Patent Application
20150166533
The invention concerns novel 1,3-dihydro-2H-benzimidazol-2-one derivatives substituted with benzimidazoles having antiviral activity, in particular, having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). The invention further concerns the preparation of such novel compounds, compositions comprising these compounds, and the compounds for use in the treatment of respiratory syncytial virus infection.
Human RSV or Respiratory Syncytial Virus is a large RNA virus, member of the family of Paramyxoviridae, subfamily pneumoviridae together with bovine RSV virus. Human RSV is responsible for a spectrum of respiratory tract diseases in people of all ages throughout the world. It is the major cause of lower respiratory tract illness during infancy and childhood. Over half of all infants encounter RSV in their first year of life, and almost all within their first two years. The infection in young children can cause lung damage that persists for years and may contribute to chronic lung disease in later life (chronic wheezing, asthma). Older children and adults often suffer from a (bad) common cold upon RSV infection. In old age, susceptibility again increases, and RSV has been implicated in a number of outbreaks of pneumonia in the aged resulting in significant mortality.
Infection with a virus from a given subgroup does not protect against a subsequent infection with an RSV isolate from the same subgroup in the following winter season. Re-infection with RSV is thus common, despite the existence of only two subtypes, A and B.
Today only three drugs have been approved for use against RSV infection. A first one is ribavirin, a nucleoside analogue that provides an aerosol treatment for serious RSV infection in hospitalized children. The aerosol route of administration, the toxicity (risk of teratogenicity), the cost and the highly variable efficacy limit its use. The other two drugs, RespiGam® (RSV-IG) and Synagis® (palivizumab), polyclonal and monoclonal antibody immunostimulants, are intended to be used in a preventive way. Both are very expensive, and require parenteral administration.
Other attempts to develop a safe and effective RSV vaccine have all met with failure thus far. Inactivated vaccines failed to protect against disease, and in fact in some cases enhanced disease during subsequent infection. Life attenuated vaccines have been tried with limited success. Clearly there is a need for an efficacious non-toxic and easy to administer drug against RSV replication. It would be particularly preferred to provide drugs against RSV replication that could be administered perorally.
A reference on benzimidazole antiviral agents is WO 01/95910. Herein compounds are presented to have antiviral activity, yet with EC50 values over a wide range of from 0.001 μm to as high as 50 μM (which does not normally represent the desired biological activity). Another reference, relating to substituted 2-methyl-benzimidazole RSV antiviral agents, in the same range of activities is WO 03/053344. Another related background reference on compounds in the same range of activities, is WO 02/26228 regarding benzimidazolone antiviral agents. A reference on structure-activity relations, in respect of RSV inhibition, of 5-substituted benzimidazole compounds is Kuo-Long Yu et al., Bioorganic and Medicinal Chemistry Letters 17 (2007) 895-901, and X. A. Wang et al., Bioorganic and Medicinal Chemistry Letters 17 (2007) 4592-4598.
WO-2012/080446, WO-2012/080447, WO-2012/080449, WO-2012/080450 and WO-2012/080481 all filed on 16 Dec. 2011 and published on 21 Jun. 2012 disclose benzimidazole derivatives having antiviral activity against respiratory syncytial virus.
It is desired to provide new drugs that have antiviral activity. Particularly, it would be desired to provide new drugs that have RSV replication inhibitory activity. Further, it would be desired to retrieve compound structures that allow obtaining antiviral biological activities of the order of magnitude in the stronger regions of the prior art (i.e. at the bottom of the above-mentioned range of up to 50 μM), and preferably at a level of about the most active, more preferably of even stronger activity, than the compounds disclosed in the art. A further desire is to find compounds having oral antiviral activity.
In order to better address one or more of the foregoing desires, the invention, in one aspect, presents antiviral compounds represented by formula (I),
and stereoisomeric forms thereof, wherein
Het is a heterocycle having formula (a)
In another aspect, the invention relates to the foregoing compounds for use in the treatment of RSV infections in warm-blooded animals, preferably humans. In yet another aspect, the invention presents a method of treatment of viral RSV infections in a subject in need thereof, comprising administering to said subject an effective amount of a compound as defined above. In still another aspect, the invention resides in the use of a compound as defined above, for the manufacture of a medicament in the treatment of RSV infections.
In a further aspect, the invention relates to a pharmaceutical composition comprising a compound as defined above, and a pharmaceutically acceptable excipient.
In a still further aspect, the invention provides methods for preparing the compounds defined above.
The invention, in a broad sense, is based on the judicious recognition that the compounds of Formula (I) generally possess an interesting RSV inhibitory activity. Moreover, these compounds enable access to anti-RSV activities at the higher regions (lower end of the EC50 values) of the range available in the aforementioned references. Particularly, on the basis of these compounds, molecular structures can be uncovered that even outperform the reference compounds in terms of biological activities.
The present invention will further be described with respect to particular embodiments and with reference to certain examples but the invention is not limited thereto but only by the claims. Where the term “comprising” is used in the present description and claims, it does not exclude other elements or steps. Where an indefinite or definite article is used when referring to a singular noun e.g. “a” or “an”, “the”, this includes a plural of that noun unless something else is specifically stated.
Whenever the term “substituted” is used in the present invention, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one or more hydrogens, in particular from 1 to 4 hydrogens, preferably from 1 to 3 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using “substituted” are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
As used herein “C1-C4alkyl” as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl and the like.
As used herein “C1-C6alkyl” as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl, pentyl, hexyl, 2-methylbutyl and the like.
“C1-C10alkyl” as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 10 carbon atoms such as the groups defined for C1-C6alkyl and heptyl, octyl, nonyl, 2-methylhexyl, 2-methylheptyl, decyl, 2-methylnonyl, and the like.
The term “C2-C10alkenyl” used herein as a group or part of a group is meant to comprise straight or branched chain unsaturated hydrocarbon radicals having at least one double bond, and preferably having one double bond, and from 2 to 10 carbon atoms such as ethenyl, propenyl, buten-1-yl, buten-2-yl, penten-1-yl, penten-2-yl, hexen-1-yl, hexen-2-yl, hexen-3-yl, 2-methylbuten-1-yl, hepten-1-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, 2-methylhexen-1-yl, octen-1-yl, octen-2-yl, octen-3-yl, octen-4-yl, 2-methylhepten-1-yl, nonen-1-yl, nonen-2-yl, nonen-3-yl, nonen-4-yl, nonen-5-yl, 2-methylocten-1-yl, decen-1-yl, decen-2-yl, decen-3-yl, decen-4-yl, decen-5-yl, 2-methylnonen-1-yl, and the like.
