Patent Application
20220144822
The present invention relates to a process for synthesizing N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide, an imidazoquinoline derivative useful as toll-like receptor agonist, in particular as an agonist of TLR7, which promotes induction of certain cytokines. Furthermore, the present invention also provides intermediates useful in the synthesis of N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide.
The present disclosure relates generally to the field of organic synthetic methodology for the preparation of Toll-like receptor 7 agonists and their synthetic intermediates. Toll-like receptors (TLR) currently comprising a gene family of 13 receptors with different specificities, 11 of them found in humans, are part of the cellular pathogen pattern recognition system, which has evolved for defense against a variety of infections (bacteria, virus, fungi). Activation of TLRs leads to cytokine responses, e.g. with release of interferons and activation of specified immune cells. The functional expression of selected TLRs in tissues is highly different. Part of the receptors are located at the cell surface such as TLR4 (stimulated by E. coli lipopolysaccharide LPS), e.g. on epithelial cells, or TLR3, 7, 8 and 9 located at endosomal membranes in specified immune cells. The latter are all activated by nucleic acids, but recognize various types of them. For instance, TLR9 is activated by single-stranded DNA containing CpG subsequences, TLR7 and 8 are activated by single-stranded RNA, and TLR3 is activated by double-stranded RNA.
Some small-molecule (SMOL) TLR7 or TLR8 agonists have been identified. Those agonists can be grouped into purine-like molecules, such as 7-thia-8-oxoguanosine (TOG, isatoribine) or the imidazoquinoline-based compounds like imiquimod. Imiquimod is so far the only approved definitive TLR7 agonist, marketed as 5% cream)(Aldara®). It generates approx. 80% 5-year clearance of superficial basal cell carcinomas, which is the most frequent cancer worldwide. Imiquimod activates TLR7. The functional expression of TLR7 appears to be restricted to specific immune cells, i.e. in humans plasmacytoid dendritic cells, B-cells and probably eosinophils are known to be activated by TLR7 agonists.
For several years, strong efforts have been ongoing worldwide trying to exploit the strong immune activation induced by TLR7, 8 or 9 agonists for the treatment of cancer. Cancer immunotherapy, however, experienced a long history of failures. In recent years, though, the knowledge on cancer immune surveillance and the function of subsets of immune cells thereby has improved drastically. TLR7, TLR8 or TLR9 agonists are in clinical development for cancer mono- or combination therapies, or as vaccine adjuvants.
The TLR agonist approach for cancer immunotherapy is different from earlier efforts using, e.g. cytokines, interferons or monovalent vaccinations. TLR agonist mediated immune activation is pleiotropic via specified immune cells (primarily dendritic cells and B-cells, subsequently other cells), which generates an innate and adaptive immune response. Moreover, not only one interferon is induced, but rather the many different isoforms altogether, and not only type I (alpha, beta), but also (indirectly) type II (gamma) interferon. At least for local application, Aldara® has delivered a remarkable proof-of-concept. This demonstrates that antigens are released by tumors, and that immune therapy in principle can work for cancer indications, even also in monotherapy. For a systemic administration route, though, the clinical proof-of-concept is pending for TLR7 agonists. For advanced cancers and systemic application (particularly s.c. or i.v. administration route) it appears to be clear that such TLR agonists might provide stronger, i.e. synergistic, efficacy in combination with other therapeutic interventions.
In case of earlier stages of cancer, the situation might be different. Tumor metastasis is a severe aspect of tumor development in patients, largely because tumors are detected too late when metastasis already has occurred. Established tumor therapies mostly include cytotoxic drugs with rather narrow therapeutic windows. Hence, for the treatment in earlier tumor stages, when the suppression of metastasis spread might still be possible, the need is high for new therapies with good tolerability and safety.
The activation of the immune system and, in particular, the activation of toll-like receptor (TLR) signaling offers new promising approaches. TLR9 agonistic CpG-ODN like H2006 or H1826, and TLR7 agonists like the guanosine derivative isatoribine or an Imiquimod derivative were tested in a murine Renca lung metastasis model. All tested molecules virtually completely suppressed the emergence of lung metastases with good tolerability. This provides a convincing rational for clinical development of such molecules for suppression of cancer metastasis and points to the possibility of systemic application of such drugs. However, the SMOL type TLR7 agonists have the advantage of established and cost effective synthesis if compared to the nucleic acid type TLR9 agonists, and are well suited for topical as well as for systemic application.
U.S. Pat. No. 6,573,273 describes imidazoquinoline and tetrahydroimidazoquinoline compounds that contain urea, thiourea, acylurea, sulfonylurea or carbamate functionality. The compounds are said to be useful as immunomodulators.
U.S. Pat. No. 6,677,349 describes imidazoquinoline and tetrahydroimidazoquinoline compounds that contain sulfonamide functionality at the 1-position. The compounds are said to be useful as immunomodulators.
US-A-2003/0144283 and WO-A-00/76505 describe imidazoquinoline and tetrahydroimidazoquinoline compounds that contain amide functionality at the 1-position. The compounds are said to be useful as immunomodulators.
WO-A-2005/051324 describes imidazoquinoline, pyridine and naphthyridine ring systems substituted in 1-position with oxime or a special N-oxide functionality. The compounds are said to be useful as immunomodulators.
WO-A-2009/118296 describes imidazoquinoline compounds. The compounds are described as toll-like receptor agonist/TLR7 activators.
N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide and a process for its preparation are disclosed in PCT/EP2018/073470, which is hereby incorporated by reference.
The present disclosure provides a novel process for the preparation of N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide or a solvate or salt thereof that employs novel intermediates.
A first aspect of the present invention provides a process for synthesizing N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide, or a solvate or salt thereof, as further described in the following. Said compound is an agonist or activator for TLR7 and may serve as cytokine inducing substance. Said compound has the following chemical formula (I):
The process of the first aspect comprises the following steps:
a) providing a compound of formula (3):
or a solvate or salt thereof, wherein each of R1 and R2 is independently selected from the group consisting of —H and an amino protecting group, and at least one of R1 and R2 is an amino protecting group;
b) reacting the compound of formula (3) or a solvate or salt thereof with one or more reagents to remove the amino protecting group(s) at position R1 and R2 to give a compound of formula (4):
or a solvate or salt thereof;
c) reacting the compound of formula (4) or a solvate or salt thereof with one or more reagents for introducing (i) a tetrahydropyranyl group and (ii) an acetyl group to give a compound of formula (5):
or a s solvate or salt thereof; and
d) subjecting the compound of formula (5) or a solvate or salt thereof to an oxidative amination reaction to give the compound of formula (I) or a solvate or salt thereof. Preferred embodiments of the process of the first aspect are specified below, in the claims, and in any one of
In a second aspect, the present invention provides a compound selected from the group consisting of:
and a solvate or salt thereof. These compounds are intermediates useful in the process of the first aspect.
In a third aspect, the present invention provides a use of a compound of the second aspect for synthesizing a compound of formula (I).
Although the present invention is further described in more detail below, it is to be understood that this invention is not limited to the particular methodologies, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.
In the following, the elements of the present invention will be described in more detail. These elements are listed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and/or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise. For example, if in a preferred embodiment of the process of the present invention a solvent exchange is performed after step d) and in another preferred embodiment of the process of the present invention a crystallization step is performed after step d), then in a further preferred embodiment of the process of the present invention, a solvent exchange is performed after step d) and a crystallization step is performed after step d).
Preferably, the terms used herein are defined as described in “A multilingual glossary of biotechnological terms: (IUPAC Recommendations)”, H. G. W. Leuenberger, B. Nagel, and H. Kölbl, Eds., Helvetica Chimica Acta, CH-4010 Basel, Switzerland, (1995).
