Viral inhibitors, the synthesis thereof, and intermediates thereto

Abstract

This disclosure discloses compositions comprising maribavir, methods for providing such compositions, and compositions for use in providing intermediates of maribavir.

Description

Viral inhibitors, their synthesis and intermediates This invention relates to compounds that can be used as antiviral agents, pharmaceutical compositions thereof, and methods for preparing such compounds and compositions. Cytomegalovirus (CMV) is a member of the herpesvirus family. Human cytomegalovirus (HCMV) infection is common, with serological evidence of prior infection in 40% to 100% of various adult populations. However, severe HCMV disease occurs almost exclusively in individuals with compromised or immature immune systems. HCMV remains a significant concern for patients undergoing various types of transplants (including hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT)) in connection with effective immunosuppressive chemotherapy. Marabavir is a benzimidazole riboside and an orally administered antiviral drug for CMV. Marabavir is also marketed under the brand name LIVTENCITY. TM Known to the public. Mabavir ((2S,3S,4R,5S)-2-(5,6-dichloro-2-(isopropylamino)-1H-benzo[d]imidazol-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol), a compound having the following chemical structure: This is an effective, orally available antiviral agent used to treat CMV infection and disease in transplant recipients. Transplant recipients are at high risk of CMV infection. The synthesis of mabavir is described in Examples 1, 2 and 5 of US 6,077,832 ('832 patent). This synthesis is depicted in Scheme 1 below, consisting of three chemical transformation steps, with a combined yield of approximately 27%. plan 1 The synthesis described in Scheme 1 first involves coupling 2-bromo-5,6-dichlorobenzimidazole with 1,2,3,5-tetra-O-acetylglucanose. Next, the acetylglucanose group is removed, followed by the placement of isopropylamine to provide mabavir. Notably, the first step also yields the α-mutant isomer in approximately 6% yield. See Example 1 of '832 Patent'. The synthesis of mabavir is also described in Examples 1-4 and 7 of WO 2001 / 077083 ('083 Publication). This synthesis is depicted in Scheme 2 below, consisting of five chemical transformations, with a combined yield of approximately 18-20%. plan 2 The synthesis in Scheme 2 follows a similar route to that provided in Scheme 1 as disclosed in the '832 patent, but replaces some reagents in the first step. In addition, the '083 publication also discloses a two-step process for providing 2-bromo-5,6-dichlorobenzimidazole. US 6,617,315 ('315 patent) discloses an alternative approach: using 1-cyclohexyl-3-(2-morpholinylethyl)carbodiimide methyl p-toluenesulfonate as a desulfurizing agent to synthesize 2-(alkylamino)-1H-benzimidazole; coupling 2-(alkylamino)-1H-benzimidazole with 1,2,3,5-tri-O-acetylglucofuranosyl-ribofuranosyl; and deprotecting 2-(alkylamino)-1-(2,3,5-tri-O-acetylglucofuranosyl-β-L-ribofuranosyl-1H-benzimidazole). See Sections 27-28 of the '315 patent for general procedure I, II, and III. Specifically, the '315 patent discloses the synthesis of the acetyl-protected intermediate in Scheme 3 in Examples 24 and 25: plan 3 The combined yield of these two steps is approximately 49%. It is noteworthy that the '315 patent does not exemplify the deacetylation of 5,6-dichloro-2-(isopropylamino)-1-(2,3,5-tri-O-acetylated-β-L-furanoribosyl)-1H-benzimidazole to provide mabavir. Although the synthesis disclosed in the '315 patent appears to be a significant improvement over the synthesis described in the '832 patent and '083 publication, the yield of mabavir is still expected to be less than 49% (e.g., when assuming a deacetylation yield of 75%, as exemplified in the '832 patent and '083 publication, it is 37%). Therefore, in some embodiments, the present invention encompasses the understanding that the synthesis of mabavir can be modified to increase the overall yield. In some embodiments, mabavir or a pharmaceutically acceptable salt thereof is prepared according to scheme 4 or scheme 5 set forth below: plan 4 plan 5 In some embodiments, this disclosure provides an improved synthesis of mabavir in Scheme 5, wherein the overall yield is at least 45%. It should be understood that certain intermediate compounds (e.g., compound...) 2- 3 or 5- 8) The physical and / or chemical properties of the solvent and / or reagents and reaction conditions may contribute to the overall yield of mabavir and / or help control impurities, especially when scaling up the synthesis. Alternatively or additionally, this disclosure also provides the understanding that mabavir of acceptable quality is important for proper grinding and formulation into tablets. For example, in some embodiments, a specific polymorphic form of mabavir (e.g., form VI as disclosed in US 6,482,939) is required, which is free from other crystalline forms, solvates, or hydrates. In some embodiments, this disclosure provides a method for preparing mabavir in a specific polymorphic form (e.g., form VI as disclosed in US 6,482,939) free from other crystalline forms, solvates, or hydrates. Alternatively or additionally, in some embodiments, a specific size distribution of mabavir is important for tablet manufacturing. In some embodiments, this disclosure provides a method for preparing mabavir with a specific particle size distribution suitable for grinding and formulation into tablets. Alternatively or additionally, in some embodiments, a specific size distribution of mabavir is important for manufacturing oral solid formulations. In some embodiments, this disclosure provides a method for preparing mabavir with a specific particle size distribution suitable for formulation into an oral solid formulation. Alternatively or additionally, in some embodiments, the