to immunotherapy and including, but not limited to, renal cell carcinoma, lung cancer, breast cancer, colorectal cancer, cancer bladder, melanoma, leukemia, lymphoma and ovarian cancer, basal cell carcinoma; actinic keratosis; genital papillomavirus infections; and regeneration of the liver. It will be understood by those skilled in the art that references herein to treatment or therapy extend to prophylaxis as well as treatment of established conditions.
As described herein, the compounds of the invention may be useful as therapeutic agents.
The compounds of formula (I) are believed to be useful for the treatment of a hepatitis C virus infection in a subject, such as a mammal, particularly a human being.
The compounds of formula (I) are believed to be useful for the treatment of basal cell carcinoma in a subject, such as a mammal, particularly a human being.
In treating dyslipidemia, it is currently believed that the compounds of formula (I) are useful in the treatment of actinic keratosis in a subject such as a mammal, particularly a human being.
The compounds of formula (I) are useful for the treatment of genital papillomavirus infection in a subject, such as a mammal, particularly a human being.
The compounds of formula (I) are useful as a vaccine adjuvant in a subject, such as a mammal, particularly a human being.
The present invention provides a method of treating a hepatitis C virus infection in a subject, such as a mammal, particularly a human being, in need thereof. The present invention also provides the use of a compound of formula (I) for the preparation of a medicament for the treatment of hepatitis C virus infection in a subject. In one embodiment, the compound of formula (I) is 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-triethyleneglycol-phospho) -ethyl] -2-n-butyl 1H-imidazo [4,5-c] quinoline or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (I) is 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-hexaethyleneglycol-phospho) ethyl] -2-n-butyl 1H-imidazo [4,5-c] quinoline or a pharmaceutically acceptable salt thereof.
The present invention provides a method of treating basal cell carcinoma in a subject, such as a mammal, particularly a human being, in need thereof. The present invention also provides the use of a compound of formula (I) for the preparation of a medicament for the treatment of basal cell carcinoma in a subject. In one embodiment, the compound of formula (I) is 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-triethyleneglycol-phospho) -ethyl] -2-n-butyl 1H-imidazo [4,5-c] quinoline or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (I) is 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-hexaethyleneglycol-phospho) ethyl] -2-n-butyl 1H-imidazo [4,5-c] quinoline or a pharmaceutically acceptable salt thereof.
The present invention provides a method of treating actinic keratosis in a subject, such as a mammal, particularly a human being, in need thereof. The present invention also provides the use of a compound of formula (I) for the preparation of a medicament for the treatment of actinic keratosis in a subject. In one embodiment, the compound of formula (I) is 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-triethyleneglycol-phospho) -ethyl] -2-n-butyl 1H-imidazo [4,5-c] quinoline or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (I) is 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-hexaethyleneglycol-phospho) ethyl] -2-n-butyl 1H-imidazo [4,5-c] quinoline or a pharmaceutically acceptable salt thereof.
The present invention provides a method of treating genital papillomavirus infections in a subject, such as a mammal, particularly a human being, in need thereof. The present invention also provides the use of a compound of formula (I) for the preparation of a medicament for the treatment of genital papillomavirus infections in a subject. In one embodiment, the compound of formula (I) is 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-triethyleneglycol-phospho) -ethyl] -2-n-butyl 1-Imidazo [4,5-c] quinoline or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (I) is -amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-hexaethyleneglycol-phospho) ethyl] -2-n-butyl- 1H-imidazo [4,5-c] quinoline or a pharmaceutically acceptable salt thereof.
The present invention also provides the use of a compound of formula (I) as a vaccine adjuvant in a subject, such as a mammal, particularly a human being, in need thereof. In one embodiment, the compound of formula (I) is 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-triethyleneglycol-phospho) -ethyl] -2-n-butyl 1H-imidazo [4,5-c] quinoline or a pharmaceutically acceptable salt thereof. In another embodiment, the compound of formula (I) is -amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-hexaethyleneglycol-phospho) ethyl] -2-n-butyl- 1H-imidazo [4,5-c] quinoline or a pharmaceutically acceptable salt thereof.