The practice of the present invention will employ, unless otherwise indicated, conventional chemistry methods which are explained in the literature in the field (cf., e.g., Organikum, Deutscher Verlag der Wissenschaften, Berlin 1990; Streitwieser/Heathcook, “Organische Chemie”, VCH, 1990; Beyer/Walter, “Lehrbuch der Organischen Chemie”, S. Hirzel Verlag Stuttgart, 1988; Carey/Sundberg, “Organische Chemie”, VCH, 1995; March, “Advanced Organic Chemistry”, John Wiley & Sons, 1985; Römpp Chemie Lexikon, Falbe/Regitz (Hrsg.), Georg Thieme Verlag Stuttgart, New York, 1989).
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated member, integer or step or group of members, integers or steps but not the exclusion of any other member, integer or step or group of members, integers or steps. The term “consisting essentially of” means excluding other members, integers or steps of any essential significance. The term “comprising” encompasses the term “consisting essentially of” which, in turn, encompasses the term “consisting of”. Thus, at each occurrence in the present application, the term “comprising” may be replaced with the term “consisting essentially of” or “consisting of”. Likewise, at each occurrence in the present application, the term “consisting essentially of” may be replaced with the term “consisting of”.
The terms “a”, “an” and “the” and similar references used in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g., “such as”), provided herein is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
Where used herein, “and/or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, “X and/or Y” is to be taken as specific disclosure of each of (i) X, (ii) Y, and (iii) X and Y, just as if each is set out individually herein.
In the context of the present invention, the terms “about” and “approximately” are used interchangeably and denote an interval of accuracy that the person of ordinary skill will understand to still ensure the technical effect of the feature in question. The term typically indicates deviation from the indicated numerical value by ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, and for example ±0.01%. As will be appreciated by the person of ordinary skill, the specific such deviation for a numerical value for a given technical effect will depend on the nature of the technical effect. For example, a natural or biological technical effect may generally have a larger such deviation than one for a man-made or engineering technical effect.
Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
The use of any and all examples, or exemplary language (e.g., “such as”), provided herein is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
The term “alkyl” refers to a monoradical of a saturated straight or branched hydrocarbon. Preferably, the alkyl group comprises from 1 to 12 (such as 1 to 10) carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 1 to 8 carbon atoms, such as 1 to 6 or 1 to 4 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, iso-propyl (also called 2-propyl or 1-methylethyl), butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, 1,2-dimethyl-propyl, iso-amyl, n-hexyl, iso-hexyl, sec-hexyl, n-heptyl, iso-heptyl, n-octyl, 2-ethyl-hexyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, and the like. A “substituted alkyl” means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1st level substituent, a 2nd level substituent, or a 3rd level substituent as specified herein, such as halogen, —OH, —NH2, —NHCH3, —N(CH3)2, —CN, —OCH3, —OCF3, or optionally substituted aryl. Examples of a substituted alkyl include trifluoromethyl, 2-hydroxyethyl, 2-aminoethyl, 2-(dimethylamino)ethyl, arylalkyl (also called “aralkyl”, e.g., benzyl), or heteroarylalkyl (also called “heteroaralkyl”).
The term “alkenyl” refers to a monoradical of an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Generally, the maximal number of carbon-carbon double bonds in the alkenyl group can be equal to the integer which is calculated by dividing the number of carbon atoms in the alkenyl group by 2 and, if the number of carbon atoms in the alkenyl group is uneven, rounding the result of the division down to the next integer. For example, for an alkenyl group having 9 carbon atoms, the maximum number of carbon-carbon double bonds is 4. Preferably, the alkenyl group has 1 to 6 (such as 1 to 4), i.e., 1, 2, 3, 4, 5, or 6, carbon-carbon double bonds. Preferably, the alkenyl group comprises from 2 to 12 (such as 2 to 10) carbon atoms, i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms (such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 2 to 8 carbon atoms, such as 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferred embodiment, the alkenyl group comprises from 2 to 12 (e.g., 2 to 10) carbon atoms and 1, 2, 3, 4, 5, or 6 (e.g., 1, 2, 3, 4, or 5) carbon-carbon double bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds, such as 2 to 6 carbon atoms and 1, 2, or 3 carbon-carbon double bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon double bonds. The carbon-carbon double bond(s) may be in cis (Z) or trans (E) configuration. Exemplary alkenyl groups include vinyl, 1-propenyl, 2-propenyl (i.e., allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, 11-dodecenyl, and the like. If an alkenyl group is attached to a nitrogen atom, the double bond cannot be alpha to the nitrogen atom. A “substituted alkenyl” means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkenyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkenyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1st level substituent, a 2nd level substituent, or a 3rd level substituent as specified herein, such as halogen or optionally substituted aryl. An example of a substituted alkenyl is styryl (i.e., 2-phenylvinyl).
The term “alkynyl” refers to a monoradical of an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Generally, the maximal number of carbon-carbon triple bonds in the alkynyl group can be equal to the integer which is calculated by dividing the number of carbon atoms in the alkynyl group by 2 and, if the number of carbon atoms in the alkynyl group is uneven, rounding the result of the division down to the next integer. For example, for an alkynyl group having 9 carbon atoms, the maximum number of carbon-carbon triple bonds is 4. Preferably, the alkynyl group has 1 to 6 (such as 1 to 4), i.e., 1, 2, 3, 4, 5, or 6, more preferably 1 or 2 carbon-carbon triple bonds. Preferably, the alkynyl group comprises from 2 to 12 (such as 2 to 10) carbon atoms (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, more preferably 2 to 8 carbon atoms, such as 2 to 6 carbon atoms or 2 to 4 carbon atoms. Thus, in a preferred embodiment, the alkynyl group comprises from 2 to 12 (such as 2 to 10) carbon atoms and 1, 2, 3, 4, 5, or 6 (such as 1, 2, 3, 4, or 5 (preferably 1, 2, or 3)) carbon-carbon triple bonds, more preferably it comprises 2 to 8 carbon atoms and 1, 2, 3, or 4 (preferably 1 or 2) carbon-carbon triple bonds, such as 2 to 6 carbon atoms and 1, 2 or 3 carbon-carbon triple bonds or 2 to 4 carbon atoms and 1 or 2 carbon-carbon triple bonds. Exemplary alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 3-nonynyl, 4-nonynyl, 5-nonynyl, 6-nonynyl, 7-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 3-decynyl, 4-decynyl, 5-decynyl, 6-decynyl, 7-decynyl, 8-decynyl, 9-decynyl, and the like. If an alkynyl group is attached to a nitrogen atom, the triple bond cannot be alpha to the nitrogen atom. A “substituted alkynyl” means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an alkynyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the alkynyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1st level substituent, a 2nd level substituent, or a 3rd level substituent as specified herein, such as halogen or optionally substituted aryl.
The term “aryl” or “aromatic ring” refers to a monoradical of an aromatic cyclic hydrocarbon. Preferably, the aryl group contains 3 to 14 (e.g., 5, 6, 7, 8, 9, or 10, such as 5, 6, or 10) carbon atoms which can be arranged in one ring (e.g., phenyl) or two or more condensed rings (e.g., naphthyl). Exemplary aryl groups include cyclopropenylium, cyclopentadienyl, phenyl, indenyl, naphthyl, azulenyl, fluorenyl, anthryl, and phenanthryl. Preferably, “aryl” refers to a monocyclic ring containing 6 carbon atoms or an aromatic bicyclic ring system containing 10 carbon atoms. Preferred examples are phenyl and naphthyl. Aryl does not encompass fullerenes. A “substituted aryl” means that one or more (such as 1 to the maximum number of hydrogen atoms bound to an aryl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the aryl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1st level substituent, a 2nd level substituent, or a 3rd level substituent as specified herein, such as halogen, —OH, —NH2, —NHCH3, —N(CH3)2, —CN, —OCH3, —OCF3, nitro, alkyl (e.g., C1-6 alkyl), alkenyl (e.g., C2-6 alkenyl), and alkynyl (e.g., C2-6 alkynyl). Examples of a substituted aryl include biphenyl, 2-fluorophenyl, 2-chloro-6-methylphenyl, anilinyl, 3-nitrophenyl, 4-hydroxyphenyl, methoxyphenyl (i.e., 2-, 3-, or 4-methoxyphenyl), and 4-ethoxyphenyl.