specific size distribution of mabavir may affect its bioavailability. In some embodiments, this disclosure provides a solid oral formulation comprising a mabavir polymorph VI with a specific particle size distribution (e.g., d(50) between about 50 and about 400 µm). In some embodiments, this disclosure provides a method for crystallizing a mabavir polymorph VI with a specific particle size distribution (e.g., d(50) between about 50 and about 400 µm). Alternatively, this disclosure provides the understanding that when manufacturing pharmaceutical products, it is important to minimize certain impurities. For example, impurity morphologies should be consistent to maintain efficacy consistency and minimize potential side effects. In some embodiments, when the synthesis of a pharmaceutical product consists of multiple steps, it should be understood that impurities formed in earlier steps can be carried over to subsequent steps, forming additional impurities. Therefore, reducing impurities in each step of the mabavir synthesis (e.g., steps 1, 2, or 3) is important for maintaining the consistency of the manufactured pharmaceutical product. Therefore, in some embodiments, this disclosure provides compositions comprising mabavir or a pharmaceutically acceptable salt thereof, and methods for preparing the same. In some embodiments, the provided compositions comprise mabavir and one or more compounds selected from: Or a medically acceptable salt. In some embodiments, the provided composition is prepared according to the methods disclosed herein (e.g., steps 1-3). In some embodiments, the provided composition comprises at least 90%, 95%, 99%, 99.5%, or 99.9% mabavir by weight. In some embodiments, the provided composition comprises mabavir that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the composition or compound does not contain significant amounts of foreign substances. Such foreign substances may include starting materials, residual solvents, or other impurities that may arise from the preparation and / or separation of mabavir. In some embodiments, the provided composition comprises mabavir or a pharmaceutically acceptable salt thereof, and a compound in an amount less than 0.10% (w / w HPLC) relative to mabavir. 2. 3 and / or 4. In some embodiments, the provided composition comprises babavir or a pharmaceutically acceptable salt thereof, and a compound in an amount of less than 0.10% (w / w HPLC) relative to babavir. 2. 3 and / or 4. In some embodiments, the provided composition comprises babavir or a pharmaceutically acceptable salt thereof, and a compound in an amount less than 0.10% (a / a HPLC) relative to babavir. 2. 3 and / or 4. In some embodiments, the provided composition comprises mabavir or a pharmaceutically acceptable salt thereof, and a amount of the compound that is not detectable by HPLC. 2. 3 and / or 4. In some embodiments, the provided composition comprises mabavir in form VI (as described in US 6,482,939). In some embodiments, the provided composition comprises at least 90%, 95%, 99%, 99.5%, or 99.9% mabavir in form VI by weight. In some embodiments, the provided composition comprises mabavir substantially free of other polymorphic forms (e.g., as described in US 6,482,939, US 8,546,344, or US 11,130,777). In some embodiments, the provided composition comprises mabavir having a specific size distribution as defined and described herein. Impurities (e.g., intermediates, mirror-image isomers) can potentially affect the quality of the active pharmaceutical ingredient and the pharmaceutical product and may represent a risk to the safety of the pharmaceutical product. If certain impurities are present in amounts exceeding the defined limits, they may affect patient safety. There are unknown risks regarding the safety of pharmaceutical products with unknown impurities. definition The compounds of this invention include those outlined above, and are further explained by the classes, subclasses and species disclosed herein. Unless otherwise indicated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are identified according to the periodic table (CAS version, Handbook of Chemistry and Physics, 75th edition). Furthermore, the general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th edition, edited by Smith, MB, and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. As used herein, the term "aliphatic" or "aliphatic group" means a fully saturated or branched, substituted or unsubstituted hydrocarbon chain containing one or more unsaturated units (i.e., unbranched) or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocycle / carbocyclic," "cycloaliphatic," or "cycloalkyl") having a single connection point to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "carbocyclic" (or "cycloaliphatic" or "carbocyclic" or "cycloalkyl") refers to a fully saturated or non-aromatic monocyclic C-ring containing one or more unsaturated units. 3-C 8. Hydrocarbons having a single connection point to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, ynyl and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The term "halogen" refers to F, Cl, Br, or I. The term "aryl," used alone or as part of a larger portion of terms such as "aralkyl," "aralkyloxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments of the invention, "aryl" refers to an aromatic ring system and exemplary groups include phenyl, biphenyl, naphthyl, anthracene, and similar groups, which may carry one or more substituents. As used herein, the scope of the term "aryl" also includes groups in which an aromatic ring is fused with one or more non-aromatic rings, such as indanyl, phthalimino, naphthimidyl, phenidyl, or tetrahydronaphthyl and similar groups. The terms "heteroaryl" and "heteroar-", used alone or as part of a larger portion of, for example, "heteroalkyl" or "heteroalkoxy", refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 p electrons shared in a cyclic array; and having one to five heteroatoms in addition to a carbon atom. