NZ614009B2 - Methods for synthesizing molybdopterin precursor z derivatives - Google Patents

Methods for synthesizing molybdopterin precursor z derivatives Download PDF

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NZ614009B2
NZ614009B2 NZ614009A NZ61400912A NZ614009B2 NZ 614009 B2 NZ614009 B2 NZ 614009B2 NZ 614009 A NZ614009 A NZ 614009A NZ 61400912 A NZ61400912 A NZ 61400912A NZ 614009 B2 NZ614009 B2 NZ 614009B2
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New Zealand
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formula
compound
prepare
pharmaceutically acceptable
acceptable salt
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NZ614009A
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NZ614009A (en
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Sylvia Myrna Baars
Andreas Brunner
Keith Clinch
Danmei Dai
Rachel Anne Dixon
Cyrille Abel Sebastien Landreau
Gillian Mary Little
Xiangtian Long
Nicolas Georges Rene Proisy
Derek Kevin Watt
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Alexion Pharma International Sarl
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Priority claimed from PCT/US2012/025689 external-priority patent/WO2012112922A1/en
Publication of NZ614009A publication Critical patent/NZ614009A/en
Publication of NZ614009B2 publication Critical patent/NZ614009B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems

Abstract

Provided herein are synthetic methods for preparing a compound of formula (I): Also provided herein are synthetic methods for preparing a compound of formula (XIII): The disclosure also provides useful intermediates, derivatives, prodrugs, and pharmaceutically acceptable salts, solvates and hydrates of the formula (I) and formula (XIII) compounds. These compounds are useful for treating diseases associated with molybdenum cofactor deficiency. of the formula (I) and formula (XIII) compounds. These compounds are useful for treating diseases associated with molybdenum cofactor deficiency.

Description

‘Methods for Synthesizing Molybdopterin sor Z Derivatives CROSS-REFERENCE TO RELATED APPLICATIONS This application claims ty to US Provisional Application Serial Nos. 61/444,399, filed February 18, 2011; 61/498,801, filed June 20, 2011; 61/444,280, filed February 18, 2011; 61/498,808, filed June 20, 2011; and 61/444,389, filed February 18, 2011; and ,314, filed February 15, 2012; all of which are incorporated by nce in their entireties.
TECHNICAL FIELD Provided herein are synthetic methods for preparing the molybdopterin derivative precursor Z and novel synthetic intermediates useful therein. Also provided herein are useful intermediates, derivatives, prodrugs, and pharmaceutically able salts, solvates, and es of precursor Z. These compounds are usefiil for, among other things, treating diseases associated with enum cofactor deficiency.
BACKGROUND Molybdenum cofactor (Moco) deficiency is a pleiotropic genetic disorder. Moco consists of molybdenum covalently bound to one or two dithiolates attached to a unique tricyclic pterin moiety ly referred to as molybdopterin (MPT). Moco is sized by a biosynthetic pathway that can be divided into four steps, according to the biosynthetic intermediates precursor Z (cyclic pyranopterin monophosphate; cPMP), MPT, and adenylated MPT. ons in the Moco thetase genes result in the loss of production of the molybdenum dependent enzymes sulfite—oxidase, xanthine oxidoreductase, and de oxidase. Whereas the activities of all three of these cofactor-containing enzymes are impaired by cofactor deficiency, the devastating consequences of the disease can be traced to the loss of sulfite oxidase activity.
Human Moco deficiency is a rare but severe disorder accompanied by serious neurological symptoms including attenuated growth of the brain, untreatable es, dislocated ocular lenses, and mental retardation. Until recently, no effective therapy was available and afflicted patients suffering from Moco deficiency died in early infancy.
It has been found that administration of the molybdopterin derivative precursor Z, a relatively stable intermediate in the Moco biosynthetic pathway, is an effective means of therapy for human Moco deficiency and associated diseases related to altered Moco synthesis (see US.
Patent No. 7,504,095). As with most replacement therapies for illnesses, however, the treatment is limited by the bility of the therapeutic active agent.
SUMMARY Precursor Z (a compound of formula (I) and (XIII)) has previously been prepared using fermentation processes. These processes, however, have stability issues, low yields, and are rohibitive for large-scale production. The following synthetic processes are proposed as an alternative to these fermentation processes.
Provided herein is a process for preparing a compound of formula (I): O HO OH or a pharmaceutically acceptable salt thereof, the s comprising: reacting a nd of formula (II): R NH 1\N 2 l (11) \ \ T N NH2 wherein each R1 is independently H or at protecting group, with a nd of formula (III): HO 0R1 (III) HO 0 to e a compound of formula (IV): 0 CR1 R1 H OR \ 1 ’ (1V) R1 x 0R1 \N N N o l H selectively protecting the compound of formula (IV) to prepare a compound of formula (V): 0 R1 0R1 1\ N OR1 I (V) R1 \ 0R1 \T N T 0 R1 R1 0 R1 0R1 I 0R1 R1\N N O\on | | (VI) 1\N \N O N 0 FL FL oxidizing the compound of formula (VI) to prepare a compound of formula (VII): 0 R1 HO OH R N 1\N o /OR1 I (VII) 1\Nk \N o N o ; and deprotecting the compound of formula (VII) to prepare the compound of formula (I).
In some embodiments, the pharmaceutically acceptable salt is an HCl salt. In some embodiments, the pharmaceutically able salt is an HBr salt.