The term “heteroaryl” or “heteroaromatic ring” means an aryl group as defined above in which one or more carbon atoms in the aryl group are replaced by heteroatoms (such as O, S, or N). Preferably, heteroaryl refers to a five or six-membered aromatic monocyclic ring, wherein 1, 2, or 3 carbon atoms are replaced by the same or different heteroatoms of O, N, or S. Alternatively, it means an aromatic bicyclic or tricyclic ring system wherein 1, 2, 3, 4, or 5 carbon atoms are replaced with the same or different heteroatoms of O, N, or S. Preferably, in each ring of the heteroaryl group the maximum number of O atoms is 1, the maximum number of S atoms is 1, and the maximum total number of O and S atoms is 2. For example, 3- to 14-membered heteroaryl encompasses monocyclic heteroaryl (e.g., 5- or 6-membered), bicyclic heteroaryl (e.g., 9- or 10-membered), and tricyclic heteroaryl (e.g., 13- or 14-membered). Exemplary heteroaryl groups include furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl (also called pyridinyl), pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, benzodiazinyl, quinoxalinyl, quinazolinyl, benzotriazinyl, pyridazinyl, phenoxazinyl, thiazolopyridinyl, pyrrolotriazolyl, phenothiazinyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, pyrrolizinyl, indolizinyl, indazolyl, purinyl, quinolizinyl, phthalazinyl, naphthyridinyl, cinnolinyl, pteridinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolooxazolyl, and pyrrolopyrrolyl. Exemplary 5- or 6-membered heteroaryl groups include furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, and pyridazinyl. A “substituted heteroaryl” means that one or more (such as 1 to the maximum number of hydrogen atoms bound to a heteroaryl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the heteroaryl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1st level substituent, a 2nd level substituent, or a 3rd level substituent as specified herein, such as halogen, —OH, —NH2, —NHCH3, —N(CH3)2, —CN, —OCH3, —OCF3, alkyl (e.g., C1-6 alkyl), alkenyl (e.g., C2-6 alkenyl), and alkynyl (e.g., C2-6 alkynyl). Examples of a substituted heteroaryl include 2,4-dimethylpyridin-3-yl, 2-methyl-4-bromopyridin-3-yl, 3-methyl-2-pyridin-2-yl, 3-chloro-5-methylpyridin-4-yl, 4-chloro-2-methylpyridin-3-yl, 3,5-dimethylpyridin-4-yl, 2-methylpyridin-3-yl, 2-chloro-4-methyl-thien-3-yl, 1,3,5-trimethylpyrazol-4-yl, 3,5-dimethyl-1,2-dioxazol-4-yl, 1,2,4-trimethylpyrrol-3-yl, 3-phenylpyrrolyl, 2,3′-bifuryl, 4-methylpyridyl, 2-, or 3-ethylindolyl.
The term “cycloalkyl” or “cycloaliphatic” represents cyclic non-aromatic versions of “alkyl” and “alkenyl” with preferably 3 to 14 carbon atoms, such as 3 to 12 or 3 to 10 carbon atoms, i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms), more preferably 3 to 7 carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, cyclononyl, cyclononenyl, cyclodecyl, cyclodecenyl, and adamantyl. The term “cycloalkyl” is also meant to include bicyclic and tricyclic versions thereof. If bicyclic rings are formed it is preferred that the respective rings are connected to each other at two adjacent carbon atoms, however, alternatively the two rings are connected via the same carbon atom, i.e., they form a spiro ring system or they form “bridged” ring systems. Preferred examples of cycloalkyl include C3-8-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, bicyclo[4.1.0]heptyl, bicyclo[3.2.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[5.1.0]octyl, and bicyclo[4.2.0]octyl. Cycloalkyl does not encompass fullerenes. A “substituted cycloalkyl” means that one or more (such as 1 to the maximum number of hydrogen atoms bound to a cycloalkyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the cycloalkyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1st level substituent, a 2nd level substituent, or a 3rd level substituent as specified herein, such as halogen, —OH, —NH2, —NHCH3, —N(CH3)2, —CN, —OCH3, —OCF3, ═O, ═S, ═NH, alkyl (e.g., C1-6 alkyl), alkenyl (e.g., C2-6 alkenyl), and alkynyl (e.g., C2-6 alkynyl). Examples of a substituted cycloalkyl include oxocyclohexyl, oxocyclopentyl, fluorocyclohexyl, and oxocyclohexenyl.
The term “heterocyclyl” or “heterocyclic ring” means a cycloalkyl group as defined above in which from 1, 2, 3, or 4 ring carbon atoms in the cycloalkyl group are replaced by heteroatoms (such as those selected from the group consisting of O, S, S(O), S(O)2, N, B, Si, and P, preferably selected from the group consisting of O, S, S(O)2, and N, more preferably selected from the group consisting of O, S, and N). If a ring of the heterocyclyl group only contains one type of heteroatom, the maximum number of said heteroatom in the ring of said heterocyclyl group may be as follows: 2 O atoms (preferably 1 O atom); 2 S atoms (preferably 1 S atom); 4 N atoms (such as 1, 2, or 3 N atoms); 2 B atoms (preferably 1 B atom); 1 Si atom; and/or 1 P atom. If a ring of the heterocyclyl group contains two or more types of heteroatoms, the maximum number of said heteroatoms in the ring of said heterocyclyl group may be as follows: 1 O atom; 1 S atom; 2 N atoms (preferably 1 N atom); 1 B atom; 1 Si atom; and/or 1 P atom, wherein the maximum total number of heteroatoms in the ring of said heterocyclyl group is 4 and the maximum total number of each heteroatom in the ring of said heterocyclyl group is as follows: 1 O atom; 1 S atom; 1 or 2 N atoms; 1 B atom (preferably 0 B atom); 1 Si atom (preferably 0 Si atom); and/or 1 P atom (preferably 0 P atom). In one embodiment, the heteroatoms of the heterocyclyl group are selected from the group consisting of O, S, and N. In this embodiment, preferably, in each ring of the heterocyclyl group the maximum number of O atoms is 1, the maximum number of S atoms is 1, and the maximum total number of O and S atoms is 2. For example, 3- to 14-membered heterocyclyl encompasses monocyclic heterocyclyl (e.g., 3-, 4-, 5-, 6-, or 7-membered, preferably 4- to 7-membered), bicyclic heterocyclyl (e.g., 8-, 9-, or 10-membered), and tricyclic heterocyclyl (e.g., 12-, 13-, or 14-membered). If a heterocyclyl group comprises two or more rings, these rings either are fused (such as in quinolinyl or purinyl), are a spiro moiety, are a bridged structure, are linked via a double bond, or are a combination thereof. In other words, an unsubstituted heterocyclyl group does not encompass two heterocyclyl groups linked via a single bond. The term “heterocyclyl” is also meant to encompass partially or completely hydrogenated forms (such as dihydro, tetrahydro, hexahydro, octahydro, decahydro, dodecahydro, etc., or perhydro forms) of the above-mentioned heteroaryl groups. Exemplary heterocyclyl groups include azetidinyl, morpholino, isochromanyl, chromanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, triazininanyl; dihydro forms of pyrrolyl, imidazolyl, and pyrazolyl; di- and tetrahydro forms of furanyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, thiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, and triazinyl; di-, tetra- and hexahydro forms of pyrimidinyl, pyridazinyl, pyrrolothiazolyl, and pyrrolizinyl. A “substituted heterocyclyl” means that one or more (such as 1 to the maximum number of hydrogen atoms bound to a heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atoms of the heterocyclyl group are replaced with a substituent other than hydrogen (when more than one hydrogen atom is replaced the substituents may be the same or different). Preferably, the substituent other than hydrogen is a 1st level substituent, a 2nd level substituent, or a 3rd level substituent as specified herein, such as halogen, —OH, —NH2, —NHCH3, —N(CH3)2, —CN, —OCH3, —OCF3, ═O, ═S, ═NH, alkyl (e.g., C1-6 alkyl), alkenyl (e.g., C2-6 alkenyl), and alkynyl (e.g., C2-6 alkynyl).