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternary ammonium form of basic nitrogen. Exemplary heteroaryl groups include thienyl, furanyl, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, indazinyl, purinyl, naphridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroary-" also include groups in which a heteroaryl ring is fused with one or more aryl, cycloaliphatic, or heterocyclic rings, wherein the linking group or dot is located on the heteroaryl ring. Exemplary groups include indolyl, isoindolyl, benzothiopheneyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzolinyl, phthalazinyl, quinazolinyl, quinolinyl, 4- H-quinazinyl, carbazolyl, acridinel, benzylinyl, benzythiazinyl, benzyoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl," or "heteroarylene," each of which includes, where appropriate, a substituted ring. The term "heteroarylalkyl" refers to a heteroaryl-substituted alkyl group, wherein the alkyl and heteroaryl portions are independently substituted, where appropriate. As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic portion that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above, in addition to a carbon atom. When referring to the ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (e.g., 3,4-dihydro-2-oxohydrogen ions). In H-pyrrole, NH (such as in pyrrolidinyl) or + NR (e.g.) (in N-substituted pyrrolidinyl groups). Heterocycles can be attached to their side groups at any heteroatom or carbon atom, resulting in a stable structure, and any ring atom can be substituted as appropriate. Examples of such saturated or partially unsaturated heterocyclic groups include tetrahydrofuranyl, tetrahydrothiophenylpyrrolidyl, piperidinyl, pyrrololinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazine, dioxoalkyl, dioxopentyl, diazapyryl, oxonitrilepyryl, thiopyryl, morpholinyl, and quininecycloyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which the heterocyclyl ring is fused with one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinel, 3... H-indolyl, chromyl, phenidyl, or tetrahydroquinolinyl, wherein the linking group or dot is located on the heterocyclic ring. The heterocyclic group can be monocyclic or bicyclic. The term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl and heterocyclic portions are substituted independently, as appropriate. As described herein, compounds may contain a "substituted" portion, as appropriate. Generally, the term "substituted" (regardless of whether it is preceded by the phrase "as appropriate") means that one or more hydrogen atoms in a specified portion of the compound have been replaced by suitable substituents. "Substituted" applies to one or more hydrogen atoms explicitly or implicitly present in the structure (e.g., It refers to at least ;and It refers to at least , or Unless otherwise indicated, a "substituted" group may have suitable substituents at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure is substituted by more than one substituent selected from the prescribed group. The combinations of substituents contemplated in this disclosure are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" means that a compound remains substantially unchanged when subjected to conditions that allow it to be generated, detected, and, in some embodiments, recovered, purified, and used for one or more of the purposes disclosed herein. The suitable monovalent substituent on the substituted carbon atom of the "substituted" group, as appropriate, is independently a halogen; -(CH 2) 0-4 R°;-(CH 2) 0-4 OR°;-O(CH 2) 0-4 R o -O-(CH 2) 0-4 C(O)OR°;-(CH 2) 0-4 CH(OR°) 2; -(CH 2) 0-4 SR°;-(CH 2) 0-4 Ph, which can be substituted by R°; -(CH 2) 0-4 O(CH 2) 0-1 Ph, which can be substituted by R°; -CH=CHPh, which can be substituted by R°; -(CH 2) 0-4 O(CH 2) 0-1 -pyridyl group, which can be substituted via R°; -NO 2; -CN; -N 3; -(CH 2) 0-4 N(R°) 2; -(CH 2) 0-4 N(R°)C(O)R°; -N(R°)C(S)R°; -(CH 2) 0-4 N(R°)C(O)NR° 2;-N(R°)C(S)NR° 2; -(CH 2) 0-4N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR° 2;-N(R°)N(R°)C(O)OR°;-(CH 2) 0-4 C(O)R°;-C(S)R°;-(CH 2) 0-4 C(O)OR°;-(CH 2) 0-4 C(O)SR°;-(CH 2) 0-4 C(O)OSiR° 3;-(CH 2) 0-4 OC(O)R°;-OC(O)(CH 2) 0-4 SR°、SC(S)SR°;-(CH 2) 0-4 SC(O)R°;-(CH 2) 0-4 C(O)NR° 2;-C(S)NR° 2;-C(S)SR°;-SC(S)SR°、-(CH 2) 0-4 OC(O)NR° 2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH 2C(O)R°;-C(NOR°)R°;-(CH 2) 0-4 SSR°; -(CH 2) 0-4 S(O) 2R°;-(CH 2) 0-4 S(O) 2OR°;-(CH 2) 0-4 OS(O) 2R°;-S(O) 2NR° 2; -(CH 2) 0-4 S(O)R°;-N(R°)S(O) 2NR° 2;-N(R°)S(O) 2R°;-N(OR°)R°;-C(NH)NR° 2; -P(O) 2R°;-P(O)R° 2; -OP(O)R° 2; -OP(O)(OR°) 2; SiR° 3; -(C 1-4 (Straight-chain or branched alkyl) ON(R°) 2; or -(C 1-4 Straight-chain or branched alkyl groups) C(O)ON(R°) 2, where each R° can be substituted and independently formed as defined below, consisting of hydrogen, C 1-6 Aliphatic group, -CH 2Ph、-O(CH 2) 0-1 Ph、-CH 2-(5-6 member heteroaryl ring) or a 5-6 member saturated, partially unsaturated or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur, or, notwithstanding the foregoing definition, two independently occurring R° together with intercalation atoms to form a 3-12 member saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur, which may be substituted as defined below. A suitable monovalent substituent on R° (or by using a ring formed by two independently occurring R° and their intercalation atoms) is independently halogen, -(CH 2) 0-2 R ● -(halogenated R) ● ), -(CH 2) 0-2 OH, -(CH 2) 0-2 OR ● , -(CH 2) 0-2 CH(OR ● ) 2; -O(haloalkylR ● ), -CN, -N 3, -(CH <00: / / github.com / apache / rocketmq / blob / 4.9.4 / docs / cn / api-reference / rest-api.md#%E6%96%B0%E5%A2%9E%E6%89%B9%E7%90%86%E7%9A%84%E6%8E%A5%E5%8F%A3%E6%8C%87%E5%8D%97> 2) 0-2 C(O)R ● , -(CH 2) 0-2 C(O)OH, -(CH 2) 0-2 C(O)OR ● , -(CH