In some embodiments, the nd of formula (II) is: H2N N NH2 In some embodiments, the compound of formula (III) is a protected or unprotected galactose, mannose, e, or gulose. For example, a compound of formula (III) can be: In some embodiments, two nt R1 groups come together to form an isopropylidine acetal or benzylidine acetal moiety.
In some embodiments, the reaction between the compounds of formula (II) and (III) comprises reacting the compound of formula (II) and the compound of formula (III) in the presence of a hydrazine. For example, the hydrazine can be selected from the group consisting of hydrazines and alkylhydrazines. In some embodiments, the hydrazine is hydrazine.
In some embodiments, the phosphorylation step comprises reacting the compound of formula (V) with a P(V) phosphorylating agent. For example, a P(V) phosphorylating agent can be ed from the group consisting of: POC13; H3PO4; PO(OBn)XC13_x; Cl3CCH20P(O)C12; and (BnO)2P(O)OP(O)(OBn)2. In some embodiments, the P(V) phosphorylating agent is POC13.
In some embodiments, the phosphorylation step comprises reacting the compound of formula (V) with a P(III) phosphitylating agent. For e, the P(III) phosphitylating agent can be selected from the group consisting of: P(OCHzCHzCN)2Cl; P(OCHZCHZCN)(NPr2-i)Cl; and cyanoethyl—O—P [N(i-Pr)2)]2. In some embodiments, the phosphorylation step r comprises oxidizing the ing phosphite to prepare the phosphate of compound (VI).
In some embodiments, the oxidation step comprises reacting the compound of formula (V1) with an oxidizing agent ed from the group consisting of: RuO4; Dess-Martin; DMSO/triflic anhydride; and PDC.
In some embodiments, the deprotection of the compound of formula (VII) is performed under anaerobic conditions.
Also ed herein is a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, the process comprising: reacting a compound of formula (II-A): k , (II-A) HZN N NH2 with a compound of formula (III-A): HO OH (III-A) HO 0 in the presence of a hydrazine to produce a compound of formula (IV—A): O OH N OH ‘ (IV-A) X OH H2N N P1 0 selectively protecting the compound of formula (IV-A) to prepare a compound of a (V-A): 0 R1 OH N OH | (V-A> \ OH H2N N u 0 wherein R1 is a protecting group; phosphorylating the compound of formula (V—A) to prepare a compound of formula (VI—A): 0 R1 OH N o /OH HN \P=O I | (VI-A) \ o HZN N N o ing the nd of formula (VI-A) to prepare a nd of formula (VII-A): 0 R1 HO OH N o /OH HN \P:O l | (VII-A) \ o H2N N u o ; and deprotecting the compound of formula (VII-A) to prepare the compound of formula (I).
Further provided herein is a process for preparing a compound of formula (I), or a pharrnaceutically acceptable salt f, the process comprising: reacting a compound of formula (II-A) with a compound of formula (III-A) in the presence of a hydrazine to produce a compound of formula (IV-A); selectively protecting the compound of formula (IV-A) to prepare a nd of formula (V-B): 0 R1 OH N OH l (VB) R1 /|\\ OH \Q N N 0 wherein each R1 is ndently a protecting group; phosphorylating the compound of formula '5 (V—B) to prepare a compound of formula (VI—B): 0 R1 OH I 0R1 N o \T/=o ‘ (VI-B) R o 1\” \N T 0 oxidizing the compound of formula (VI-B) to prepare a compound of formula (VII-B): C)\P_._—_—'O | (VII-B) R1\N 0 ; and deprotecting the compound of formula (VII—B) to prepare the nd of formula (I).
Also ed herein is a process for preparing a compound of formula (I), or a pharmaceutically able salt thereof, comprising: reacting a compound of formula (II) with a compound of formula (VIII): HO 0 \P=O I (VIII) HO 0 wherein each R1 and R2 are independently H or a protecting group; to produce a compound of formula (IX): 0 CR1 R1 N o /OR2 \N \P=O i (IX) R k ('3 1 \N N N o I H R1 selectively protecting the compound of formula (IX) to prepare a compound of formula (X): . R3 0R1 | OR? R1\N N O\P/—O R \ r 1 \T .
N T 0 R1 R4 wherein R3 is a protecting group and R4 is H or a protecting group; oxidizing the nd of a (X) to prepare a compound of formula (XI): 0 R3 HO OH R1 N o /OR2 \N \on R l 1\T \ N T ° R1 R4 ;and deprotecting the compound of formula (XI) to prepare the compound of formula (1).
Further provided herein is a process for preparing a compound of a (I), or a pharmaceutically acceptable salt f, the process comprising reacting a compound of formula (H) with a compound of formula (III) to produce a compound of formula (IV); selectively protecting the compound of formula (IV) to prepare a compound of formula (V); oxidizing the compound of formula (V) to prepare a compound of formula (XII): R N OR 1\ 1 | (XII) \T \ 0R1 N T 0 R1 R1 phosphorylating the nd of formula (XII) to prepare a compound of formula (VII); and deprotecting the compound of formula (VII) to prepare the compound of formula (I).
This sure also provides a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, the process comprising: reacting a compound of formula (II) with a compound of formula : HO 0R1 (XXII) PhHNN HO wherein each R1 is independently H or a protecting group, to e a nd of formula (IV); selectively protecting the compound of formula (IV) to prepare a compound of a (V); phosphorylating the nd of formula (V) to prepare a compound of formula (VI); oxidizing the compound of formula (VI) to prepare a compound of formula (VII) ; and deprotecting the compound of formula (VII) to prepare the compound of formula (I).