The expression “partially hydrogenated form” of an unsaturated compound or group as used herein means that part of the unsaturation has been removed by formally adding hydrogen to the initially unsaturated compound or group without removing all unsaturated moieties. The phrase “completely hydrogenated form” of an unsaturated compound or group is used herein interchangeably with the term “perhydro” and means that all unsaturation has been removed by formally adding hydrogen to the initially unsaturated compound or group. For example, partially hydrogenated forms of a 5-membered heteroaryl group (containing 2 double bonds in the ring, such as furan) include dihydro forms of said 5-membered heteroaryl group (such as 2,3-dihydrofuran or 2,5-dihydrofuran), whereas the tetrahydro form of said 5-membered heteroaryl group (e.g., tetrahydrofuran, i.e., THF) is a completely hydrogenated (or perhydro) form of said 5-membered heteroaryl group. Likewise, for a 6-membered heteroaryl group having 3 double bonds in the ring (such as pyridyl), partially hydrogenated forms include di- and tetrahydro forms (such as di- and tetrahydropyridyl), whereas the hexahydro form (such as piperidinyl in case of the heteroaryl pyridyl) is the completely hydrogenated (or perhydro) derivative of said 6-membered heteroaryl group. Consequently, a hexahydro form of an aryl or heteroaryl can only be considered a partially hydrogenated form according to the present invention if the aryl or heteroaryl contains at least 4 unsaturated moieties consisting of double and triple bonds between ring atoms.
The term “aromatic” as used in the context of hydrocarbons means that the whole molecule has to be aromatic. For example, if a monocyclic aryl is hydrogenated (either partially or completely) the resulting hydrogenated cyclic structure is classified as cycloalkyl for the purposes of the present invention. Likewise, if a bi- or polycyclic aryl (such as naphthyl) is hydrogenated the resulting hydrogenated bi- or polycyclic structure (such as 1,2-dihydronaphthyl) is classified as cycloalkyl for the purposes of the present invention (even if one ring, such as in 1,2-dihydronaphthyl, is still aromatic). A similar distinction is made within the present application between heteroaryl and heterocyclyl. For example, indolinyl, i.e., a dihydro variant of indolyl, is classified as heterocyclyl for the purposes of the present invention, since only one ring of the bicyclic structure is aromatic and one of the ring atoms is a heteroatom.
The term “polycyclic” as used herein means that the structure has two or more (such as 2, 3, 4, 5, 6, 7, 8, 9, or 10), preferably, 2, 3, 4, or 5, more preferably, 2, 3, or 4, rings. Therefore, according to the invention, the term “polycyclic” does not encompass monocyclic structures, wherein the structures only contain one ring. Examples of polycyclic groups are fused structures (such as naphthyl or anthryl), spiro compounds, rings that are linked via single or double bonds (such as biphenyl), and bridged structures (such as bornyl). Exemplary polycyclic structures are those aryl, heteroaryl, cycloalkyl, and heterocyclyl groups specified above which have at least two rings.
The term “halogen” or “halo” means fluoro, chloro, bromo, or iodo.
The term “azido” means —N3.
The term “N-oxide” means an amine oxide or amine-N-oxide which is a chemical compound containing the functional group (Rn)3N+—O− or (Rn)3N+—OH, i.e., an N—O coordinate covalent bond, wherein Rn is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups is optionally substituted with one or more (such as 1 to the maximum number of hydrogen atoms bound to the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) independently selected R20, the R20 preferably being a 1st level substituent, a 2nd level substituent, or a 3rd level substituent as specified herein.
The term “optionally substituted” indicates that one or more (such as 1 to the maximum number of hydrogen atoms bound to a group, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10, such as between 1 to 5, 1 to 4, or 1 to 3, or 1 or 2) hydrogen atom(s) may be replaced with a group (i.e., a 1st level substituent) different from hydrogen such as alkyl (preferably, C1-6 alkyl), alkenyl (preferably, C2-6 alkenyl), alkynyl (preferably, C2-6 alkynyl), aryl (preferably, 6- to 14-membered aryl), heteroaryl (preferably, 3- to 14-membered heteroaryl), cycloalkyl (preferably, 3- to 14-membered cycloalkyl), heterocyclyl (preferably, 3- to 14-membered heterocyclyl), halogen, —CN, azido, —NO2, —OR71, —N(R72)(R73), —S(O)0-2R71, —S(O)1-2OR71, —OS(O)1-2R71, —OS(O)1-2OR71, —S(O)1-2N(R72)(R73), —OS(O)1-2N(R72)(R73), —N(R71)S(O)1-2R71, —NR71S(O)1-2OR71, —NR71S(O)1-2N(R72)(R73), —OP(O)(OR71)2, —C(═X1)R71, —C(═X1)X1R71, —X1C(═X1)R71, and —X1C(═X1)X1R71, and/or any two 1st level substituents which are bound to the same carbon atom of a cycloalkyl or heterocyclyl group may join together to form ═X1, wherein each of the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl groups of the 1st level substituent may themselves be substituted by one or more (e.g., one, two or three) substituents (i.e., a 2nd level substituent) selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 6- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, halogen, —CF3, —CN, azido, —NO2, —OR81, —N(R82)(R83), —S(O)0-2R81, —S(O)1-2OR81, —OS(O)1-2R81, —OS(O)1-2OR81, —S(O)1-2N(R82)(R83), —OS(O)1-2N(R82)(R83), —N(R81)S(O)1-2R81, —NR81S(O)1-2OR81, —NR8'S(O)1-2N(R82)(R83), —OP(O)(OR81)2, —C(═X2)R81, —C(═X2)X2R81, —X2C(═X2)R81, and —X2C(═X2)X2R81, and/or any two 2nd level substituents which are bound to the same carbon atom of a cycloalkyl or heterocyclyl group being a 1st level substituent may join together to form ═X2, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 6- to 14-membered aryl, 3- to 14-membered heteroaryl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl groups of the 2nd level substituent is optionally substituted with one or more (e.g., one, two or three) substituents (i.e., a 3rd level substituent) independently selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —OCF3, —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2-z(C1-3 alkyl)z, —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl), —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2 (C1-3 alkyl), and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl)z, wherein each z is independently 0, 1, or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl, and/or any two 3rd level substituents which are bound to the same carbon atom of a 3- to 14-membered cycloalkyl or heterocyclyl group being a 2nd level substituent may join together to form ═O, ═S, ═NH, or ═N(C1-3 alkyl);
wherein
each of R71, R72, and R73 is independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 3- to 7-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 7-membered heterocyclyl groups is optionally substituted with one, two or three substituents independently selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —OCF3, ═O, —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2-z(C1-3 alkyl)z, —C(═O)(C1-3 alkyl), —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl), —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl), and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl), wherein each z is independently 0, 1, or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl;
each of R81, R82, and R83 is independently selected from the group consisting of H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl, wherein each of the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3- to 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 3- to 6-membered heterocyclyl groups is optionally substituted with one, two or three substituents independently selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —OCF3, ═O, —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alky)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2-z(C1-3 alkyl)z, —C(═O)(C1-3 alkyl), —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl)z, —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl), and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl)z, wherein each z is independently 0, 1, or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl; and
each of X1 and X2 is independently selected from O, S, and N(R84), wherein R84 is H or C1-3 alkyl.