All of the methods of the present invention comprise the step of administering a therapeutically effective amount of the compound of formula (I). As used herein, the term "therapeutically effective amount" refers to an amount of a compound of formula (I) that is sufficient to achieve the effect indicated in the subject to which it is administered. Therefore, a therapeutically effective amount of a compound of formula (I) used in the method of treating a TLR7- and / or TLR8-mediated disease in a human will be an amount sufficient for the treatment of cancer. A disease mediated by the activity of TLR7 and / or TLR8 in a human being. A therapeutically effective amount of a compound of formula (I) for use in the method of treating a hepatitis C virus infection in a human will be an amount sufficient for the treatment of an infection with the hepatitis C virus. hepatitis C virus in a human being. A therapeutically effective amount of a compound of formula (I) for use in the method of treating basal cell carcinoma in a human will be an amount sufficient for the treatment of basal cell carcinoma in a human . A therapeutically effective amount of a compound of formula (I) for use in the method of treating actinic keratosis in a human will be an amount sufficient for the treatment of actinic keratosis in a human. A therapeutically effective amount of a compound of formula (I) for use in the method of treating genital papillomavirus infections in a human will be an amount sufficient for the treatment of genital papillomavirus infections in a human.
The amount of a compound of formula (I) that is required to achieve the desired therapeutic or biological effect will depend on a number of factors such as the use for which it is intended, the means of administration, the recipient and the type and severity of the condition or condition being treated, and it will ultimately be at the discretion of the attending physician or veterinarian. This dose may be administered as a single unit dose or in the form of several separate unit doses or as a continuous infusion. Similar dosages will be applicable to the treatment of other diseases, conditions and therapies in humans.
While it is possible for therapeutic use that a therapeutically effective amount of a compound of formula (I) can be administered in the form of the raw chemical, it is generally in the form of the active ingredient. of a pharmaceutical composition or formulation. Therefore, the invention further provides a pharmaceutical composition comprising a compound of formula (I). The pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers or diluents. The carrier (s) and / or diluent (s) must be acceptable in the sense of being compatible with the other components of the formulation and not deleterious to their recipient. In a particular embodiment, the compound is in crystalline form. Therefore, in another aspect of the invention, there is also provided a process for preparing a pharmaceutical formulation comprising mixing a compound of formula (I) with one or more pharmaceutically acceptable carriers and / or diluents.
The pharmaceutical formulations may be in unit dose form containing a predetermined amount of active ingredient per unit dose. Such a unit may contain a therapeutically effective dose of the compound of formula (I) or a fraction of a therapeutically effective dose such that a plurality of unit dosage forms may be administered at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage formulations are those containing a daily dose or a sub-dose, as mentioned above, or an appropriate fraction thereof, of an active ingredient. In addition, such pharmaceutical formulations can be prepared by any of the methods well known in the art of pharmacy.
The pharmaceutical formulations may be adapted for administration by any suitable route, for example, orally (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (including subcutaneous) administration. -cutaneous, intramuscular, intravenous or intradermal). Such formulations may be prepared by any method known in the art of pharmacy, for example by combining the active ingredient with the carrier (s) or excipient / excipients.
Pharmaceutical formulations adapted for oral administration may be in the form of discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible mousse or whipped cream; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with a non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. The powders are prepared by grinding the compound to a suitable fine size and mixing with a similarly ground pharmaceutical carrier such as an edible carbohydrate such as, for example, starch or mannitol. A flavoring, preserving, dispersing and coloring agent may also be present.
The capsules are made by preparing a powder mixture as described above, and filling shaped gelatin casings. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol may be added to the powder mixture prior to the filling operation. A disintegrating or solubilizing agent such as agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug when the capsule is ingested.