In some embodiments, the compound of formula (II) is: H2N N NH2 In some embodiments, the compound of formula (XXII) is: HO/l’ln, 0R1 / 0R1 PhHNN HO In some embodiments, the phosphorylation step comprises reacting the compound of formula (V) with a P(V) phosphorylating agent. For example, a P(V) phosphorylating agent can be selected from the group consisting of: POClg; H3PO4; PO(OBn)xC13_x; C13CCHZOP(O)C12; and (BnO)2P(O)OP(O)(OBn)2. In some embodiments, the P(V) orylating agent is C12PO(OCH3).
In some embodiments, the oxidation step comprises reacting the compound of formula (V1) with an oxidizing agent selected from the group consisting of: RuO4; Dess—Martin; DMSO/triflic anhydride; DMSO/TFAA; and PDC.
In some embodiments, the deprotection of the compound of formula (VII) is med under anaerobic ions.
Further provided herein is a s for preparing a compound of formula (I), or a pharmaceutically able salt thereof, the process comprising: reacting a compound of formula (II-A): /i\ \ (II-A) H2N N NH2 with a compound of formula (XXII-A): HO OH PhHNN/ OH in the presence of a base to produce a compound of a (IV-A): ZI OH kl (IV—A) H2N N 3:2 0 selectively protecting the compound of formula (IV-A) to prepare a compound of formula (V-C): 0 CR1 R N OR 1\ 1 | (V—C) R1 \ 0R1 \T N T o .
R1 R1 wherein each R1 is ndently H or a protecting group, phosphorylating the compound of a (V-C) to prepare a compound of formula (VI-C): 0 CR1 R H 0 I 1\ \ /OR1 N P:O t | ' (VI-C) R O 1\Nk\N N 0 FL l, oxidizing the compound of formula (VI-C) to prepare a compound of a (VII-C): 0 HO OH R N o / 1\N \ ‘ | (VII-C) R o 1\N \N N 0 i1 FL ; and deprotecting the compound of formula (VII-C) to prepare the compound of formula (I).
This disclosure also provides a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, the process comprising: reacting a compound of formula ): R4) 0R1 (XXIII) o o wherein each R1 is independently H or a protecting group and R4 is H or a leaving group; to produce a nd of formula (XXIV): o 0 (xxno « u reacting a compound of formula (XXIV) with a compound of formula (II) to produce a compound of formula (XXV): R1 0R1 R1 \ H 0R1 N // (XXV) NH2 0R1 O O catalyzing ring formation of the compound of formula (XXV) to produce a compound of formula (IV); selectively protecting the compound of formula (IV) to prepare a compound of formula (V); orylating the compound of formula (V) to prepare a compound of formula (VI); oxidizing the compound of a (VI) to e a compound of formula (VII); and deprotecting the compound of formula (VII) to e the compound of formula (I).
In some embodiments, the nd of formula (XXIII) is selected from the group consisting of: HO OH O O K and HO O O O In some embodiments, the compound of formula (XXIV) can be: O O In some embodiments, the compound of a (XXV) is: N OBn N / O NH2 0 o In some embodiments, the phosphorylation step comprises reacting the compound of formula (V) with a P(V) phosphorylating agent. For example, a P(V) phosphorylating agent can be selected from the group consisting of: POC13; H3PO4; PO(OBn)xC13-X; ClgCCH20P(O)Clz; and (BnO)2P(O)OP(O)(OBn)2. In some embodiments, the P(V) phosphorylating agent is C12PO(OCH3).
In some ments, the oxidation step comprises reacting the compound of formula (V1) with an oxidizing agent selected from the group consisting of: RuO4; Dess-Martin; DMSO/triflic anhydride; DMSO/TFAA; and PDC.
In some embodiments, the deprotection of the compound of formula (VII) is performed under anaerobic ions.
In some embodiments, the compound of formula ) is: R10 0R1 0 o In some embodiments, the compound of formula (XXIV) is: (CI/0R10R1.
H) O In some embodiments, the compound formula (XXV) is: R\1 0R1 R1/N\( \ \ H OR N / 1 NH2 OR1 OH O In some embodiments, a leaving group is selected from the group ting of: tosylates, brosylates, nosylates, mesylates, oxoniums, triflates, nonaflates, and tresylates.
Also provided herein is a process for preparing a compound of formula (I), or a pharmaceutically able salt thereof, the process comprising: reacting a compound of formula (XXIII-A): Ho 0R1 (XXIII-A) O O K ; wherein: each R1 is independently H or a protecting group, and R4 is H or a leaving group, to produce a compound of formula (XXIV): o 0 (XXIV) K ; reacting a compound of a (XXIV) with a compound of formula : l (II-A) HZN N NH2 to produce a compound of formula (XXV-A): H2N\( \ OH \ H (XXV-A) NH2 OR1 0 O W ; WO 12922 catalyzing ring formation of the compound of formula (XXV-A) to produce a compound of formula (IV-D): 0R1 OH H OR1 x 1 (IV—D) H2N N m o selectively protecting the compound of formula (IV-D) to prepare a compound of formula (V-D): 0R1 0R1 iiKi 0R1 R1 151; W0R1 \T \N T 0 R1 R1 ; phosphorylating the compound of formula (V-D) to e a compound of formula (VI-D): 0R1 0R1 N/ \on l | I R o 1\T \N T 0 R1 R1 ing the compound of formula (VI-D) to prepare a compound of formula (VII-D): 0R1 HO OH H 0 /OR1 N/ \on X 1 | (VII-D) R1 \ O \T N T 0 R1 R1 ;and deprotecting the compound of a (VII—D) to prepare the compound of formula (I).