Whenever a “C2-C10alkenyl” group is linked to a heteroatom it preferably is linked via a saturated carbon atom.
“C1-C4alkyloxy” or “C1-C4alkoxy”, as a group or part of a group defines an O—C1-C4alkyl radical, wherein C1-C4alkyl has, independently, the meaning given above.
“C1-C6alkyloxy” or “C1-C6alkoxy”, as a group or part of a group defines an O—C1-C6alkyl radical, wherein C1-C6alkyl has, independently, the meaning given above.
The term “C3-C7cycloalkyl” alone or in combination, refers to a cyclic saturated hydrocarbon radical having from 3 to 7 carbon atoms. Non-limiting examples of suitable C3-C7cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term “—(CR8aR9a)n—” used herein defines n repetitions of the CR8aR9a subgroup, wherein each of these subgroups is independently defined.
The term “halo” or “halogen” as a group or part of a group is generic for fluoro, chloro, bromo, iodo unless otherwise is indicated or is clear from the context.
A term of the form NRCOOR is identical to N(R)COOR.
Examples of (but not limited to) a 4 to 6 membered aliphatic ring optionally containing one or more heteroatoms selected from the group consisting of N, S and O, as used in the definitions of R8a, R9a and R10a, are cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, azetidinyl, thiolanyl, piperazinyl, pyrrolidinyl.
Examples of (but not limited to) a 5 to 6 membered aromatic ring; optionally containing one or more heteroatoms selected from the group consisting of N, S and O, as used in the definition of R10a, are furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl.
An example of (but not limited to) Het1 is.
An example of (but not limited to) Het2 is thiazolyl, pyridinyl, quinolinyl.
It should be noted that the radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable.
Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated. For instance pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.
When any variable occurs more than one time in any constituent, each definition is independent.
Hereinbefore and hereinafter, the term “compound of formula (I)” or “compounds of formula (I)” is meant to include the stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof.
The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.
The term “stereochemically isomeric forms” as used hereinbefore defines all the possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) may possess.
It will be appreciated that some of the compounds of formula (I) may contain one or more centers of chirality and exist as stereochemically isomeric forms.
The invention includes all stereoisomers of the compound of Formula (I), either as a pure stereoisomer or as a mixture of two or more stereoisomers.
Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture. Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Therefore, the invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.
The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved compounds whose absolute configuration is not known can be designated by (+) or (−) depending on the direction in which they rotate plane polarized light.
When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other isomers. Thus, when a compound of formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a compound of formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
Some of the compounds according to formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyl-tartaric acid, ditoluoyltartaric acid and camphosulfonic acid. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The diastereomeric racemates of formula (I) can be obtained separately by conventional methods. Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography.
For some of the compounds of formula (I) and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof; and intermediates used in the preparation thereof, the absolute stereochemical configuration was not experimentally determined. A person skilled in the art is able to determine the absolute configuration of such compounds using art-known methods such as, for example, X-ray diffraction.
The present invention is also intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
For therapeutic use, salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butane-dioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.
The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
The term solvate comprises the hydrates and solvent addition forms which the compounds of Formula (I) are able to form, as well as the salts thereof. Examples of such forms are e.g. hydrates, alcoholates and the like.
It will be appreciated that the compounds of the invention, with reference to the aforementioned left- and right-hand parts of formula I, present a wide variety of modification.
Without detracting from the overall scope of the invention, certain embodiments are discussed in more detail below.
A compound according to the invention therefore inherently comprises a compound with one or more isotopes of one or more element, and mixtures thereof, including a radioactive compound, also called radiolabelled compound, wherein one or more non-radioactive atoms has been replaced by one of its radioactive isotopes. By the term “radiolabelled compound” is meant any compound according to Formula (I) which contains at least one radioactive atom. For example, a compound can be labelled with positron or with gamma emitting radioactive isotopes. For radioligand-binding techniques, the 3H-atom or the 125I-atom is the atom of choice to be replaced. For imaging, the most commonly used positron emitting (PET) radioactive isotopes are 11C, 18F, 15O and 13N, all of which are accelerator produced and have half-lives of 20, 100, 2 and 10 minutes (min) respectively. Since the half-lives of these radioactive isotopes are so short, it is only feasible to use them at institutions which have an accelerator on site for their production, thus limiting their use. The most widely used of these are 18F, 99mTc, 201Tl and 123I. The handling of these radioactive isotopes, their production, isolation and incorporation in a molecule are known to the skilled person.
In particular, the radioactive atom is selected from the group of hydrogen, carbon, nitrogen, sulfur, oxygen and halogen. In particular, the radioactive isotope is selected from the group of 3H, 11C, 18F, 122I, 123I, 125I, 131I, 75Br, 76Br, 77Br and 82Br.
The terms described above and others used in the specification are well understood to those in the art.
Preferred features of the compounds of this invention are now set forth.