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Claims

1. A pharmaceutical composition comprising mabavir and compound 4:

1. Compound 4 is present in amounts of 0.1% w / w or less relative to mabavir.

2. The composition of claim 1, wherein compound 4 is present in an amount between 0.01% w / w and 0.1% w / w relative to mabavir.

3. The composition of claim 1, wherein compound 4 is present in an amount of 0.05% w / w or less relative to mabavir.

4. The composition of claim 3, wherein compound 4 is present in an amount between 0.01% w / w and 0.05% w / w relative to mabavir.

5. The composition of claim 1, further comprising compound 3:

5. Compound 3 is present in amounts of 0.1% w / w or less relative to mabavir.

6. The composition of claim 2, further comprising compound 3:

6. Compound 3 is present in amounts ranging from 0.01% w / w to 0.1% w / w relative to mabavir.

7. The composition of claim 1, further comprising compound 2:

7. Compound 2 is present in a concentration of 0.1% w / w or less relative to mabavir.

8. The composition of claim 2, further comprising compound 2:

8. Compound 2 is present in amounts ranging from 0.01% w / w to 0.1% w / w relative to mabavir.

9. The composition of claim 6, further comprising compound 2:

9. Compound 2 is present in amounts ranging from 0.01% w / w to 0.1% w / w relative to mabavir.

10. The composition of claim 1, further comprising D-mabavir, wherein D-mabavir is present in an amount of 0.1% w / w or less relative to mabavir.

11. The composition of claim 9 further comprises D-mabavir, wherein D-mabavir is present in an amount of 0.1% w / w or less relative to mabavir.

12. The composition of claim 1, wherein mabavir has a particle size distribution (PSD) between about 170 and about 350 μm d(50).

13. The composition of claim 12, wherein the d(50) is between about 170 and about 226 μm.

14. The composition of claim 12, wherein the d(50) is between about 227 and about 280 μm.

15. The composition of claim 12, wherein the d(50) is between about 281 and about 336 μm.

16. A pharmaceutical composition comprising a composition as claimed in any one of claims 1 to 15 and one or more pharmaceutically acceptable excipients.

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