WO 12922 This disclosure also provides a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, the process comprising: oxidizing the compound of formula (VI) to e a compound of formula (VII); and deprotecting the compound of formula (VII) to prepare the compound of formula (I).
In some embodiments, a nd of formula (I), or a pharmaceutically acceptable salt thereof, can be prepared by phosphorylating the compound of formula (V) to prepare a compound of formula (VI); oxidizing the compound of formula (VI) to prepare a nd of formula (VII); and deprotecting the compound of formula (VII) to prepare the nd of formula (I).
Also provided herein is a process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, the process comprising: selectively protecting the compound of formula (IV) to prepare a nd of formula (V); phosphorylating the compound of formula (V) to prepare a compound of formula (VI); ing the compound of formula (VI) to prepare a compound of formula (VII); and deprotecting the compound of formula (VII) to e the compound of formula (I).
In some embodiments, the processes described above further comprise formulating the compound of formula (I) as a pharmaceutical composition.
Further provided herein is a compound of formula (I), or a pharmaceutically able salt thereof, prepared by any of the processes bed above. In some embodiments, a pharmaceutical composition is provided comprising a compound of formula (I), or a phannaceutically acceptable salt thereof, prepared by any of the processes described above and a pharmaceutically acceptable excipient.
This disclosure also provides a process for preparing a compound of formula (XIII): O O H2N N N O I - Illlluu or a pharrnaceutically acceptable salt form thereof, the s comprising: reacting a nd of formula (II): R1\N R1\NliN‘ wherein each R1 is independently H or a protecting group, with a compound of formula (III): HO 0R1 (111) HO 0 to produce a compound of formula (IV): 0 CR1 R H OR 1\ 1 | (IV) R1 k OR1 \N N N o I H selectively protecting the compound of formula (IV) to prepare a compound of formula (V): R1\N R1\T R1 R1 3 phosphorylating the compound of a (V) to prepare a nd of formula (VI): 0 R1 0R1 | . 0R1 R1\ N o\ / N P=o A l I R o 1\N \N N 0 FL FL oxidizing the compound of formula (VI) to prepare a compound of a (XIV): 0 R1 0 )il IUI/ /OR1 R1\ N o\ N P=o l | (XIV) R \ O 1\T N T 0 R1 R1 ; and (e) deprotecting the compound of formula (XIV) to e the compound of formula (XIII).
Also provided herein is a process for preparing a compound of formula (XIII), or a pharmaceutically acceptable salt thereof, the process comprising: reacting a compound of formula (II) with a compound of formula : HO 0\P/é-ORZ I (VIII) HO 0 wherein each R1 and R2 is H or a protecting group, to produce a compound of formula (IX): 0 CR1 R1 N O /OR2 l \T20 0X) R1\ \ O N N N O I H selectively protecting the nd of formula (IX) to prepare a compound of formula (X): 0 R3 0R1 R1\N O\P/(:20 l (X) \ (l) N N N 0 FL l4 wherein R3 is a protecting group and R4 is H or a protecting group; oxidizing the compound of formula (X) to prepare a nd of formula (XV): 0 R3 0 R1 N o \ \ /0R2 N P=O R I 1 \ \T N T 0 R1 R4 ; and deprotecting the compound of formula (XV) to prepare the compound of formula (XIII).
Further provided herein is a process for preparing a compound of formula (XIII), or a pharmaceutically acceptable salt f, the process comprising: reacting a compound of formula (II) with a nd of a (III) to produce a compound of formula (IV); selectively protecting the compound of formula (IV) to prepare a compound of formula (V); phosphorylating the compound of formula (V) to prepare a nd of formula (VI); oxidizing the compound of formula (VI) to prepare a compound of formula (XIV); and deprotecting the compound of formula (XIV) to prepare the compound of formula .
This disclosure also provides a process for ing a compound of formula (XIII), or a pharmaceutically acceptable salt form thereof, the s comprising: oxidizing the compound of formula (VI) to prepare a compound of formula (XIV); and deprotecting the compound of formula (XIV) to prepare the compound of formula .
In some ments, a compound of formula (XIII), or a pharmaceutically acceptable salt thereof, is prepared phosphorylating the compound of formula (V) to prepare a nd of formula (VI); oxidizing the compound of formula (VI) to prepare a compound of formula (XIV); and deprotecting the compound of formula (XIV) to e the compound of formula (XIII).
(Also provided herein is a process for preparing a compound of formula (XIII), or a pharmaceutically able salt form thereof, the process comprising: selectively protecting the compound of formula (IV) to prepare a compound of formula (V); phosphorylating the compound of formula (V) to prepare a compound of a (VI); oxidizing the compound of formula (VI) to prepare a compound of formula (XIV); and deprotecting the compound of formula (XIV) to prepare the compound of a (XIII).