Typical 1st level substituents are preferably selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 6- to 14-membered (such as 6- to 10-membered) aryl, 3- to 14-membered (such as 5- or 6-membered) heteroaryl, 3- to 14-membered (such as 3- to 7-membered) cycloalkyl, 3- to 14-membered (such as 3- to 7-membered) heterocyclyl, halogen, —CN, azido, —NO2, —OR71, —N(R72)(R73), —S(O)0-2R71, —S(O)1-2OR71, —OS(O)1-2R71, —OS(O)1-2OR71, —S(O)1-2N(R72)(R73), —OS(O)1-2N(R72)(R73), —N(R71)S(O)1-2R71, —NR71S(O)1-2OR71, —C(═X1)R71, —C(═X1)X1R71, —X1C(═X1)R71, and —X1C(═X1)X1R71, such as C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 6-membered aryl, 5- or 6-membered heteroaryl, 3- to 7-membered cycloalkyl, 3- to 7-membered (such as 5- or 6-membered) heterocyclyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2-z(C1-3 alkyl), —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl), —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl)z, and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl), wherein each z is independently 0, 1, or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl; wherein X1 is independently selected from O, S, NH and N(CH3); and each of R71, R72, and R73 is as defined above or, preferably, is independently selected from the group consisting of H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 5- or 6-membered cycloalkyl, 5- or 6-membered aryl, 5- or 6-membered heteroaryl, and 5- or 6-membered heterocyclyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups is optionally substituted with one, two or three substituents independently selected from the group consisting of C1-3 alkyl, halogen, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2-z(C1-3 alkyl)z, —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl)z, —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl), and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl)z, wherein each z is independently 0, 1, or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl. Particular examples of 1st level substituents are independently selected from the group consisting of C1-3 alkyl, phenyl, imidazolyl, thiazolyl, cyclopentyl, cyclohexyl, dihydrothiazolyl, thiazolidinyl, halogen, —CF3, —CN, —OH, —O(C1-3 alkyl), —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl), —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl), and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl)z, wherein each z is independently 0, 1, or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl. Particularly preferred 1st level substituents are independently selected from the group consisting of C1-3 alkyl, phenyl, thiazolidinyl, halogen (such as F, Cl, or Br), —NH2, —NHS(O)2(C1-3 alkyl), —NHC(═O)(C1-3 alkyl), and —NHC(═NH)NHz-2(C1-3 alkyl)z, wherein z is 0, 1, or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl.
Typical 2nd level substituents are preferably selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 6- or 10-membered aryl, 5- or 6-membered heteroaryl, 5- or 6-membered cycloalkyl, 5- or 6-membered heterocyclyl, halogen, ═O, ═S, —CF3, —CN, azido, —NO2, —OH, —O(C1-3 alkyl), —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —S(O)2NH2-z(C1-3 alkyl)z, —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl), —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl), and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl), wherein each z is independently 0, 1, or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl. Particular examples of 2nd level substituents are independently selected from the group consisting of C1-3 alkyl, phenyl, 5- or 6-membered heteroaryl, 5- or 6-membered cycloalkyl, 5- or 6-membered heterocyclyl, halogen, ═O, ═S, —CF3, —CN, —OH, —O(C1-3 alkyl), —S(C1-3 alkyl), —NH2, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, —NHS(O)2(C1-3 alkyl), —C(═O)OH, —C(═O)O(C1-3 alkyl), —C(═O)NH2-z(C1-3 alkyl), —NHC(═O)(C1-3 alkyl), —NHC(═NH)NHz-2(C1-3 alkyl)z, and —N(C1-3 alkyl)C(═NH)NH2-z(C1-3 alkyl), wherein each z is independently 0, 1, or 2 and each C1-3 alkyl is independently methyl, ethyl, propyl or isopropyl. Particularly preferred 2nd level substituents are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, phenyl, ═O, and ═S.
Typical 3rd level substituents are preferably selected from the group consisting of C1-3 alkyl, phenyl, halogen, —CF3, —OH, —OCH3, —SCH3, —NH2-z(CH3)z, —C(═O)OH, and —C(═O)OCH3, wherein z is 0, 1, or 2 and C1-3 alkyl is methyl, ethyl, propyl or isopropyl. Particularly preferred 3rd level substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, halogen (such as F, Cl, or Br), and —CF3, such as halogen (e.g., F, Cl, or Br), and —CF3.
The term “optional” or “optionally” as used herein means that the subsequently described event, circumstance or condition may or may not occur, and that the description includes instances where said event, circumstance, or condition occurs and instances in which it does not occur.
“Isomers” are compounds having the same molecular formula but differ in structure (“structural isomers”) or in the geometrical (spatial) positioning of the functional groups and/or atoms (“stereoisomers”). “Enantiomers” are a pair of stereoisomers which are non-superimposable mirror-images of each other. A “racemic mixture” or “racemate” contains a pair of enantiomers in equal amounts and is denoted by the prefix (±). “Diastereomers” are stereoisomers which are non-superimposable and which are not mirror-images of each other. “Tautomers” are structural isomers of the same chemical substance that spontaneously and reversibly interconvert into each other, even when pure, due to the migration of individual atoms or groups of atoms; i.e., the tautomers are in a dynamic chemical equilibrium with each other. Examples of tautomers are the isomers of the keto-enol-tautomerism. “Conformers” are stereoisomers that can be interconverted just by rotations about formally single bonds, and include—in particular—those leading to different 3-dimensional forms of (hetero)cyclic rings, such as chair, half-chair, boat, and twist-boat forms of cyclohexane.
“Polymorphism” as referred to herein means that a solid material (such as a compound) is able to exist in more than one form or crystalline structure, i.e., “polymorphic modifications” or “polymorphic forms”. The terms “polymorphic modifications”, “polymorphic forms”, and “polymorphs” are used interchangeable in the present invention. According to the present invention, these “polymorphic modifications” include crystalline forms, amorphous forms, solvates, and hydrates Mainly, the reason for the existence of different polymorphic forms lies in the use of different conditions during the crystallization process, such as the following:
Polymorphic forms may have different chemical, physical, and/or pharmacological properties, including but not limited to, melting point, X-ray crystal and diffraction pattern, chemical reactivity, solubility, dissolution rate, vapor pressure, density, hygroscopicity, flowability, stability, compactability, and bioavailability. Polymorphic forms may spontaneously convert from a metastable form (unstable form) to the stable form at a particular temperature. According to Ostwald's rule, in general it is not the most stable but the least stable polymorph that crystallizes first. Thus, quality, efficacy, safety, processability and/or manufacture of a chemical compound, such as a compound of the present invention, can be affected by polymorphism. Often, the most stable polymorph of a compound (such as a compound of the present invention) is chosen due to the minimal potential for conversion to another polymorph. However, a polymorphic form which is not the most stable polymorphic form may be chosen due to reasons other than stability, e.g. solubility, dissolution rate, and/or bioavailability.