In addition, where desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may also be included in the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, gum tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated, for example, by preparing a mixture of powder, granulating or briquetting, adding a lubricant and a disintegrating agent and compressing into tablets. A powder mixture is prepared by mixing the appropriately ground compound with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, alginate, gelatin, or polyvinylpyrrolidone, a retardant in solution such as paraffin, a resorption accelerator such as a quaternary salt and / or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, gum arabic mucilage or solutions of cellulosic or polymeric materials and forcing through a sieve. As an alternative to granulation, the powder mixture can be passed through a tablet machine and the result is imperfectly formed briquettes broken into granules. The granules can be lubricated to prevent adhesion to the tabletting matrices by the addition of stearic acid, stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention may also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulation or briquetting steps. A clear or opaque protective coating consisting of a shellac waterproof coating, a sugar coating or polymeric material and a wax polish layer may be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
Oral liquids such as solutions, syrups and elixirs may be prepared in unit dosage form so that a given amount contains a predetermined amount of active ingredient. The syrups can be prepared by dissolving the compound in an appropriately flavored aqueous solution, while the elixirs are prepared by the use of a nontoxic alcoholic vehicle. The suspensions may be formulated by dispersing the compound in a nontoxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners can also be added. , and the like.
Where appropriate, unit dosage formulations for oral administration may be microencapsulated. The formulation may also be prepared to prolong or sustain the release such as, for example, by embedding or embedding the particulate material in polymers, wax or the like.
A compound of formula (I) may also be administered in the form of liposomal delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various lipids, such as cholesterol, stearylamine or phospholipids such as phosphatidylcholines.
A compound of formula (I) may also be administered in the form of nanoparticulate delivery systems, such as nanoparticles or microspheres of solid lipids.
A compound of formula (I) may also be administered in the form of an emulsion-based delivery system, such as an oil-in-water emulsion.
A compound of formula (I) may also be administered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compounds can be coupled to a class of biodegradable polymers useful in obtaining controlled release of a drug, for example, poly lactic acid, polycaprolactone epsilon, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
Pharmaceutical compositions adapted for transdermal administration may be in the form of separate patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient can be administered from the patch by iontophoresis as generally described in 1986 Pharmaceutical Research 3: 318.
Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For treatments of the eye or other external tissues, for example the mouth and the skin, the compositions are preferably applied in the form of a topical ointment or cream. When formulated in an ointment, the active ingredient can be used with a base of either paraffinic ointment or miscible with water. Alternatively, the active ingredient can be formulated in a cream with a cream oil base in water or water in oil.
Pharmaceutical compositions adapted for topical administration to the eye include ophthalmic drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, lozenges and mouthwashes.
Pharmaceutical compositions adapted for rectal administration may be in the form of suppositories or in the form of enemas.
Pharmaceutical compositions adapted for nasal administration in which the carrier is a solid include a coarse powder having a particle size of, for example, in the range of about 20 microns to about 500 microns which is administered in a preferred manner, that is, by rapid inhalation through the nasal passage from a container of powder kept close to the nose. Suitable formulations in which the carrier is a liquid, for administration in the form of nasal sprays or in the form of nasal drops, include aqueous or oily solutions of the active ingredient.
Pharmaceutical compositions adapted for administration by inhalation include dusts or mists of fine particles, which can be produced by means of various types of aerosols, nebulizers or pressurized insufflators with calibrated doses.
Pharmaceutical compositions adapted for vaginal administration may be in the form of ova, pads, creams, gels, pastes, foams or spraying formulations.
Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be in unit dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (freeze-dried) state requiring only the addition of the sterile liquid carrier, for example water for injection, immediately before use. Extemporaneous injectable solutions and suspensions may be prepared from sterile powders, granules and tablets.
It should be understood that in addition to the above-mentioned components, the compositions may comprise other agents conventional in the art with respect to the type of formulations in question, for example those suitable for oral administration may include flavoring agents.
In the methods of treatment and the uses described above, a compound of formula (I) may be used alone, in combination with one or more other compounds of formula (I) or in combination with other therapeutic agents. Thus, the present invention also encompasses pharmaceutical compositions further comprising one or more therapeutic agents. In one embodiment, the pharmaceutical compositions further comprise a vaccine. Examples of other therapeutic agents include, but are not limited to, TLR3 agonists, TLR4 agonists, or agonists of other innate immunity receptors, for example, agonists of the binding oligomerization domains. nucleotides (NOD), agonists of retinoic acid inducible genes (RIG) and interferon gene stimulator agonists (STINGs). A compound of formula (I) may be further employed with a metal salt such as an aluminum salt.
The methods and uses employing these combinations may include administering the compound of formula (I) and another therapeutic agent simultaneously into separate or combined pharmaceutical compositions. When combined in the same composition, it should be understood that the compounds should be stable and compatible with each other and with the other components of the composition and that they can be formulated for administration. When formulated separately, they may be provided in any convenient formulation, as is known for such compounds in the art.
When a compound of formula (I) is used in combination with another therapeutic agent, the dose of each compound may differ from that when the compound is used alone. The appropriate doses will be readily appreciated by those skilled in the art. The appropriate doses of the compound (s) of formula (I) and of the other therapeutic agent (s) and the relative times of administration will be selected to achieve the desired combined therapeutic effect. and are within the competencies and at the discretion of the attending clinician.
The compounds of the invention may be manufactured by any suitable method of organic chemistry.
In addition, it will be apparent to those skilled in the art that certain reaction steps can be performed more efficiently by installing protecting groups prior to the reaction, which are subsequently removed. The choice of protective groups and the general techniques for their installation and disposal are within the skills of the skilled person. It will be understood by those skilled in the art that certain ring systems represented in the generic ring structure will require the use of a protecting group to minimize the possibility of occurrence of undesired side reactions. The protecting group can be easily installed by methods contained in the literature and likewise can be removed once it is no longer needed.
According to one method, a compound of formula (I) can be prepared using the method illustrated in Scheme 1, below.
Diagram 1
wherein PG represents a suitable protecting group for the production of hydroxyl group, including but not limited to cyanoethyl, methyl, ethyl, benzyl and allyl groups; R represents
R 'represents
all other variables are as defined above for formula (I).
In general, the process for preparing a compound of formula (I) as illustrated in Scheme 1 comprises the following steps: a) the reaction of a compound of formula (III) with a compound of formula (V) to prepare a compound of formula (VI); b) reacting a compound of formula (VI) with a compound of formula (VII) to prepare a compound of formula (IX); and c) oxidizing a compound of formula (IX) and removing the hydroxy-protecting group to obtain a compound of formula (I); d) optionally converting the compound of formula (I) into a pharmaceutically acceptable salt thereof; e) the optional conversion of the compound of formula (I) into a compound of formula (I) different.
Figure 2