This disclosure also provides a process for preparing a compound of a , or a pharmaceutically acceptable salt f, the process comprising: reacting a compound of formula (II) with a nd of formula (XXII) to produce a compound of a (IV); selectively ting the compound of a (IV) to prepare a compound of formula (V); phosphorylating the compound of formula (V) to prepare a compound of formula (VI); oxidizing the compound of formula (VI) to prepare a nd of formula (XIV); and deprotecting the compound of a (XIV) to prepare the compound of formula (XIII).
Also provided herein is a process for preparing a compound of formula (XIII), or a pharmaceutically acceptable salt thereof, the process comprising: ng a compound of formula (XXIII) to produce a compound of formula (XXIV); reacting a compound of formula (XXIV) with a compound of formula (II) to produce a compound of formula (XXV); catalyzing ring formation of the compound of formula (XXV) to produce a nd of formula (IV); selectively protecting the compound of formula (IV) to prepare a compound of formula (V); phosphorylating the compound of formula (V) to prepare a compound of formula (VI); oxidizing the compound of formula (VI) to prepare a compound of formula (XIV); and deprotecting the compound of formula (XIV) to prepare the nd of a (XIII).
In some embodiments, the processes described above further comprise formulating the compound of formula (XIII) as a pharmaceutical composition.
Further provided herein is a compound of formula (XIII) prepared by any of the processes described above. In some embodiments, a pharmaceutical composition is provided comprising a compound of formula (XIII), or a pharmaceutically acceptable salt thereof, ed by any of the processes described above and a pharmaceutically acceptable excipient.
This disclosure also provides a compound of formula (IV): WO 12922 O 0R1 R H OR 1\ 1 I (IV) R1 k 0R1 \T N n 0 or a pharmaceutically acceptable salt form thereof, wherein each R1 is independently H or a protecting group. For example, a compound of formula (IV) can be: 0 OH ZI OH HZN N 12 or a pharmaceutically acceptable salt form thereof. In some embodiments, the compound of formula (IV) is: 0 CR1 0 R1 0R1 R N OR 1\ 1 l (V) R1 \ 0R1 \T N T 0 R1 R1 WO 12922 or a pharmaceutically acceptable salt form thereof, wherein each R1 is independently H or a protecting group. For example, a compound of formula (V) can be selected from the group consisting of: 0 R1 OH N OH k l OH HZN N n o 0 R1 OH N OH /i\ ‘ H2N N T 0 O OR1 R N OR R1 \ 0R1 \T N T 0 R1 R1 or a pharmaceutically acceptable salt form f. In some embodiments, a compound of formula (V) is selected from the group consisting of: WO 12922 0800 0800 N 0800 Boc\W\ OBoc ,lq O Boc Boc O 0800 Boc\N N OBoc BocWAN\ 0800 v 0 Boc Boc O 0800 N 0800 Boc 1\ 0800 \N N N o Boc Boc OBoc 0800 N 0800 k I 0800 HN N N O Boc Boc O 0800 Boc N 0800 x 0300 HN N N O 1,111“ OBoc or a pharmaceutically ableBsalt thereof. In some embodiments, the compound of formula (V) is: 0 R1 0R1 | 0R1 R N o ‘ ' \T/zo (W) R o 1\T \N T 0 R1 R1 or a pharmaceutically acceptable salt form thereof, wherein each R1 is independently H or a protecting group. For example, a compound of a (VI) can be selected from the group consisting of: 0 R1 OH N o /OH k I \Tzo HZN N u o 0 R1 OH N o /OR1 | \Tzo' x O HZN N T 0 o 0R1 R1 x O \T N T 0 R1 R1 or a pharmaceutically acceptable salt form thereof. In some ments, a compound of formula (VI) is selected from the group consisting of: O OH Boc H O \ \ /O N » P:0 HN N N 0 La lot 0300 OH H 0 \ /° N / P:0 HN N N O loo loo O OH N O ! Ci) Boc\ k N N N O Boo Boo or a pharmaceutically acceptable salt f. In some embodiments, the compound formula (VI) is: 0 R1 0R1 R , R1 \ Provided herein is a compound of formula (VII): 0 T1 HO OH R1\N N N \N N 0 FL FL H or a or a pharmaceutically acceptable salt form thereof, wherein each R1 is independently protecting group. For example, a compound of a (VII) is selected from the group consisting of: O T1 HO OH /i\ } H2N N N o 0 R1 HO OH or a pharmaceutically able salt form thereof. In some embodiments, a compound of formula (VII) is selected from the group consisting of: Boc\N N O\P/=O k l i HN N N 0 ice loo . \Tzo Boc \ O \T N T 0 B00 Boc OBOC HO OH \ N o / . \TZO Boc \ O \T N 0 ‘ T Boc 800 or a pharmaceutically acceptable salt form thereof. In some ments, the compound of formula (VII) is: R1\N R1\N \N This disclosure also provides a process of preparing a compound of formula (XXIV): o o 2012/025689 or a pharmaceutically acceptable salt thereof, wherein each R1 is H or a protecting group, method comprising: reacting a compound of formula (XXIII): R10 0R1 (XXIII) o o wherein R1 is H or a protecting group and R4 is H or a leaving group, with a base to prepare a compound of formula (XXIV).