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
Het2 represents a monocyclic 5 to 6 membered aromatic heterocycle containing one or more heteroatoms each independently selected from the group consisting of O, S and N; or a bicyclic 8 to 12 membered aromatic heterocycle containing one or more heteroatoms each independently selected from the group consisting of O, S and N; said Het2 optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C1-C4alkyloxy, OH, CN, CF2H, CF3, SO2C1-C10 alkyl, and C1-C4alkyl;
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
In an embodiment, the present invention concerns novel compounds of Formula (I), and stereoisomeric forms thereof, wherein
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein
R10a is selected from the group consisting of H, OH, CF3, CHF2, F, Cl, SO2CH3, SO2C3-C7cycloalkyl, NR8aSO2R8a, SO2NR8aR9a, NR8aSO2C3-C7cycloalkyl, CN, NR8aR9a, COOH, COOR8a, CONR8aR9a, OCOC1-C6alkyl, CONR8aSO2R9a, CONR8aSO2NR8aR9a, a 4 to 6 membered aliphatic ring and a 5 to 6 membered aromatic ring; wherein the aliphatic or aromatic ring optionally contains one or more heteroatoms selected from the group consisting of N, S and O;
in particular wherein R10a is selected from the group consisting of H, C1-C6alkyl, OH, CF3, CHF2, F, Cl, SO2CH3, SO2C3-C7cycloalkyl, CN; a 4 to 6 membered aliphatic ring and a 5 to 6 membered aromatic ring; wherein the aliphatic or aromatic ring optionally contains one or more heteroatoms selected from the group consisting of N, S and O;
more in particular wherein R10a is selected from the group consisting of H, C1-C6alkyl, OH, CF3, CHF2, F, Cl, SO2CH3, SO2C3-C7cycloalkyl and CN.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R4 is selected from the group consisting of aryl, Het1, Het2 and C3-C7cycloalkyl substituted with one or more substituents selected from the group consisting of halo and C1-C4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein
R4 is selected from the group consisting of tert-butyl, aryl, Het1, Het2 and C3-C7cycloalkyl substituted with C1-C4alkyl;
Z is C or N; R5 is present where Z is C, whereby R5 is selected from the group consisting of hydrogen; R5 is absent where Z is N.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R4 is selected from the group consisting of tert-butyl, CH(CH3)(CF3), aryl and Het2.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein
R4 is selected from the group consisting of tert-butyl, aryl, Het1, Het2 and cyclopropyl substituted with methyl;
aryl represents phenyl substituted with one substituent selected from the group consisting of halo and C1-C4alkyloxy;
Het1 represents azetidinyl substituted with C1-C4alkyloxycarbonyl;
Het2 represents quinolinyl, pyridinyl or thiazolyl;
said Het2 optionally being substituted with one halo substituent;
Z is C or N; R5 is present where Z is C, whereby R5 is hydrogen; R5 is absent where Z is N.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R4 is selected from the group consisting of tert-butyl, CH(CH3)(CF3), Het1 and C3-C7cycloalkyl substituted with one or more substituents selected from the group consisting of halo and C1-C4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R4 is aryl or Het2; in particular R4 is aryl.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R4 is selected from the group consisting of Het1 and C3-C7cycloalkyl substituted with one or more substituents selected from the group consisting of halo and C1-C4alkyl; in particular R4 is Het1.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R4 is Het2.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R4 is C3-C7cycloalkyl substituted with one or more substituents selected from the group consisting of halo and C1-C4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein
Het1 represents a monocyclic 4 to 6 membered non-aromatic heterocycle containing one or two heteroatoms each independently selected from the group consisting of O, S and N; said Het1 optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C1-C4alkyloxy, SO2R8a, C1-C4alkylcarbonyl, C1-C4alkyloxycarbonyl, CO(aryl), COHet2, pyridinyl, CF3, SO2N(C1-C4alkyl)2, SO2NH(C1-C4alkyl), NH(C═O)(C1-4alkyl), (C═O)NH(C1-4alkyl), (C═S)NH(C1-4alkyl), C1-C4alkyl and C1-C4alkyl substituted with one hydroxyl.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R4 is aryl or Het2.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R4 is aryl.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R4 is Het2.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R4 is cyclopropyl.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein each R8a and R9a are independently chosen from the group consisting of H, C1-C10 alkyl and C3-C7cycloalkyl; in particular wherein each R8a and R9a are H.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein
aryl represents phenyl or naphthalenyl; said aryl optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C1-C4alkyloxy, OH, CN, CF2H, CF3, CONR8aR9a, COOR8a, CON(R8a)SO2R9a, CON(R8a)SO2N(R8aR9a), NR8aR9a, NR8aCOOR9a, OCOR8a, NR8aSO2R9a, SO2NR8aR9a, SO2R8a, OCONR8aR9a, N(R8a)CON(R8aR9a) and C1-C4alkyl;
Het1 represents a monocyclic 4 to 6 membered non-aromatic heterocycle containing one or two heteroatoms each independently selected from the group consisting of O, S and N; or a bicyclic 7 to 11 non-aromatic heterocycle containing one or two heteroatoms each independently selected from the group consisting of O, S and N; said Het1 optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C1-C4alkyloxy, SO2R8a, C1-C4alkylcarbonyl, C1-C4alkyloxycarbonyl, pyridinyl, CF3, SO2N(C1-C4alkyl)2, SO2NH(C1-C4alkyl), NH(C═O)(C1-4alkyl), (C═O)NH(C1-4alkyl), (C═S)NH(C1-4alkyl), C1-C4alkyl and C1-C4alkyl substituted with one hydroxy;
Het2 represents a monocyclic 5 to 6 membered aromatic heterocycle containing one or more heteroatoms each independently selected from the group consisting of O, S and N; or a bicyclic 8 to 12 membered aromatic heterocycle containing one or more heteroatoms each independently selected from the group consisting of O, S and N; said Het2 optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C1-C4alkyloxy, OH, CN, CF2H, CF3, CONR8aR9a, COOR8a, CON(R8a)SO2R9a, CON(R8a)SO2N(R8aR9a), NR8aR9a, NR8aCOOR9a, OCOR8a, NR8aSO2R9a, SO2NR8aR9a, SO2R8a, OCONR8aR9a, N(R8a)CON(R8aR9a) and C1-C4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein
Het1 represents a 4 to 6 membered non-aromatic heterocycle containing one N atom, optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C1-C4alkyloxy, SO2R8a, C1-C4alkylcarbonyl, CO(aryl), COHet2, C1-C4alkyloxycarbonyl, pyridinyl, CF3, SO2N(C1-C4alkyl)2, SO2NH(C1-C4alkyl), (C═O)NH(C1-4alkyl), (C═S)NH(C1-4alkyl), C1-C4alkyl and C1-C4alkyl substituted with one hydroxy; or
Het1 represents a 4 to 6 membered non-aromatic heterocycle containing one 0 atom, substituted with one or more substituents each independently selected from the group consisting of halo, C1-C4alkyloxy, CF3, NH(C═O)(C1-4alkyl), (C═O)NH(C1-4alkyl) and C1-C4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein
Het1 represents a 4 to 6 membered non-aromatic heterocycle containing one N atom, optionally being substituted with one or more substituents each independently selected from the group consisting of halo, C1-C4alkyloxy, SO2R8a, C1-C4alkylcarbonyl, CO(aryl), COHet2, C1-C4alkyloxycarbonyl, pyridinyl, CF3, SO2N(C1-C4alkyl)2, SO2NH(C1-C4alkyl), (C═O)NH(C1-4alkyl), (C═S)NH(C1-4alkyl), C1-C4alkyl and C1-C4alkyl substituted with one hydroxy; or
Het1 represents a 4 to 6 membered non-aromatic heterocycle containing one O atom, substituted with one or more substituents each independently selected from the group consisting of halo, C1-C4alkyloxy, CF3, NH(C═O)(C1-4alkyl), (C═O)NH(C1-4alkyl) and C1-C4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein Z is N.