wherein R 1 is selected from H, C 1 -C 6 alkyl, C 1 -C 4 alkyl: amino, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl-C 1 -C 6 alkyl, C 3 cycloalkyl, C 1-6 alkyl; C 1-6 alkyl; cycloalkyl; C1-C4-alkoxy-C1-C4-alkoxy: C1-C4-alkyl, C1-C6-alkoxy-C1-C6-alkyl: amino and C1-C5 alkoxy C5-alkoxy; C 1 -C 5 alkyl, C 1 -C 5 alkylamino, C 1 -C 6 alkoxy, C 3 -C cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 5 alkylamino groups; amino, C 3 -C 6 cycloalkyl-C 1 -C 6 alkoxy, C 1 -C 4 alkoxy, -C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy-C 1 -C 5 -alkyl-amino or C 1 -C 6 -alkoxy-alkoxy C5-C5 being branched or unbranched and optionally substituted at their end by a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl or maleimido group; Z is selected from C2 to C6 alkyl and C2 to C6 alkenyl, C2 to C6 alkyl and C2 to C6 alkenyl unsubstituted or substituted at the end with a - (O-C2-C6alkyl) group; Ce) 1 to 6; X is 0 or S; R2 represents H or a linear or branched, optionally unsaturated C4 to C24 alkyl group or a linear or branched, optionally unsaturated C4 to C24 acyl group; R3 represents a linear or branched, optionally unsaturated C4-C24 alkyl group or a linear or branched, optionally unsaturated C4-C24 acyl group; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
In another aspect, the present invention provides another method for preparing a compound of formula (I). This process comprises the following steps: a) reacting a compound of formula (VII) with an H-phosphonate compound of formula (X) to form a compound of formula (I); b) optionally converting the compound of formula (I) into one of its pharmaceutically acceptable salts; c) optionally converting the compound of formula (I) into a compound of formula (I) different.
In one embodiment, a compound of formula (I) may be prepared according to scheme 2 wherein step a) uses methods described in Crossman, et al. J Chem Soc, Perkin Trans I, 1997, 2769, Westerduin, et al. Tet Lett, 1986, 15, 6271; or Nikolaev, et al., Carbohydr Res, 1990, 204, 65.
Based on these examples and the disclosure contained herein, those skilled in the art can easily convert compounds of formula (I) into other compounds of formula (I), or their salts.
The following examples are for illustrative purposes only and are not intended to limit the scope of the invention in any way, the present invention being defined by the claims.
In the examples, the following terms have the designated meaning: eq. = equivalents; ES TOF-MS = electrospray - time-of-flight mass spectroscopy; h = hour; H = hydrogen atom;
Hz = Hertz; mHz = megaHertz; LC-MS: liquid chromatography - mass spectroscopy; min = minute; ml = milliliter; M = molar; NMR = nuclear magnetic resonance; TA = ambient temperature; TEA = triethylamine; gg = microgram; μΐ = microliter; v = volume.
Example 1 - General Procedure for the Synthesis of the Compound of Formula (I)
The imidazoquinoline monophosphate glycerides (I) were prepared by a) reaction of a compound of formula (III) (prepared according to methods known in the art, Bioorg Med Chem, 2013, 21, 3066, ChemBioChem, 2012, 13, 2331, Chem Eur J, 2006, 6, 111), with a phosphoriamidite reagent of formula (II) (commercially available) according to methods known in the art; b) reaction of a compound of formula (IV) (not isolated) in situ with an imidazoquinoline of formula (VII) (Gerster et al., J. Med Chem, 2005, 48, 3481; Izumi et al., Bioorg Med Chem, 2003, 11, 2541) according to methods known in the art; c) oxidation of a compound of formula (VIII) and removal of the protecting group according to methods known in the art to produce a compound of formula (I).
A compound of formula (III) (2.0 eq.) And 2-cyanoethyl N, N, N ', AU-tetraisopropylphosphordiamidite of formula (II) (2.1 eq.) Was dissolved in chloride of anhydrous methylene (0.4 M) at RT. 1H-Tetrazole (2.1 eq) was added in four portions over 20 min and the reaction mixture was stirred at RT for 1 h. The reaction mixture was cooled to 0 ° C, imidazoquinoline of formula (VII) (1.0 eq) and imidazolium triflate (1.5 eq) were added, and the reaction mixture was stirred. allowed to warm up to RT. The reaction was usually completed after 1 hour at RT. The resulting phosphite of formula (VIII) was purified at this stage (after volume reduction by concentration in vacuo) or subsequently oxidized by addition of t-butyl hydroperoxide (1.5 eq.) To the reaction mixture and stirring at RT. for 30 minutes. At the end of the oxidation, the reaction mixture was concentrated in vacuo and purified by silica gel chromatography. The resulting protected phosphotriester was
dissolved in acetonitrile (0.06M). Triethylamine (acetonitrile / TEA, 1 / 0.35 v / v) was added and the reaction mixture was stirred at RT for 6 to 18 h. After the deprotection was complete, the reaction mixture was filtered through a Buchner filter and the isolated solid was rinsed with acetonitrile and dried under high vacuum, or purified by silica gel chromatography.
Example 2 - Synthesis of 4-amino-1- [2- (1,2-dipalmitoyl-5n-qlycero-3-ethyleneglycolphospho) ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinoline ._Désignée
Compound 2 in HEK293 cell results
4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-ethyleneglycol-phospho) ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinoline was prepared in a yield of 66% by following the general procedure described in Example 1. NMR: H (400 MHz, CDCl 3 ./CD ... OD) δ 8.19 (bs, 1H), 7.38 ( s, 1H), 7.13 (bs, 1H), 6.93 (bs, 1H), 5.24 (s, 1H), 4.83 (bs, 2H), 4.58 (bs, 2H), 4.39 (dd, 1H), 4.17 (m, 1H), 4.02 (dd, 2H), 3.68 (m, 4H), 2.98 (bs, 2H), 2.31 (dd; , 4H), 1.93 (bs, 2H), 1.58 (m, 2H), 1.25 (m, 48H), 1.03 (t, 3H), 0.86 (t, 6H); ES negative TOF-MS, calculated for [M-H] ~ 957.6445, found 957.6414.