The term “crystalline form” of a material as used herein means that the smallest components (i.e., atoms, molecule or ions) of said material form crystal structures. A “crystal structure” as referred to herein means a unique three-dimensional arrangement of atoms or molecules in a crystalline liquid or solid and is characterized by a pattern, a set of atoms arranged in a particular manner, and a lattice exhibiting long-range order and symmetry. A lattice is an array of points repeating periodically in three dimensions and patterns are located upon the points of a lattice. The subunit of the lattice is the unit cell. The lattice parameters are the lengths of the edges of a unit cell and the angles between them. The symmetry properties of the crystal are embodied in its space group. In order to describe a crystal structure the following parameters are required: chemical formula, lattice parameters, space group, the coordinates of the atoms and occupation number of the point positions.
The term “amorphous form” of a material as used herein means that the smallest components (i.e., atoms, molecule or ions) of said material are not arranged in a lattice but are arranged randomly. Thus, unlike crystals in which a short-range order (constant distances to the next neighbor atoms) and a long-range order (periodical repetition of a basic lattice) exist, only a short-range order exists in an amorphous form.
The term “solvate” as used herein refers to an addition complex of a dissolved material in a solvent (such as an organic solvent (e.g., an aliphatic alcohol (such as methanol, ethanol, n-propanol, isopropanol), acetone, acetonitrile, ether, and the like), water or a mixture of two or more of these liquids), wherein the addition complex exists in the form of a crystal or mixed crystal. The amount of solvent contained in the addition complex may be stoichiometric or non-stoichiometric. A “hydrate” is a solvate wherein the solvent is water.
In isotopically labeled compounds one or more atoms are replaced by a corresponding atom having the same number of protons but differing in the number of neutrons. For example, a hydrogen atom may be replaced by a deuterium atom. Exemplary isotopes which can be used in the compounds of the present invention include deuterium, 11C, 13C, 14C, 15N, 18F, 32P, 32S, 35S, 36Cl, and 125I.
The compounds which are used and/or synthesized in the process of the invention and which contain a basic functionality may form salts, in particular pharmaceutically acceptable salts, with a variety of inorganic or organic acids. The compounds which are used and/or synthesized in the process of the invention and which contain an acidic functionality may form salts, in particular pharmaceutically acceptable salts, with a variety of inorganic or organic bases. Exemplary inorganic and organic acids/bases as well as exemplary acid/base addition salts of these compounds are given below. The compounds which are used and/or synthesized in the process of the invention and which contain both basic and acidic functionalities may be converted into either base or acid addition salt. The neutral forms of the compounds which are used and/or synthesized in the process of the invention may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The salts are preferably pharmaceutically acceptable salts.
The term “pharmaceutically acceptable” refers to the non-toxicity of a material which does not interact with the (e.g., therapeutic) action of the active component of a pharmaceutical composition.
“Pharmaceutically acceptable salts” comprise, for example, acid addition salts which may, for example, be formed by mixing a solution of compounds with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compound carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, arginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, galactate, galacturonate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate/diphosphate, phthalate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, suberate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see, for example, Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci., 66, pp. 1-19 (1977)).
The expression “reflux temperature” as used herein in conjunction with a reaction mixture refers to the boiling point of the liquid contained in the reaction mixture which has the lowest boiling point of all liquids contained in the reaction mixture.
Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
In a preferred embodiment, the product obtained by the process of the invention (in particular the compound of formula (I)) is substantially free of contaminants.
The term “substantially free of contaminants” as used herein in conjunction with product obtained by the process of the invention means that the amount of contaminants in the product obtained by the process of the invention is at most 5% by weight (preferably at most 4% by weight, at most 3% by weight, at most 2% by weight, at most 1% by weight, at most 0.5% by weight, at most 0.1% by weight, at most 0.05% by weight, at most 0.01% by weight, at most 0.005% by weight, at most 0.001% by weight), based on the total weight of said product.
The term “chromatography-free manner” as used herein in the context of the synthesis of a compound of interest (such as a compound of formula (I) or a solvate or salt thereof or an intermediate of any one of formulas (3), (4), and (5)) means that in at least one of the steps of said synthesis (preferably in all steps of said synthesis) the separation of the compound of interest from other compounds (such as contaminants) is achieved by means other than chromatography, preferably by means of precipitating the compound of interest, optionally washing the precipitated compound of interest with a suitable solvent (in particular, a solvent in which the compound of interest is poorly soluble), and optionally drying the precipitated compound of interest. However, the term “chromatography-free manner” as used herein in the context of the synthesis of a compound of interest does not mean that the analysis of a sample obtained during the synthesis is performed using chromatography (i.e., a process for synthesizing a compound of interest which is performed in a chromatography-free manner merely excludes preparative steps using chromatography, but does not exclude analytical steps using chromatography).
The term “equivalent” as used herein means the amount of a compound containing 1 mole of hydrogen (i.e., 1.008 g of hydrogen) or 1 mole of a different element (e.g., 12.011 g for carbon or 15.999 g for oxygen). For example, a solution of NaOH having a concentration of 40 g/l is equivalent to (i) a solution of KOH having a concentration of 56.5 g/l, (ii) a solution of HCl having a concentration of 36.5 g; or (iv) a solution of H2SO4 having a concentration of 49 g/l. Furthermore, in the context of, for example, a condensation reaction of a first compound with a second compound, wherein the first and second compounds react in a molar ratio of 1:1, the term “1 equivalent” means that x moles (e.g., x=2) of the first compound and x moles of the second compound are used, i.e., the molar amount of the first compound is the same as the molar amount of the second compound.
The terms “poorly soluble” compound and “insoluble” compound are used herein interchangeably in the context with a solvent and mean that under standard conditions less than 0.5 parts by weight of the compound (preferably, less than 0.4 parts by weight, such as less than 0.3 parts by weight, less than 0.2 parts by weight, less than 0.1 parts by weight, less than 0.09 parts by weight, less than 0.08 parts by weight, less than 0.07 parts by weight, less than 0.06 parts by weight, less than 0.05 parts by weight, less than 0.04 parts by weight, less than 0.03 parts by weight, less than 0.02 parts by weight, less than 0.01 parts by weight, less than 0.009 parts by weight, less than 0.005 parts by weight, or less than 0.004 parts by weight) dissolve in 100 parts by weight of the solvent.
The term “standard conditions” as used herein refers to a temperature of 25° C. and an absolute pressure of 101.325 kPa.
In a first aspect, the present invention is directed to a process for synthesizing N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide, i.e. a compound of formula (I), a solvate or salt thereof. Within the context of the present invention, novel intermediates are generated as part of the novel synthesis process. Together, the present invention provides an improved, efficient process for the synthesis of N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide, a solvate or salt thereof.
More specifically, the present invention relates to a process for synthesizing N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide, a solvate or salt thereof, the process comprising the following steps:
a) providing a compound of formula (3):
or a solvate or salt thereof, wherein each of R1 and R2 is independently selected from the group consisting of —H and an amino protecting group, and at least one of R1 and R2 is an amino protecting group;
b) reacting the compound of formula (3) or a solvate or salt thereof with one or more reagents to remove the amino protecting group(s) at position R1 and R2 to give a compound of formula (4):
or a solvate or salt thereof;
c) reacting the compound of formula (4) or a solvate or salt thereof with one or more reagents for introducing (i) a tetrahydropyranyl group and (ii) an acetyl group to give a compound of formula (5):
or a s solvate or salt thereof; and
d) subjecting the compound of formula (5) or a solvate or salt thereof to an oxidative amination reaction to give the compound of formula (I) or a solvate or salt thereof.