In another embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein Z is CH.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein Z is C or N; R5 is present where Z is C, whereby R5 is selected from the group consisting of CF3 and halogen; R5 is absent where Z is N.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R4 is cyclopropyl wherein the carbon atom attached to the remainder of the molecule is substituted with methyl.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R4 is selected from the group consisting of tert-butyl, Het1, aryl, Het2 and C3-C7cycloalkyl substituted with one or more substituents selected from the group consisting of halo and C1-C4alkyl.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein, when present, R5 is H.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein, when present, R5 is halogen, in particular fluoro.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein n comprises a carbon chain of 2-6 atoms, in particular 2-4 atoms, more in particular 3-5 atoms.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R1a is Br.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R1a is Cl.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein both R8a and R9a are H; and wherein n is 2-4, preferably n is 3 or 4.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein n is 2-4.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein n is 3-4.
In an embodiment, the present invention relates to those compounds of formula (I), or any subgroup thereof as mentioned in any of the other embodiments, wherein R10a is selected from the group consisting of H, OH, F, CF3, CN and SO2CH3; in particular SO2CH3.
Preferred compounds are compounds P1-P9, stereoisomeric forms thereof,
and pharmaceutically acceptable addition salts, free bases and solvates thereof.
The compounds of formula I may be prepared by the methods described below, using synthetic methods known in the art of organic chemistry, or modifications and derivatisations that are familiar to those skilled in the art. The starting materials used herein are commercially available or may be prepared by routine methods known in the art such as those methods disclosed in standard reference books. Preferred methods include, but are not limited to, those described below.
During any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which are hereby incorporated by reference.
Compounds of formula I, or their pharmaceutically acceptable salts, can be prepared according to the reaction schemes discussed herein below. Unless otherwise indicated, the substituents in the schemes are defined as above. Isolation and purification of the products is accomplished by standard procedures, which are known to a chemist of ordinary skill.
Scheme 1 illustrates a method for the preparation of compounds of formula I, where R1a, R2a, R4, R5 and Z are defined as above.
The compounds of formula (I) can be synthesized for instance using one of the methods shown in Scheme 1. In general, a fragment A or B is coupled with a fragment C resulting in derivatives of formula (I).
For method 1, an example of suitable “coupling conditions” to react a fragment A with a fragment C to form formula (I) type compounds is a Mitsunobu reaction. A suitable solvent for this type of reaction is THF (tetrahydrofuran).
Alternatively (but not limited to), a fragment B type intermediate wherein Z═Cl, Br, OTos (tosylate), OMs (mesylate) can be reacted with a fragment C type intermediate through a base mediated coupling reaction. (Method 2) Possible bases to effect this reaction (but not limited to) are K2CO3, Cs2CO3, triethylamine, sodium hydride. A suitable solvent (but not limited to) for this type of base mediated coupling is DMF (dimethylformamide).
Fragment A type intermediates can be generally prepared as depicted in scheme 2.
In general, fragment B type intermediates can be prepared from fragment A type intermediates through reaction with reagents like (but not limited to) SOCl2, PBr3, p-TsCl (4-toluenesulfonyl chloride), MsCl (methane sulfonyl chloride).
Fragment C type intermediates of formula III can be prepared as depicted in Scheme 4.
The synthesis of 2-oxo-imidazopyridine derivatives and 2-oxo-imidazobenzene derivatives is shown in scheme 4. Intermediates of formula III can be synthesized using the procedure depicted in scheme 4. Displacement of W, which is a halide, preferably fluorine, or an alkoxy group, preferably methoxy, of the nitro pyridine or of the nitro aryl of formula XVII with an amine, in a suitable solvent such as THF or DMF, in the presence of an organic base such as triethyl amine or diisopropyl ethyl amine, gives an intermediate of formula XVIII. Reduction of the nitro group to the amine XIX can be done in a catalytic way using hydrogen in the presence of a catalyst such as palladium or platinum, in a suitable solvent such as methanol, or in a stoichiometric way using iron in the presence of ammonium chloride or tin chloride in the presence of concentrated hydrochloric acid. The cyclisation of the resulting diamine XIX using CDI (1,1′-carbonyldiimidazole), phosgene or triphosgene, in a solvent such as acetonitril or THF, provides N3-substituted 2-oxo-imidazopyridine or N3-substituted 2-oxo-imidazobenzene of formula III. Alternatively, the intermediate of formula III may be prepared starting from commercially available dianilines XX which can be cyclized by ring closure with CDI, phosgene or triphosgene yields intermediates of type XXI. Introduction of a R4 substituent (other than H) on an intermediate of formula XXI can be accomplished by a Mitsunobu reaction with commercially available alcohols, or by displacement of the LG in the intermediates of formula XXII, where LG is a leaving group such as halide, preferably bromine, or sulfonate, in the presence of a base such as sodium hydride, potassium carbonate or cesium carbonate in a suitable solvent such as DMF or THF. This will finally yield intermediates of formula III.
All starting materials can be obtained commercially or can be prepared by those skilled in the art.
Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g., counter-current distribution, liquid chromatography and the like.
The compounds of formula (I) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) which are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomeric ally pure starting materials.
In a further aspect, the present invention concerns a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as specified herein, or a compound of any of the embodiments of compounds of formula (I) as specified herein, and a pharmaceutically acceptable carrier. A therapeutically effective amount in this context is an amount sufficient to prophylaxictically act against, to stabilize or to reduce viral infection, and in particular RSV viral infection, in infected subjects or subjects being at risk of being infected. In still a further aspect, this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of formula (I), as specified herein, or of a compound of any of the embodiments of compounds of formula (I) as specified herein.
Therefore, the compounds of the present invention or any embodiment thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
The compounds of the present invention may also be administered via oral inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder, a solution being preferred. Any system developed for the delivery of solutions, suspensions or dry powders via oral inhalation or insufflation are suitable for the administration of the present compounds.
Thus, the present invention also provides a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Preferably, the compounds of the present invention are administered via inhalation of a solution in nebulized or aerosolized doses.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
The compounds of formula (I) show antiviral properties. Viral infections treatable using the compounds and methods of the present invention include those infections brought on by ortho- and paramyxoviruses and in particular by human and bovine respiratory syncytial virus (RSV). A number of the compounds of this invention moreover are active against mutated strains of RSV. Additionally, many of the compounds of this invention show a favorable pharmacokinetic profile and have attractive properties in terms of bioavailabilty, including an acceptable half-life, AUC and peak values and lacking unfavourable phenomena such as insufficient quick onset and tissue retention.