Example 3 - Synthesis of 4-amino-1- [2- (1,2-dipalmitoyl-5-n-glycero-3-triethyleneglycol-phospho) -ethyl] -2-n-butyl-1H-imidazo [4,5-c] ] quinoline. Designated Compound 3 in the results of HEK293 cells
4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-triethyleneglycol-phospho) -ethyl] -2-n-butyl-1H-imidazo [4,5-c] guinoline was prepared in 62% yield by following the general procedure described in Example 1. NMR: H (400 MHz, CDCl3 / CD3OD) δ 8.23 (d, 1H), 7.42 (t, 1H), 7.20 (t, 1H), 6.97 (t, 1H), 5.23 (m, 1H), 4.74 (bd, 2H), 4.63 (bd, 2H), 4.34 (dd). , 1H), 4.15 (dd, 1H), 4.05 (m, 2H), 3.58-3.71 (m, 12H), 3.04 (bt, 2H), 2.31 (dd, 4H), 1.92 (m, 2H), 1.52-1.59 (m, 6H), 1.26 (m, 48H), 1.04 (t, 3H), 0.88 (t, 6H); ); ES negative TOF-MS, calculated for [M-H] - 1045.6970, found 1045.6855.
Example 4 - Synthesis of 4-amino-1- [2- (1,2-dipalitiitoyl-5-n-glycero-3-hexaethyleneglycol-phospho) -ethyl] -2-n-butyl-1H-imidazo [4,5-c] ] quinoline. Designated Compound 4 in the results of HEK293 cells
4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-hexaethyleneglycol-phospho) -ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinoline was prepared in a yield of 76% by following the general procedure described in Example 1. 1 H NMR (400 MHz, CDCl 3 / CDO) δ 8.18 (bs, 1H), 7.36 (t, 1H), 7.18 (bs, 1H), 6.97 (bs, 1H), 5.20 (m, 1H), 4.67 (bs, 2H), 4.33 (dd, 1H), 4.15 (dd; , 1H), 4.06 (m, 2H), 3.57-3.71 (m, 26H), 3.01 (bs, 2H), 2.31 (dd, 4H), 1.93 (m, 2H), 2H), 1.52-1.61 (m, 6H), 1.25 (m, 48H), 1.04 (t, 3H), 0.87 (t, 6H); ES negative TOF-MS, calculated for [M-H] - 1177.7756, found 1177.9063.
Example 5 - Synthesis of 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-nonaethyleneglycol-phospho) ethyl] -2-n-butyl-1H-imidazo [4,5-c] gu inoléine. Designated Compound 5 in HEK293 Cell Results
4-Amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-nonaethyleneglycol-phospho) ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinoline was prepared in a yield of 53% by following the general procedure described in Example 1. NMR Ή (400 MHz, CDCl3 / CD30D) δ 8.19 (bs, 1H), 7.40 (t, 1H), 7, 19 (bs, 1H), 6.96 (bs, 1H), 5.23 (m, 1H), 4.50-4, 80 (bm, 4H), 4.35 (dd, 1H), 4.16 (bs, 1H), (dd, 1H), 4.03 (bs, 2H), 3.58-3.71 (m, 33H), 3.03 (bs, 2H), 2.84 (m, 2H), 2.30 (bs, 2H), dd, 4H), 1.93 (m, 2H), 1.52-1.63 (m, 6H), 1.25 (m, 48H), 1.04 (t, 3H), 0.88 (t. , 6H); ES negative TOF-MS, calculated for [M-H] ~ 1309.8543, found 1310.0106.
Example 6 - Binding Test in HEK293 Cells
The determination of TLR agonist activity was performed using the binding assay in HEK293 cells. This test measures the selectivity of TLR7 and TLR8 and the potency of the compounds tested. The HEK2 93 cells expressing TLR7 or human TLR8 and the NFkB sensitive secreted embryonic alkaline phosphatase reporter gene (SEAP) were obtained from InvivoGen (San Diego, CA). These cells were maintained in culture medium, Dulbecco's Modified Eagle's Medium (DMEM) (Invitrogen, Grand Island, NY), 10% fetal bovine serum (FBS) (Sigma, St. Louis, Missouri), and selection antibiotics (Invitrogen, and Invivogen). HEK293 cells stably transfected with human TLR7 (hTLR7) or human TLR8 (hTLR8) were stimulated for 24 h with aqueous formulations of the compounds and the culture supernatants were assayed for activation of NFkB using the colorimetric detection kit of the SEAP QuantBlue (InvivoGen).
Compounds 2, 3, 4 and 5 are as described above. Compound 1 is 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-phospho) ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinoline. It is included although it is not a PEGylated derivative to show the increase of TLR7 / 8 activity and the induction of cytokines during the introduction of a PEGylated radical in compound 1. The results of Binding assay in HEK293 cells are shown in Figure 1 and summarized in Table 1.
Table 1
Example 7 - Test for Measuring Cytokine Induction Pegylated analogs were evaluated for cytokine induction in human peripheral blood mononuclear cells (hCMSP).
Preparation of hCMSP
Primary human PBMCs were isolated from fresh blood from healthy donors by Ficoll gradient separation and plated at 0.5 x 10 6 cells / well in 96 well tissue culture plates (RPMI-1640 plus 10% FBS ). HCMSP were maintained with RPMI-1640 culture medium (Invitrogen, Grand Island, NY), antibiotics (Invitrogen) and 10% FBS (Sigma).
Incubation and tests for interferon-alpha and TNF-alpha
HCMSP was stimulated for 24 h with aqueous formulations of compounds 1 to 5. Culture supernatants were assayed for induction of TNF-α using multiplex kits (FluoroKine multiplex kits from R & D Systems, Minneapolis). , MN) and for the induction of IFN-α using the VeriKine ELISA kit for human IFN-α (Pestka Biomedical Laboratories, Inc., Piscataway, NJ). The induction of TNF-α from hCMSP is shown in Figure 2. The induction of IFN-α from hCMSP is shown in Figure 3.