In one embodiment of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect, step a) may comprise reacting a compound of formula (1):
or a solvate or salt thereof with HOOC(CH2)2OCH3 (formula (2)) or a derivative thereof to give a compound of formula (3) or a solvate or salt thereof. In this embodiment (such as in the process as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect, the reaction of the compound of formula (1) with the compound of formula (2) may be performed for a sufficient amount of time (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In step b) of the process of the first aspect, the compound of formula (3) or a solvate or salt thereof is reacted with one or more reagents to remove the amino protecting group(s) at position R1 and R2 to give a compound of formula (4):
or a solvate or salt thereof. Thus, in other words, in step b) the protected primary amino group of the compound of formula (3) is deprotected in order to give the compound of formula (4) having a free primary amino group.
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
(1) Boc: addition of a strong acid (e.g., selected from the group consisting of trifluoroacetic acid (TFA; e.g., 25-50% in DCM), HCl (e.g., 4-6 M in an organic solvent), CH3SO3H (e.g., 2 M in dioxane), and (H3C)3SiCl (TMSCl; e.g., 1 M TMSCl-phenol in DCM));
(2) Trt: addition of a strong acid (e.g., TFA (e.g., 1% in DCM or 0.2%, 1% H2O in DCM), HOBt (e.g., 0.1 M in 2,2,2-trifluoroethanol), or trichloroacetic acid (TCA; e.g., 3% in DCM));
(3) Fmoc: addition of a base, in particular a secondary amine (e.g., NH3 (e.g., as liquid; about 10 h), morpholine or piperidine (within minutes), diethylamine (DEA; e.g., 10%), dimethylacetamide (DMA; e.g., 2 h), or polymeric (silica gel or polystyrene) secondary amines (i.e., piperazine or piperidine) in organic solvents;
(4) Cbz: catalytical hydrogenolysis or addition of a strong acid (e.g., HBr (e.g., in in acetic acid), TFA (e.g., at high temperature; TFA-thioanisole), HF (e.g., liquid), or BBr3);
(5) Alloc: Pd-catalyzed transfer of the allyl group to a nucleophile or scavenger (e.g., Pd(PPh)3; scavengers: H3N.BH3, Me2NH.BH3 or PhSiH3 in organic solvents)
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect, in which in step b) an acid is added (in particular in the embodiments of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in
In step c) of the process of the first aspect, the compound of formula (4) or a solvate or salt thereof is reacted with one or more reagents for introducing (i) a tetrahydropyranyl group and (ii) an acetyl group to give a compound of formula (5):
or a s solvate or salt thereof. Thus, in other words, in step c) the primary amino group is converted into a tertiary amino group bearing a tetrahydropyranyl group and an acetyl group.
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
It is to be understood that in any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in
In step d) of the process of the first aspect, the compound of formula (5) or a solvate or salt thereof is subjected to an oxidative amination reaction to give the compound of formula (I) or a solvate or salt thereof. In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in
In one mode (in particular of the embodiments of the process of the invention as specified in any one of
In any of the above embodiments of the process of the first aspect (in particular of the process of the invention as specified in any one of
In particular, the present inventors found that it is possible to avoid chromatography in the preparative steps of the process of the first aspect and that by using alternative means, especially precipitating the compound of interest (i.e., a compound of formula (I) or a solvate or salt thereof or an intermediate of any one of formulas (3), (4), and (5)), the compound of formula (I) or a solvate or salt thereof can be obtained in a much larger scale, in higher yield and in a purity similar to that achieved by a comparative process for synthesizing N-(4-(4-amino-2-(2-methoxy ethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide which uses several chromatographic purification steps.
In a second aspect, the present invention provides a compound selected from the group consisting of:
and a solvate or salt thereof. These compounds are intermediates useful in the process of the first aspect.
In a third aspect, the present invention provides a use of a compound of the second aspect for synthesizing a compound of formula (I). In this respect, it is noted that the embodiments specified above for the first aspect equally apply to the third aspect. Thus, for example, in one embodiment of the third aspect, a compound of formula (5) or a solvate or salt thereof is subjected to an oxidative amination reaction to give the compound of formula (I) or a solvate or salt thereof and, optionally, the compound of formula (I) or a solvate or salt is crystallized, preferably from an alcoholic solvent.
The following abbreviations are used throughout description: SM: starting material for the respective synthetic step; IPC: In-Process Control; DCM: dichloromethane; TBME: tert-butyl methyl ether; MeOH: methanol; EtOH: ethanol; HCl: hydrochloric acid; NaOH: sodium hydroxide; Ac2O: acetic anhydride; HPLC: High Performance Liquid Chromatography; LOD: Loss On Drying; IPA: 2-propanol; pTSCl or TsCl: p-toluenesulfonyl chloride; PTSA: p-toluenesulfonic acid; STAB: sodium triacetoxyborohydride; eq.: equivalent(s); vol.: volume(s); NMR: Nuclear Magnetic Resonance; ppm: parts per million; THP: tetrahydropyranyl; Ac2O: acetic anhydride; mCPBA: 3-chloroperoxybenzoic acid.
Step a): Providing a Compound of Formula (3)
Compound 1 (1 eq.), p-toluenesulfonic acid monohydrate (0.05 eq.) and toluene (10 vol.) were charged to a reactor. After addition of 1,1,1,3-tetramethoxypropane (1.2 eq.) the contents of reactor were adjusted to reflux at approx. 95° C. and the content of compound 1 was monitored using HPLC.
Step b): Preparing a Compound of Formula (4)
When the content of compound 1 dropped to ≤1.0% area of the initial area (determined by HPLC), the contents of reactor were adjusted to 10 to 15° C., 6 N HCl (5 vol.) were added to reactor over approx. 1 h, whereby the temperature was maintained ≤25° C. The contents of the reactor were agitated at 20° C. to 25° C. for at least 2 hours and the reaction completion was monitored by HPLC. The lower aqueous layer containing the desired product was collected, the upper organic layer was discharged, the collected aqueous layer containing the desired product was transferred into the reactor, DCM (5 vol.) was added, the reaction mixture was agitated for 15 min and allowed to settle for 15 min. The lower organic layer was discharged, water (2 vol.) was added to reactor, and the contents of reactor were adjusted to 0° C. to 5° C. NaOH (11 eq.) was added to the reactor portion-wise while maintaining the temperature ≤30° C. After the pH of the reaction mixture was adjusted to ≥12, the temperature of the reaction mixture was increased to 20° C. to 25° C., DCM (5 vol.) was added, and the reaction mixture was agitated for 15 min and allowed to settle for 15 min. The lower organic layer containing the desired product was collected, DCM (5 vol.) was added, and the reaction mixture was agitated for 15 min and allowed to settle for 15 min. The lower organic layer containing the product was collected, the upper aqueous layer was discharged, and the 2 collected organic layers were combined in the reactor. A solvent exchange to ethanol was performed until the amount of DCM in the reaction mixture was ≤1%. The amount of compound 4 was determined, fumaric acid (1 eq. based on the determined amount of compound 4) was added, and the reaction mixture was agitated at 20° C. to 25° C. for at least 12 hours to precipitate the compound of formula (4) as fumaric acid addition salt. TBME (10 vol.) was added over at least 30 min and the reaction mixture was agitated at 20° C. to 25° C. for 1 to 2 hours. The precipitate was collected using filtration under nitrogen, the reactor was washed with TBME (2×3 vol.) and this washing solution was used to wash the precipitate under nitrogen. The collected precipitate was dried at 40° C. to 45° C. for at least 12 hours.