The in vitro antiviral activity against RSV of the present compounds was tested in a test as described in the experimental part of the description, and may also be demonstrated in a virus yield reduction assay. The in vivo antiviral activity against RSV of the present compounds may be demonstrated in a test model using cotton rats as described in Wyde et al. (Antiviral Research (1998), 38, 31-42).
Due to their antiviral properties, particularly their anti-RSV properties, the compounds of formula (I) or any embodiment thereof, and stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof, are useful in the treatment of individuals experiencing a viral infection, particularly a RSV infection, and for the prophylaxis of these infections. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses, in particular the respiratory syncytial virus.
The compounds of the present invention or any embodiment thereof may therefore be used as medicines. Said use as a medicine or method of treatment comprises the systemic administration to viral infected subjects or to subjects susceptible to viral infections of an amount effective to combat the conditions associated with the viral infection, in particular the RSV infection.
The present invention also relates to the use of the present compounds or any embodiment thereof in the manufacture of a medicament for the treatment or the prevention of viral infections, particularly RSV infection.
The present invention furthermore relates to a method of treating a warm-blooded animal infected by a virus, or being at risk of infection by a virus, in particular by RSV, said method comprising the administration of an anti-virally effective amount of a compound of formula (I), as specified herein, or of a compound of any of the embodiments of compounds of formula (I), as specified herein.
In general it is contemplated that an antivirally effective daily amount would be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.
Also, the combination of another antiviral agent and a compound of formula (I) can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of formula (I), and (b) another antiviral compound, as a combined preparation for simultaneous, separate or sequential use in antiviral treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. For instance, the compounds of the present invention may be combined with interferon-beta or tumor necrosis factor-alpha in order to treat or prevent RSV infections.
The invention will hereinafter be illustrated with reference to the following, non-limiting examples.
Hereinafter, the term ‘eq.’ means equivalent, ‘THF’ means tetrahydrofuran, ‘Psi’ means pound-force per square inch, ‘DMF’ means N,N-dimethylformamide, ‘DMSO’ means dimethyl sulfoxide, ‘DIEA’ means diisopropylethylamine, ‘DIAD’ means diisopropyl azodicarboxylate, ‘HOAc’ or ‘AcOH’ means acetic acid, ‘RP’ means reversed phase, ‘EtOAc’ means ethyl acetate, ‘Pd(dppf)Cl2CH2Cl2’ means [1,1′-bis(diphenylphosphino)ferrocene]palladium chloride complex with dichloromethane, ‘TPP’ means triphenylphosphine, ‘m-cPBA’ means 3-chlorobenzene-carboperoxoic acid, ‘Cu(OAc)2’ means copper(II) acetate, ‘EtOH’ means ethanol, ‘MeOH’ means methanol, ‘MeCN’ means methyl cyanide, ‘CDI’ means 1,1′-carbonyldiimidazole, ‘KOEt’ means potassium ethoxide, and ‘HPLC’ means High Performance Liquid Chromatography.
LCMS was done using either of the following methods:
The LC measurement was performed using an Acquity UPLC (Waters) (‘UPLC’ means Ultra Performance Liquid Chromatography) system comprising a binary pump, a sample organizer, a column heater (set at 55° C.), a diode-array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.18 seconds using a dwell time of 0.02 seconds. The capillary needle voltage was 3.5 kV and the source temperature was maintained at 140° C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
The HPLC measurement was performed using an Alliance HT 2790 (Waters) system comprising a quaternary pump with degasser, an autosampler, a column oven (set at 40° C., unless otherwise indicated), a diode-array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 1 second using a dwell time of 0.1 second. The capillary needle voltage was 3 kV and the source temperature was maintained at 140° C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
In addition to the general method A: Reversed phase UPLC was carried out on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 μm, 2.1×50 mm; Waters Acquity) with a flow rate of 0.8 ml/min. Two mobile phases (10 mM ammonium acetate in H2O/acetonitrile 95/5; mobile phase B: acetonitrile) were used to run a gradient condition from 95% A and 5% B to 5% A and 95% B in 1.3 minutes and hold for 0.3 minutes. An injection volume of 0.5 μl was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
In addition to the general method B: Reversed phase HPLC was carried out on an Xterra MS C18 column (3.5 μm, 4.6×100 mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mM ammoniumacetate+5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100% A to 1% A, 49% B and 50% C in 6.5 minutes, to 1% A and 99% B in 1 minute and hold these conditions for 1 minute and reequilibrate with 100% A for 1.5 minutes. An injection volume of 10 μl was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
For a number of compounds, 1H NMR spectra were recorded on a Bruker DPX-400 spectrometer operating at 400 MHz or on a Bruker DPX-360 operating at 360 MHz using CHLOROFORM-d (deuterated chloroform, CDCl3) or DMSO-d6 (deuterated DMSO, dimethyl-d6 sulfoxide) as solvent. Chemical shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane (TMS), which was used as internal standard.
For a number of compounds, melting points (m.p.) were determined with a DSC823e (Mettler-Toledo). Melting points were measured with a temperature gradient of 30° C./minute. Maximum temperature was 400° C. Values are peak values.
All the intermediates needed for the synthesis of targeted compounds of formula I are synthesized as described in the following schemes 5 to 11.
To a mixture of 2-fluoro-2-nitrobenzene, 5-a (17.278 g, 122.45 mmol, 1 eq.), triethylamine (24.782 g, 244.91 mmol, 2.0 eq.) in ethanol (170 mL) at 0° C. tert-butyl 3-aminoazetidine-1-carboxylate (23.2 g, 134.708 mmol, 1.1 eq.) was added dropwise. The resulting mixture was refluxed overnight. The mixture was cooled to room temperature and filtrated. The cake was washed with cooled ethanol and dried under vacuum. 22 g of intermediate 5-b was obtained (61.5% yield).
Intermediate 5-b (21.0 g, 71.595 mmol, 1 eq.) in methanol (70 mL), THF (70 mL) and ethyl acetate (70 mL) was hydrogenated (50 Psi) at 50° C. with Pt/C (2.1 g) as a catalyst for 12 hours. After uptake of H2 (3 eq.), the catalyst was filtered off and the filtrate was evaporated to give intermediate 5-c (18 g, Yield 95.5%).