权利要求:
Claims (24)
[1]
1. Compound, or a pharmaceutically acceptable salt thereof, of formula (I):

wherein R 1 is selected from H, C 1 -C 5 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, C 1 -C 6 cycloalkyl, C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, C1-C8 aminoalkyl, C3-C8cycloalkyl-C1-C8alkoxy, C3-C8alkoxy: -C3-C6alkyl, C1-C8alkoxy-C3-C6aminoalkyl and C3-C6alkoxy C1-C6 alkoxy; C 3 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 3 -C 8 alkoxy, C 3 -C 4 cycloalkyl, C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, C 1 -C 6 aminoalkyl, cycloalkyl groups; in C; to C: -C3 to C6 alkoxy, C1 to C6 alkoxy-C3 to C8 alkyl, C3 to C6 alkoxy: C1 to C6 aminoalkyl or C1 to C8 alkoxy-C3 to C5 alkoxy, being branched or unbranched and optionally substituted at their end by a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl or maleimido group; Z is selected from C2 to C6 alkyl and C2 to C6 alkenyl, C2 to C6 alkyl and C2 to C6 alkenyl unsubstituted or substituted at the end with a - (O-C2-C6alkyl) group; C6) i to 6_; X is 0 or S; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R2 represents H or a linear or branched, optionally unsaturated C4 to C24 alkyl group or a linear or branched, optionally unsaturated C4 to C24 acyl group; R3 represents a linear or branched, optionally unsaturated C4 to C24 alkyl group, or a linear or branched, optionally unsaturated C4 to C24 acyl group.
[2]
The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is selected from H, C 1-6 alkyl, C 1-6 aminoalkyl and C 1-6 alkoxy, C 1-6 alkyl groups. at C6, C1-C6 aminoalkyl and C1-C6 alkoxy being branched or unbranched and optionally substituted at their end by hydroxyl, amino, thio, hydrazino, hydrazino, azido, acetylenyl, carboxyl, or maleimido.
[3]
The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is n-butyl.
[4]
The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein Z represents a group (CH 2) 2.
[5]
The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein X is 0.
[6]
The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein n is selected from 3 or 6.
[7]
A compound or a pharmaceutically acceptable salt thereof as claimed in any one of the preceding claims, wherein R2 is a linear or branched, optionally unsaturated, C4-C24 acyl group.
[8]
The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein R3 represents a linear or branched, optionally unsaturated C4-C24 acyl group.
[9]
9. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of the preceding claims, wherein R2 is unbranched C16 acyl (palmitoyl, COC15H31).
[10]
The compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein R3 is unbranched C16 acyl (palmitoyl, COC15H31).
[11]
The compound of claim 1 wherein R 1 = n-butyl; Z represents a group (CH2) 2 / n is selected from 3, 6 and 9; R2 is unbranched C16 acyl (palmitoyl, COC15H31) and R3 is unbranched C16 acyl (palmitoyl, COC15H31).
[12]
The compound of claim 1 and selected from the group consisting of 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-ethyleneglycolphospho) ethyl] -2-n-butyl-1H. imidazo [4,5-c] quinoline; 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-triethyleneglycol-phospho) ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinoline; 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-hexaethyleneglycol-phospho) ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinoline; 4-amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-nonaethyleneglycol-phospho) ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinoline; and their pharmaceutically acceptable salts.
[13]
13. Compound according to claim 1 and formula
4-Amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-triethyleneglycolphospho) ethyl] -2-n -butyl-lif-imidazo [4,5-c] quinoline or one of its pharmaceutically acceptable salts.
[14]
14. Compound according to claim 1 and formula
4-Amino-1- [2- (1,2-dipalmitoyl-sn-glycero-3-hexaethyleneglycol-phospho) ethyl] -2-n-butyl-1H-imidazo [4,5-c] quinoline or one of its pharmaceutically acceptable salts.
[15]
15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable carrier or diluent.
[16]
16. Process for the preparation of a compound according to any one of claims 1 to 14 comprising the following steps: a) the reaction of a compound of formula (III)

wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R represents H or a linear or branched, optionally unsaturated C4 to C24 alkyl group, or a linear or branched, optionally unsaturated C4 to C24 acyl group; R3 represents a linear or branched, optionally unsaturated C4-C24 alkyl group or a linear or branched, optionally unsaturated, C4-C24 acyl group with a compound of formula (V)

wherein PG represents a protecting group for hydroxyl group protection, including but not limited to, cyanoethyl, methyl, ethyl, benzyl and allyl to prepare a compound of formula (VI)

in which R represents

b) the reaction of a compound of formula (VI) with a compound of formula (VII)

(VII) wherein R 1 is selected from H, C 1 to C 6 alkyl, C 1 to C 6 aminoalkyl, C 1 to C 6 alkoxy, C 3 to C 6 cycloalkyl; C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 6 -C 6 aminoalkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-C 1 -C 6 alkyl ·, C1-C6 alkoxy, -NC6-aminoalkyl and C1-C4 alkoxy: -C1-C6 alkoxy; C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, C 1 -C 6 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 5 cycloalkyl-C 1 -C 5 alkylalkyl, C 3 -C 5 cycloalkyl C 1 -C 5 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkylalkoxy or C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy Branched or unbranched and optionally substituted at their end by a hydroxyl, amino, thio, hydrazino, hydrazido, azido, acetylenyl, carboxyl or maleimido group; Z is selected from C to C 6 alkyl and C 2 to C 6 alkenyl, C 2 to C 6 alkyl and C 2 to C 6 alkenyl are unsubstituted or end-substituted with - (O-C 1 to C 6 alkyl) This to 5- / to prepare a compound of formula (IX)

(IX) wherein R represents

R 'represents

wherein PG represents a protecting group for hydroxyl group protection, including but not limited to cyanoethyl, methyl, ethyl, benzyl and allyl groups; c) oxidation of a compound of formula (IX) and removal of the hydroxy-protecting group to obtain a compound of formula (I)


[17]
17. A compound according to any one of claims 1 to 14 for use as a vaccine adjuvant.
[18]
18. A compound according to any one of claims 1 to 14 for use in therapy.
[19]
19. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14 for use in the treatment of hepatitis C virus infection in a subject in need thereof.
[20]
The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14 for use in the treatment of basal cell carcinoma in a subject in need thereof.
[21]
A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14 for use in the treatment of actinic keratosis in a subject in need thereof.
[22]
22. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14 for use in the treatment of genital papillomavirus infections in a subject in need thereof.
[23]
23. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14 for use as an adjuvant.
[24]
A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14 for use in the treatment of a condition selected from a hepatitis C virus infection, a basal cell carcinoma, actinic keratosis and genital papillomavirus infections.

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BR112018011929A2|2018-11-27|

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EP3390417A1|2018-10-24|

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法律状态:
2018-02-08| FG| Patent granted|Effective date: 20171116 |

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2021-09-03| MM| Lapsed because of non-payment of the annual fee|Effective date: 20201231 |

优先权:

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申请号 | 申请日 | 专利标题

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US201562266880P| true| 2015-12-14|2015-12-14|

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US62266880|2015-12-14|

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