Step c): Preparing a Compound of Formula (5)
Compound 4 as fumaric acid addition salt (1 eq.) obtained from step b), DCM (5 vol.), and 2 M NaOH (10 vol.) were added to a reactor, and the reaction mixture was agitated for 15 min and allowed to settle for 15 min. The lower organic layer containing compound 4 as free base was collected, the aqueous phase was extracted with DCM (5 vol.), and the lower organic layer was collected. After discharging the upper aqueous layer, the 2 organic layers were charged into the reactor, MgSO4 (0.2 wt.-%) were added to the reactor, the reaction mixture was agitated for 5 min and the contents of the reactor filtered to remove MgSO4. The filtrate was charged into a new clean reactor, tetrahydropyranone (1.1 eq.) and acetic acid (1 eq.) were added, and the temperature of the reaction mixture was adjusted to −10° C. to 0° C. STAB (1.8 eq.) was added portion-wise while maintaining the temperature ≤0° C. After completion of the addition, the temperature was increased to 20° C. to 25° C., the reaction mixture was agitated for at least 18 hours, and the reaction completion was monitored by HPLC. Once the content of compound 4 Target was ≤0.50% of the initial area, the reaction mixture was cooled to 10° C. to 15° C. and slowly quenched by the addition of 2 M NaOH (10 vol.) while maintaining the temperature ≤25° C. After completion of the NaOH addition, the reaction mixture was agitated for 15 min and allowed to settle for 15 min. The lower organic layer containing the desired product was collected, the upper aqueous layer was extracted with DCM (10 vol.), the lower organic layer containing the desired product was collected, and the upper aqueous layer was discharged. MgSO4 (0.2 wt.-%) was added to the reactor and the 2 organic layers were charged into the reactor and the reaction mixture was agitated for at least 15 min. MgSO4 was removed by filtration and the MgSO4 cake was washed with DCM (1 vol.). The filtrates were combined in a clean reactor and reduced to approx. 10 to 12 vol. under reduced pressure at 35° C. to 40° C. The temperature of the reaction mixture was adjusted to 20° C. to 25° C., acetic anhydride (1 eq.) was added slowly while maintaining the temperature between 20° C. and 30° C. After completion of the addition, the temperature of the reaction mixture was adjusted to 20° C. to 25° C., the reaction mixture was agitated for at least 24 hours, and the content of the tetrahydropyranyl adduct and STAB was monitored using HPLC. Once the content of each the tetrahydropyranyl adduct and STAB was ≤0.50% of the initial area, the reaction was slowly quenched by the addition of 5% NaHCO3 solution (10 vol.), and the reaction was agitated for 15 min and allowed to settle for 15 min. The lower organic layer containing the desired product was collected and charged into a clean reactor. MgSO4 (0.2 wt.-%) was added, the reaction mixture was agitated for at least 15 min and then filtered to remove MgSO4. The reactor was washed with DCM (1 vol.) and this washing solution was used to rinse the MgSO4 cake. The filtrates were recharged into a clean reactor and reduced to 6-7 vol. under reduced pressure at ≤30° C. A solvent exchange to TBME was performed until the content of DCM in the reaction mixture was ≤10%. Then, TBME (3 vol.) was added, the temperature of the reaction mixture was adjusted to 20° C. to 25° C. and the reaction mixture was agitated for at least 1 hour. The suspension was filtered under nitrogen and the reactor and filter cake were washed with TBME (2×2 vol.). The collected precipitate was dried at 35° C. to 40° C. for at least 12 hours.
Step d): Preparing a Compound of Formula (I)
Compound 5 (1 eq.) obtained from step c) was charged in a reactor, DCM (10 vol.) was added, and the temperature of the reaction mixture was adjusted to −10° C. to 0° C. 70% mCPBA (1.5 eq.) was added to the reactor portion-wise while maintaining the temperature ≤0° C. After completion of the addition the temperature of the reaction mixture was adjusted to 20° C. to 25° C., the reaction mixture was agitated for at least 2 hours, and the content of compound 5 in the reaction mixture was monitored using HPLC. Once the content of compound 5 in the reaction mixture was ≤4% of the initial amount, the temperature of the reaction mixture was adjusted to 0° C. to 5° C. and ammonium hydroxide (10 vol.) was added while maintaining the temperature ≤20° C. After completion of the addition, the temperature of the reaction mixture was adjusted to 0° C. to 5° C. pTsCl (1.5 eq.) dissolved in DCM (3 vol.) was slowly added to the reactor while maintaining the temperature ≤10° C. After completion of the addition, the temperature of the reaction mixture was adjusted to 20° C. to 25° C., the reaction mixture was agitated for at least 2 hours, and the content of the N-oxide intermediate in the reaction mixture was monitored using HPLC. Once the content of the N-oxide intermediate in the reaction mixture was ≤0.5% of the initial amount, the temperature of the reaction mixture was adjusted to 30° C. to 35° C. and the reaction mixture was agitated for at least 2 hours. The temperature of the reaction mixture was adjusted to 20° C. to 25° C., the lower organic layer containing the desired product was collected, charged into a clean reactor, MgSO4 (0.2 wt.-%) was added, and the reaction mixture was agitated for at least 15 min. The reaction mixture was filtered to remove MgSO4, the reactor was washed with DCM (1 vol.) and this washing solution was used to rinse the MgSO4 cake. The filtrates were combined in a clean reactor and reduced to approx. 10 vol. under reduced pressure at 35° C. to 40° C., and the content of the compound of formula (I) in the resulting solution was determined.
Step e): Precipitating the Compound of Formula (I)
The crude solution of the compound of formula (I) (1 eq.) obtained from step d) was charged into a reactor. A solvent exchange to IPA was performed until the content of DCM in the reaction mixture was ≤1%. Then, the temperature of the reaction mixture was adjusted to 5° C. to 10° C. and the reaction mixture was agitated for at least 1 h. The suspension was filtered, the reactor was washed with IPA (2 vol.), the washing solution was cooled to 5° C. to 10° C. and then used to rinse the filter cake. The reactor was washed with TBME (2×5 vol.) and each washing solution was used to rinse the filter cake. The collected precipitate was dried at 35° C. to 40° C. for at least 12 hours
Step f): Crystallization of the Compound of Formula (I)
5% water in ethanol (10 vol.) was charged into a reactor and the compound of formula (I) (1 eq.) obtained from step e) was added. The temperature of the reaction mixture was adjusted to 65° C. to 70° C. and held for at 30 min to 1 hour. Once all of the compound of formula (I) was dissolved, the solution was filtered and the filtrate was charged into a clean reactor preheated to 65° C. to 70° C. The temperature of the solution was adjusted to 45° C. to 50° C. over 3 h±30 mins. A seed crystal of the compound of formula (I) was added, temperature of the reaction mixture was adjusted to 0° C. to 5° C. over at least 7 h, and the reaction mixture was agitated at 0° C. to 5° C. for at least 2 hours. The suspension was filtered, the reactor was washed with 5% water in ethanol (2 vol.), the temperature of the washing solution was adjusted to 0° C. to 5° C. and used to rinse the filter cake. The reactor was washed with TBME (2 vol.) and the washing solution was used to rinse the filter cake. Optionally, the crystallization step was repeated.
The overall yield of the process of the present invention, the amount of compound of formula (I) produced by said process, and the time required for the synthesis are given in Table 6, below.
N-(4-(4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl)butyl)-N-(tetrahydro-2H-pyran-4-yl)acetamide was prepared according to the process set forth in
As can be seen from the results presented in Table 6, the process of the present invention provides much higher yields than the comparative process B and is capable of providing the compound of formula (I) in much higher amounts (about 1.2 kg vs. about 10 g, i.e., a factor of more than 102) than the comparative process B and in a purity comparable to that achieved by using the comparative process B.
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/EP2019/055793 | Mar 2019 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2020/056047 | 3/6/2020 | WO | 00 |