Carbonyldiimidazole (15.517 g, 95.696 mmol, 1.05 eq.) was added to a solution of intermediate 5-c (24.0 g, 91.139 mmol, 1.0 eq.) in CH3CN (240 mL) at 0° C. The reaction mixture was allowed to warm to 25° C. and stirred for 1 h. The solid was collected by filtration and was washed with CH3CN (70 mL) to afford the title compound 5-d as a white powder (19.35 g, 74%).
Intermediate 6-d was prepared by an analogous reaction protocol as intermediate 5-d using 4-chloro-3-nitropyridine 6-a and methylcyclopropylamine as starting material.
Intermediate 7-c was prepared by an analogous reaction protocol as intermediate 5-d using 4-chloro-3-nitropyridine 6-a and tert-butylamine as starting material.
Intermediate 8-c was prepared by an analogous reaction protocol as intermediate 5-d using 4-chloro-3-nitropyridine 6-a and quinolin-6-amine as starting material.
Intermediate 9-c was prepared by an analogous reaction protocol as intermediate 5-d using 4-chloro-3-nitropyridine 6-a and thiazol-2-amine as starting material.
Intermediate 10-c was prepared by an analogous reaction protocol as intermediate 5-d using 4-chloro-3-nitropyridine 6-a and 4-methoxyaniline as starting material.
Intermediate 11-a (7.6 g, 35 mmol), 3-(methylsulfonyl)propan-1-amine hydrochloride (6 g, 35 mmol) and diisopropylethylamine (DIEA) (13.5 g, 105 mmol) were dissolved in ethanol (70 mL) and refluxed for 14 h. The mixture was cooled to 20° C. The precipitate was filtered and washed with ethanol. 11 g (94%) of intermediate 11-b was obtained as an orange powder. Intermediate 11-b (10 g, 29.7 mmol) in methanol (200 mL), EtOAc (200 mL) and THF (200 mL) was hydrogenated with Raney Ni (10 g) as a catalyst at 20° C. (1 atm) for 3 h. After uptake of H2 (3 eq), the catalyst was filtered off and the filtrate was evaporated. 10 g (90%) of intermediate 11-c was obtained as a black solid. Intermediate 11-c (10 g, 29.7 mmol) and methyl dimethoxy-acetate (9.2 g, 68.31 mmol) in 24 wt % KOEt in ethanol (13.5 g, 38.5 mmol) were stirred and refluxed overnight. The mixture was evaporated under vacuum. Water (200 mL) was added. Acetic acid was added to neutralize the mixture. The mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated NaHCO3, brine and dried over Na2SO4. The solvent was removed under vacuum to yield 12.3 g (90%) of intermediate 11-d as dark oil. Intermediate 11-d (12.3 g, 29.3 mmol) in THF (100 mL) was stirred for 0.5 h at 20° C. to dissolve. Conc. HCl (21 mL) and H2O (42 mL) were added. The mixture was refluxed for 6 h and then cooled to −10° C. CH3OH (50 mL) were added, followed by careful addition of NaBH4 (24 g, 629 mmol). The mixture was stirred for 0.5 h at 10° C. and concentrated under vacuum. Water (200 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under vacuum. The resulting solid was washed with ethyl acetate (2×5 mL) and dried under vacuum. 6.8 g (60%) of intermediate 11-e was obtained as an off-white solid.
1H NMR (400 MHz, DMSO-d6) δ ppm 2.20 (dq, J=7.8, 7.5 Hz, 2H), 2.98 (s, 3H), 3.16-3.24 (m, 2H), 4.42 (t, J=7.4 Hz, 2H), 4.73 (d, J=6.0 Hz, 2H), 5.73 (t, J=5.8 Hz, 1H), 7.42 (dd, J=8.7, 1.9 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.79-7.83 (m, 1H)
To a solution of alcohol 11-e (363 mg, 1.414 mmole) in 30 mL of dichloromethane was added dropwise a solution of thionyl chloride (336 mg, 2 eq) in 10 mL of dichloromethane. The reaction mixture was stirred for one hour at 45° C. It was then concentrated under vacuum to give the desired intermediate 11-f (440 mg, 99%) as an HCl salt, which was used as such in the next step.
A detailed description of the synthesis of tert-butyl-3-(3-((5-chloro-1-(3-(methyl-sulfonyl)propyl)-1H-bezon[d]imidazol-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazo[d]imidazol-1-yl)azetidine-1-carboxylate (P1), a representative example of the invention is given in Scheme 12.
In a 100 mL dry flask, intermediate 11-f (500 mg, 1.4 mmol) and intermediate 5-d (491 mg, 1.7 mmol) were dissolved in DMF (50 mL). The resulting mixture was stirred at room temperature then cesium carbonate (1 g, 3 mmol) was added. The reaction mixture was stirred at room temperature overnight. The resulting mixture was poured in iced-water then dichloromethane was added and the water layer was extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated. The residue was triturated with dichloromethane and ether then the resulting white solid P1 was dried in the oven (642 mg, 80%).
m/z=574 (M+H)+ (LCMS Method 1)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 9H), 2.10 (t, J=7.5 Hz, 2H), 2.99 (s, 3H), 3.17-3.25 (m, 2H), 4.24-4.33 (m, 2H), 4.37 (br. s., 2H), 4.49 (t, J=7.5 Hz, 2H), 5.27 (m, J=8.4, 5.6, 2.8 Hz, 1H), 5.40 (s, 2H), 7.11 (quind, J=7.7, 7.7, 7.7, 7.7, 1.3 Hz, 2H), 7.26-7.36 (m, 2H), 7.64-7.72 (m, 2H)
A detailed description of the synthesis of 1-tert-butyl-3-((5-chloro-1-(3-(methyl-sulfonyl)propyl)-1H-benzo[d]imidazol-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (P2), a representative example of the invention is given in Scheme 13.