DESCRIPTION OF DRAWINGS shows bar graphs illustrating the in vitro sis of Moco using both synthetic and purified from a fermentation process. precursor Z (cPMP) and sor Z (cPMP) prepared provides the data from three repetitions of in vitro synthesis of MPT from synthetic precursor Z (cPMP). provides the data from three repetitions of in vitro sis of MPT from fermentation process using E. coli. precursor Z (cPMP) prepared and purified from a DETAILED DESCRIPTION It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in ation in a single embodiment. Conversely, various features of the sure which are, for brevity, described in the context of a single ment, can also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications cited herein are incorporated by reference in their ty. In the event that there is a plurality of ions for terms cited herein, those in this section prevail unless otherwise stated.
For the terms “for example” and “such as,” and grammatical equivalences thereof, the phrase “and without limitation” is tood to follow unless explicitly stated otherwise. As used , the term ” is meant to account for variations due to experimental error. All measurements reported herein are understood to be modified by the term “about”, Whether or not the term is explicitly used, unless explicitly stated otherwise. As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
The term “salt” includes any ionic form of a compound and one or more counter-ionic species (cations and/or anions). Salts also include zwitterionic compounds (i.e., a molecule containing one more cationic and anionic species, e. g., zwitterionic amino acids). Counter ions present in a salt can e any cationic, anionic, or zwitterionic species. Exemplary anions include, but are not limited to: chloride, bromide, iodide, nitrate, sulfate, bisulfate, sulfite, bisulfite, ate, acid phosphate, perchlorate, chlorate, chlorite, hypochlorite, periodate, iodate, iodite, hypoiodite, ate, onate, isonicotinate, acetate, trichloroacetate, trifluoroacetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, gluearonate, saccharate, formate, benzoate, glutamate, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, uoromethylbenzenesulfonate, hydroxide, aluminates, and borates.
Exemplary cations e, but are not limited to: monovalent alkali metal cations, such as lithium, sodium, potassium, and cesium, and divalent alkaline earth metals, such as beryllium, magnesium, calcium, strontium, and barium. Also included are transition metal cations, such as gold, silver, copper and zinc, as well as non-metal cations, such as um salts, The term ug,” as used herein, refers to a compound which, upon stration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield, e.g., the compounds described herein, and/or a salt and/or e thereof. The term “prodiugs” can include esters and carbonates formed, for example, by reacting one or more yl groups of the compounds described herein with alkyl, alkoxy, or aryl substituted acylating agents employing procedures known to those skilled in the art to generate, e. g., the corresponding acetates, pivalates, carbonates, and benzoates. For example, nds containing a carboxy group can form physiologically hydrolyzable esters which serve as prodrugs by being yzed in the body to yield the compounds provided herein. Such prodrugs can be administered orally since hydrolysis in many instances occurs under the influence of the 2012/025689 digestive enzymes. eral administration may also be used, 6. g., in situations where hydrolysis occurs in the blood.
The term “solvate” is used herein to describe a molecular complex comprising a compound provided herein and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term te” is employed when the t is water. Typical procedures for making and identifying es and solvates are described on pages 9 of K.J. Guillory, “Generation of Polymorphs, Hydrates, Solvates, and ous Solids,” in: Polymorphism in Pharmaceutical Solids, ed. Harry G. Brittan, Vol. 95, Marcel Dekker, Inc., New York, 1999, which is incorporated by reference herein in its entirety.
As used herein, chemical structures which contain one or more stereocenters ed with dashed and bold bonds (i.e., Illlll I) are meant to indicate absolute stereochemistry of the stereocenter(s) present in the chemical structure. As used , bonds symbolized by a simple line do not indicate a stereo-preference. Unless otherwise ted to the contrary, chemical absolute structures, which include one or more stereocenters, rated herein without indicating of the compound (e.g., or relative stereochemistry encompass all possible stereoisomeric forms diastereomers, enantiomers) and mixtures thereof. Structures with a single bold or dashed line, and at least one additional simple line, encompass a single enantiomeric series of all possible diastereomers.
Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An examplary method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving such as the agents for fractional recrystallization methods are, for example, optically active acids, D and L forms of tartaric acid, diacetyltartaric acid, oyltartaric acid, mandelic acid, malic acid, lactic acid, or the various optically active camphorsulfonic acids such as camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of methylbenzylamine (e. g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
WO 12922 Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e. g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one d in the art.
Compounds provided herein can also include all isotopes of atoms occurring in the intermediates or final compounds. es include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include hydrogen, tritium, and deuterium.
The term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless ise specified.
All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g, es and solvates).
In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the nment in which it was formed or detected. Partial separation can e, for example, a composition enriched in the compounds provided herein.
Substantial separation can include compositions ning at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds provided herein, or salt thereof.
Methods for isolating compounds and their salts are routine in the art.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive ty, irritation, allergic response, or other m or cation, commensurate with a reasonable benefit/risk ratio.
The expressions, “ambient temperature” and “room temperature,” as used , are understood in the art, and refer generally to a temperature, e. g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.
Also provided herein are pharmaceutically able salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts e, but are not limited to, l or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as ylic acids; and the like. The pharmaceutically acceptable salts of the nds provided herein include the conventional non—toxic salts of the parent nd formed, for example, from non—toxic inorganic or organic acids. The pharmaceutically acceptable salts of the compounds provided herein can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts with a stoichiometric can be prepared by reacting the free acid or base forms of these nds amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of alcohols (e.g, two; in some embodiments, a non-aqueous media like ether, ethyl acetate, methanol, ethanol, iso-propanol, or butanol) or itrile (ACN) can be used. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing y, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical e, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. Conventional methods for preparing salt forms are described, for example, in Handbook ofPharmaceutical Salts: ties, Selection, Use, Wiley—VCH, 2002.