In a 100 mL dry flask, 11-e (400 mg, 1.3 mmol), triphenylphosphine (TPP) (415 mg, 1.6 mmol, 1.2 eq) and intermediate 7-c (259 mg, 1.3 mmol, 1 eq) were dissolved in tetrahydrofuran (THF) (60 mL). The solution was placed under N2 atmosphere and diisopropylazodicarboxylate (DIAD) (0.395 mL, 2 mmol, 1.5 eq) was added via syringe. The reaction mixture was stirred at room temperature under nitrogen overnight. The mixture was evaporated to dryness and purified by preparative HPLC on an RP Vydac Denali C18 column (10 μm, 250 g, 5 cm) using a 0.25% NH4HCO3 in H2O/CH3CN solution as the eluent. After evaporation and drying in vacuo, 429 mg (67%) of a white solid P2 was obtained.
m/z=476 (M+H)+ (LCMS Method 1)
MP=197° C.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.73 (s, 9H) 2.09-2.22 (m, 2H) 2.99 (s, 3H) 3.20-3.26 (m, 2H) 4.50 (t, J=7.48 Hz, 2H) 5.42 (s, 2H) 7.31 (dd, J=8.58, 2.20 Hz, 1H) 7.52 (dd, J=5.61, 0.55 Hz, 1H) 7.64-7.71 (m, 2H) 8.15 (d, J=5.72 Hz, 1H) 8.45 (d, J=0.44 Hz, 1H)
Compound P3 was prepared by an analogous reaction protocol as compound P2 using intermediate 11-e and 1-(1-methylcyclopropyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 6-d as starting material.
m/z=474 (M+H)+ (LCMS Method 1)
1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.02 (m, 2H), 1.04-1.10 (m, 2H), 1.42 (s, 3H), 2.09-2.22 (m, 2H), 3.00 (s, 3H), 3.18-3.26 (m, 2H), 4.50 (t, J=7.3 Hz, 2H), 5.42 (s, 2H), 7.27-7.38 (m, 2H), 7.64-7.73 (m, 2H), 8.27 (d, J=5.3 Hz, 1H), 8.44 (s, 1H)
Intermediate 14-a was prepared by an analogous reaction protocol as intermediate 11-f using 4-chloro-3-nitropyridine 6-a and 1-bromo-4-fluorobutane as starting material.
To a solution of 1-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one hydrochloride 14-b (720 mg, 2.626 mmoles) in 10 mL of extra dry DMF was added sodium hydride (210 mg, 5.253 mmoles, 60% dispersion in oil) portionwise at room temperature. After 20 minutes, a solution of 5-chloro-2-(chloromethyl)-1-(4-fluorobutyl)-1H-benzo[d]imidazole hydrochloride 14-a (440 mg, 1.313 mmoles) in 5 mL of DMF was added dropwise. Stirring was continued overnight at room temperature. The reaction mixture was then diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The resulting slightly orange oil was triturated in DCM and the precipitate was filtered off. It was further washed with DCM, then isopropylether and dried under high vacuum, to provide the title product 3-((5-chloro-1-(4-fluorobutyl)-1H-benzo[d]imidazol-2-yl)methyl)-1-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 14-c as a white solid in 40% yield;
m/z=452 (M+H)+.
Intermediate 14-c (500 mg, 1.1 mmol) was refluxed in a solution of isopropanol hydrochloric acid 6N (100 mL) for 3 days. The reaction mixture was then cooled down to room temperature and neutralized with an aqueous solution of sodiumhydrogenocarbonate. The precipitate was filtered off and washed with water, dried in the oven to give intermediate 14-d (330 mg, 80%) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.52-1.82 (m, 4H) 4.32-4.43 (m, 3H) 4.51 (s, 1H) 5.39 (s, 2H) 7.09 (d, J=5.27 Hz, 1H) 7.29 (dd, J=8.78, 2.01 Hz, 1H) 7.65 (d, J=8.53 Hz, 1H) 7.66 (d, J=2.01 Hz, 1H) 8.17 (d, J=5.27 Hz, 1H) 8.33 (s, 1H)
In a 50 mL dry flask, intermediate 14-d (100 mg, 0.25 mmol), 4-fluorophenylboronic acid (71 mg, 0.50 mmol, 2 eq.), copper(II)acetate (93 mg, 0.50 mmol, 2 eq.) and triethylamine (106 μl, 0.76 mmol, 3 eq.) were dissolved in dimethylformamide (20 mL). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. The water (20 ml) was added to the reaction mixture and the solid was filtered off. The solid was further purified by preparative HPLC on (RP Vydac Denali C18-10 μm, 200 g, 5 cm), using a 0.25% NH4HCO3 in water-CH3CN solution as eluent which gave compound P4 30 mg (25%) as a white solid.
MP=180° C.
LCMS m/z=468 (M+H)+ (LCMS Method 1)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.89 (m, 4H) 4.36-4.45 (m, 3H) 4.51 (t, J=5.77 Hz, 1H) 5.53 (s, 2H) 7.11 (dd, J=5.40, 0.63 Hz, 1H) 7.30 (dd, J=8.66, 2.13 Hz, 1H) 7.41-7.49 (m, 2H) 7.61-7.66 (m, 2H) 7.68 (d, J=8.53 Hz, 1H) 7.70 (d, J=2.01 Hz, 1H) 8.26 (d, J=5.27 Hz, 1H) 8.56 (s, 1H)
Intermediate 15-a was prepared by an analogous reaction protocol as intermediate 11-e using 4-chloro-3-nitropyridine 6-a and 1-bromo-4-fluorobutane as starting material. Compound P5 was prepared by an analogous reaction protocol as compound P2 using intermediate 15-a and 1-(4-methoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-c as starting material.
MP=167° C.
LCMS m/z=480 (M+H)+ (LCMS Method 2)
1H NMR (360 MHz, DMSO-d6) δ ppm 1.65-1.89 (m, 4H), 3.84 (s, 3H), 4.32-4.47 (m, 3H), 4.52 (t, J=5.7 Hz, 1H), 5.52 (s, 2H), 7.05 (d, J=5.5 Hz, 1H), 7.10-7.19 (m, 2H), 7.30 (dd, J=8.6, 2.0 Hz, 1H), 7.44-7.51 (m, 2H), 7.63-7.75 (m, 2H), 8.24 (d, J=5.5 Hz, 1H), 8.53 (s, 1H)
Compound P6 was prepared by an analogous reaction protocol as compound P4 using intermediate 14-d and 2-Fluoro-5-pyridineboronic acid as starting material.
MP=208° C.
LCMS m/z=469 (M+H)+ (LCMS Method 2)
1H NMR (360 MHz, DMSO-d6) δ ppm 1.62-1.89 (m, 4H), 4.34-4.48 (m, 3H), 4.53 (t, J=5.7 Hz, 1H), 5.55 (s, 2H), 7.23 (d, J=5.5 Hz, 1H), 7.31 (dd, J=8.6, 2.0 Hz, 1H), 7.48 (dd, J=8.8, 2.9 Hz, 1H), 7.65-7.74 (m, 2H), 8.23-8.33 (m, 2H), 8.53 (d, J=2.2 Hz, 1H), 8.60 (s, 1H)
Compound P7 was prepared by an analogous reaction protocol as compound P2 using intermediate 11-e and 1-(4-methoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-c as starting material.