Synthesis The compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous le synthetic routes.
The reactions for preparing the compounds provided herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or ts at the temperatures at which the reactions are carried out, e. g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling of more than one temperature. A given reaction can be carried out in one solvent or a mixture 2012/025689 solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.
Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be y determined by one skilled in the art.
The chemistry of protecting groups can be found, for example, in Protecting Group Chemistry, 1St Ed, Oxford University Press, 2000; s ed c Chemistry: Reactions, Mechanisms, and Structure, 5th Ed., Wiley—Interscience Publication, 2001 ; and Peturssion, S. et al., “Protecting Groups in Carbohydrate Chemistry,” J Chem. Educ, 74(11), 1297 (1997) (each of which is incorporated herein by reference in its ty).
Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic 13 C), infrared resonance oscopy (e. g., 1H or spectroscopy, spectrophotometry (e. g., UV— e), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid tography—mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by those skilled in the art by a variety of methods, including high mance liquid chromatography (HPLC) (“Preparative LC—MS Purification: Improved Compound Specific Method Optimization” K.F. Blom, et al., 1 Combi.
Chem. 6(6), 874 (2004), which is incorporated herein by reference in its entirety) and normal phase silica chromatography.
The compound of formula (I), and other useful compounds and intermediates, can be formed as shown in Scheme 1. For e, a diaminopyrimidinone compound of formula (II) to give a compound can be reacted with a protected or unprotected hexose sugar of a (III) of formula (IV). The ring nitrogen atoms of the piperizine ring of formula (IV) can then be selectively protected using standard conditions to give a tive of formula (V).
Phosphorylation of the compound of formula (V) can h a phosphate intermediate of formula (VI). The phosphate of formula (VI) can be converted to a diol of formula (VII) under appropriate oxidation conditions. Finally, the compound of a (VII) can be deprotected to give the compound of formula (I).
Scheme 1 O o 0R1 . . .
. . H R1NH2 Rlngformatlon R1 N 0R1 Piperlzme \N HO 0R1 (e,g.,WIth hydrazrne). ‘ \N ring protection ———-> ———-—————> R1\N|iflni OR1 R1\NkNI 0R1 HO 0 N R1 (111) R1 (1V) R1: HOI’ protecting group 0 I 0R1 R1\N N OR‘ Phosphorylation RN1\ \/=‘——P I O R1 k \T N N o OR1R1\N R1 l R1 Ii1 (V) (VI) 0 1 HO OH 0 R1 N o f” \N \P=O Deprotection HN i I —+ i R1 \ O ——> \T N N o HZN \N R1 I (VII) Compounds of formula (112: In some ments, the preparation of compounds of formula (II) is contemplated: R1\N (11) \TFL wherein each R1 is ndently H or a protecting group.
Formula (II) can include, for example, the nd 2,5,6—triaminopyrimidin—4(3H)—one: H2N N NH2 2,5,6-triaminopyrimidin—4(3H)—one and salts and derivatives thereof. In some embodiments, a nd of formula (II) can be in the form of a hydrochloride salt: /]\ l 2HCI H2N N NH2 As indicated, certain functional groups of the formula (11) structure (e. g. , the amino group, the 2—position of the pyrimidine ring, and the ring nitrogen atom at the tion) may protected with an R1 protecting group. For this purpose, R1 may e any suitable amino protecting groups, including, but not limited to, carbamate, amide, N—alkyl, or N—aryl-derived protecting groups. The R1 protecting groups may be the same or different.
In particular, the carbamate protecting group may include, for example, 9- fluorenylmethyl ate (Fmoc), t—butyl carbamate (Boo), carboxybenzyl ate (cbz), methyl carbamate, ethyl carbamate, 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluorenylmethyl carbamate, l7-tetrabenzo[a,c,g,i]fluorenylmethyl carbamate (bemoc), 2-chloro-3—indenylmethyl carbamate (Climoc), 2,7-di—t—butyl[9-(10,lO-dioxo-l0,10,10,10- tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 1,1-dioxobenzo[b]thiophene-2—ylmethyl carbamate (Bsmoc), trichloroethyl carbamate (Troc), ethylsilylethyl carbamate (Teoc), ylethyl carbamate (hZ), 1,1-dimethylhaloethyl carbamate, 1,1-dimethyl—2,2- dibromoethyl carbamate (DB-t—boc), 1,1—dimethyl-2,2,2-trichloroethy1 carbamate (TCBoc), l— methyl-1 phenylyl)ethyl carbamate (Bpoc), 1 -(3 ,5 -di-t—butylphenyl)—1 -methylethy1 carbamate (t—Bumeoc), N—2-pivaloylarnino)-1,l-dimethylethyl carbamate, 2—[(2- nitrophenyl)dithio]—1—phenylethyl carbamate (NpSSPeoc), 2—(N,N— dicyclohexylcarboxamido)ethyl ate, l-adamantyl carbamate (l-Adoc), Vinyl ate (Voc), 1-isopropylallyl carbamate ), 4-nitrocinnamyl carbamate (Noc), 3—(3’pyridyl)prop- 2-enyl carbamate (Paloc), 8-quinoly1 carbamate, alkyldithio carbamate, p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate (Pnz), p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlor0benzyl carbarnate, 4—methylsulfinylbenzyl carbamate (Msz), diphenylmethyl carbamate, 2-methylthioethyl carbamate, ylsulfonylethyl carbamate, 2-(p- toluenesulfonyl)ethyl carbamate, [2—(1,3-dithianyl)]methyl carbamate (Dmoc), 4— methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2— phosphonoethyl carbamate (Peoc), 1,l—dimethylcyanoethyl carbamate, 2-(4-nitrophenyl)ethyl carbamate, 4-phenylacetoxybenzy1 carbamate (PhAcOZ), and m—chloro-p-acyloxybenzyl ate. In some embodiments, the carbamate protecting group is chosen from 9— fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (Boc), and ybenzyl carbamate (cbz). 2O The amide protecting group may e, for example, acetamide, phenylacetamide, 3— phenylpropanamide, pentenamide, picolinamide, 3—pyridylcarboxamide, benzamide, p- phenylbenzamide, 2-methyl—2-(o-phenylazophenoxy)propanamide), 4-chlorobutanamide, acetoacetamide, 3~(p—hydroxyphenyl)propanamide), and (N’- dithiobenzyloxycarbonylamino)acetamide.