MP=250° C.
LCMS m/z=526 (M+H)+ (LCMS Method 2)
1H NMR (360 MHz, DMSO-d6) δ ppm 2.11-2.27 (m, 2H), 2.98 (s, 3H), 3.24 (t, J=1.0 Hz, 2H), 3.84 (s, 3H), 4.53 (t, J=7.3 Hz, 2H), 5.55 (s, 2H), 7.05 (d, J=5.5 Hz, 1H), 7.14 (m, J=9.1 Hz, 2H), 7.33 (dd, J=8.6, 2.0 Hz, 1H), 7.49 (m, J=9.1 Hz, 2H), 7.65-7.78 (m, 2H), 8.25 (d, J=5.5 Hz, 1H), 8.56 (s, 1H)
Compound P8 was prepared by an analogous reaction protocol as compound P5 using intermediate 15-a and 1-(thiazol-6-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 9-c as starting material.
MP=206° C.
LCMS m/z=457 (M+H)+ (LCMS Method 2)
1H NMR (360 MHz, DMSO-d6) δ ppm 1.63-1.91 (m, 4H), 4.35-4.49 (m, 3H), 4.53 (t, J=5.5 Hz, 1H), 5.62 (s, 2H), 7.30 (dd, J=8.6, 2.0 Hz, 1H), 7.58-7.75 (m, 3H), 7.81 (d, J=3.7 Hz, 1H), 8.33 (d, J=0.7 Hz, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.67 (s, 1H)
Compound P9 was prepared by an analogous reaction protocol as compound P5 using intermediate 15-a and 1-(quinolin-6-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 8-c as starting material.
MP=231° C.
LCMS m/z=501 (M+H)+ (LCMS Method 2)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.78 (m, 2H), 1.79-1.90 (m, 2H), 4.46 (dt, J=47.3, 6.0 Hz, 2H), 4.45 (t, J=7.5 Hz, 2H), 5.58 (s, 2H), 7.30 (dd, J=5.7, 0.8 Hz, 1H), 7.31 (dd, J=8.5, 2.0 Hz, 1H), 7.65 (dd, J=8.3, 4.2 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.98 (dd, J=8.9, 2.4 Hz, 1H), 8.23 (d, J=8.9 Hz, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.30 (d, J=5.2 Hz, 1H), 8.48-8.53 (m, 1H), 8.60 (d, J=0.8 Hz, 1H), 9.01 (dd, J=4.2, 1.8 Hz, 1H).
To a solution of intermediate 14-d (400 mg, 1.07 mmol) in DMF (50 mL) was added triphenylphosphine (336 mg, 1.3 mmol, 1.2 eq.), tetrahydrofuran-3-ol (0.1 mL, 1.07 mmol, 1 eq.) and diisopropyl azodicarboxylate (0.3 mL, 1.6 mmol, 1.5 eq.) at room temperature. The solution was stirred for 16 hours. The mixture was concentrated in vacuum and the crude was purified on RP SunFire Prep column (C18 OBD-10 μm, 30×150 mm), using a 0.25% NH4HCO3 solution in water-MeOH solution to give (31 mg, 7%) of the title compound P10.
m/z=444 (M+H)+
1H NMR (400 MHz, DMSO-d6) δ ppm 1.59-1.79 (m, 4H) 2.06-2.18 (m, 1H) 2.32-2.44 (m, 1H) 3.72 (q, J=8.03 Hz, 1H) 3.85-3.93 (m, 1H) 3.94-4.02 (m, 1H) 4.20 (td, J=8.47, 4.39 Hz, 1H) 4.34-4.43 (m, 3H) 4.47-4.53 (m, 1H) 5.08-5.23 (m, 1H) 5.44 (s, 2H) 7.29 (dd, J=8.53, 2.01 Hz, 1H) 7.35 (d, J=5.27 Hz, 1H) 7.65 (d, J=8.53 Hz, 1H) 7.68 (d, J=1.76 Hz, 1H) 8.24 (d, J=5.27 Hz, 1H) 8.45 (s, 1H)
Black 96-well clear-bottom microtiter plates (Corning, Amsterdam, The Netherlands) were filled in duplicate using a customized robot system with serial 4-fold dilutions of compound in a final volume of 50 μl culture medium [RPMI medium without phenol red, 10% FBS, 0.04% gentamycin (50 mg/ml) and 0.5% DMSO]. Then, 100 μl of a HeLa cell suspension (5×104 cells/ml) in culture medium was added to each well followed by the addition of 50 μl rgRSV224 (MOI=0.02) virus in culture medium using a multidrop dispenser (Thermo Scientific, Erembodegem, Belgium). rgRSV224 virus is an engineered virus that includes an additional GFP gene (Hallak et al, 2000) and was in-licensed from the NIH (Bethesda, Md., USA). Medium, virus- and mock-infected controls were included in each test. Cells were incubated at 37° C. in a 5% CO2 atmosphere. Three days post-virus exposure, viral replication was quantified by measuring GFP expression in the cells by a MSM laser microscope (Tibotec, Beerse, Belgium).
The EC50 was defined as the 50% inhibitory concentration for GFP expression. In parallel, compounds were incubated for three days in a set of white 96-well microtitier plates (Corning) and the cytotoxicity of compounds in HeLa cells was determined by measuring the ATP content of the cells using the ATPlite kit (PerkinElmer, Zaventem, Belgium) according to the manufacturer's instructions. The CC50 was defined as the 50% concentration for cytotoxicity.
Compounds were tested for RSV inhibitory activity. The results are depicted in the Table below (n.d. means not determined):
“Active ingredient” (a.i.) as used throughout these examples relates to a compound of Formula (I), including any stereoisomeric form thereof, or a pharmaceutically acceptable addition salt or a solvate thereof; in particular to any one of the exemplified compounds.
Typical examples of recipes for the formulation of the invention are as follows:
An aqueous suspension is prepared for oral administration so that each milliliter contains 1 to 5 mg of active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.
A parenteral composition is prepared by stirring 1.5% (weight/volume) of active ingredient in 0.9% NaCl solution or in 10% by volume propylene glycol in water.
In this Example, active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.
Reasonable variations are not to be regarded as a departure from the scope of the invention. It will be obvious that the thus described invention may be varied in many ways by those skilled in the art.
| Number | Date | Country | Kind |
|---|---|---|---|
| 12172272.2 | Jun 2012 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2013/062324 | 6/14/2013 | WO | 00 |