Compounds of formula (II) can be prepared using known methods, such as those described by Sharma et al., Indian l istry, Section B: Organic Chemistry Including Medicinal Chemistry, 43B, 385 (2004). For example, the 2,5,6-triaminoprimidin— 4(3H)-one is prepared as shown in Scheme 2.
Scheme 2 1. Na, EtOH 0 2. Reflux NH NH2 )L 3. H2804, HNOg, H20 HN 4. HCI, Sn l EtO HZN NH2 ——*“—*—> )x HZN N NH2 triaminopyrimidln-4(3H)-one Compounds of formula (II) can also include the tautomeric structure: R1 x \T N NH2 or a salt thereof.
Compounds of formula (III): Another embodiment of this disclosure provides the ation of compounds of formula (III): HO 0R1 (111) HO 0 wherein each R1 is independently H or a protecting group.
Formula (111) can include, for example, protected or unprotected hexose sugars. For example, a hexose sugar of formula (111) can include e, mannose, galactose, , altrose, gulose, idose, talose, and derivatives thereof. The hexoses can be in D or L form. For example, the following hexoses are included Within the scope of formula (III): 2012/025689 O OH O OH H0/1)” HOm ”1/,l HO\\\\\\\‘ [/0H HO\\\\\\“ OH OI 011m...I Allose Altrose Glucose Mannose O OH O OH O OH HO/Ij—H HO/II HO HO "”’OH HO OH HO OH 5H 5H OH OH Gulose ldose Galactose Talose In some embodiments, the hexose is a protected or unprotected e or galactose. For example, the compound of formula (III) can be a protected or unprotected galactose (e. g., D— galactose). In some embodiments, the hexose is a protected or unprotected gulose or galactose.
As indicated, the compound of formula (111) may be in the form of a free sugar (2'. e., an ected monosaccharide). Alternatively, certain yl groups of the formula (III) structure (e.g, the yl groups at the 3, 4, and 5—positions of the hexose) may be ted with an R1 protecting group. For this e, R1 may include any suitable hydroxyl functional sulfonate protecting groups. The group including, but not limited to, ether, ester, carbonate, or R1 protecting groups may be the same or different.
In particular, the ether protecting group may include methyl, methoxy methyl (MOM), benzyloxymethyl (BOM), methoxyethoxymethyl (MEM), 2-(trimethy1si1y1)ethoxymethy1 (SEM), methylthiomethyl (MTM), phenylthiomethyl (PTM), azidomethyl, cyanomethyl, 2,2- dichloro-l,1-difluoroethyl, 2-chloroethy1, 2-bromoethy1, tetrahydropyranyl (THP), l-ethoxyethyl (BE), phenacyl, ophenacy1, cyclopropylmethyl, allyl, propargyl, isopropyl, cyclohexyl, t— butyl, benzyl, 2,6—dimethylbenzyl, 4-methoxybenzy1 (MPM-OAr), o-nitrobenzyl, 2,6- dichlorobenzyl, 3,4—dichlor0benzyl, 4-(dimethylamino)carbonylbenzyl, 4-methylsulfiny1benzyl , 9-anthry1methyl, 4-picoly1, heptafluoro—p-tolyl, tetrafluoro—4—pyridy1,trimethylsilyl (TMS), t—butyldimethylsilyl (TBDMS), t—butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS) protecting groups.
The ester protecting group may include acetoxy (OAc), aryl formate, aryl acetate, aryl levulinate, aryl pivaloate, aryl benzoate, and aryl 9—fluoroenecarboxylate. In one ment, the ester protecting group is an y group.
The carbonate protecting group may include aryl methyl carbonate, 1-adamantyl carbonate (Adoc-OAr), t-butyl carbonate (BOC-OAr), ylsulfinylbenzyl carbonate (Msz- OAr), 2,4-dimethylpent—3—yl carbonate (Doc-OAr), aryl 2,2,2-trichloroethyl ate, aryl Vinyl carbonate, aryl benzyl carbonate, and aryl carbonate.
The sulfonate protecting groups may e aryl methanesulfonate, aryl toluenesulfonate, and aryl 2—formylbenzenesulfonate.
In some embodiments, the R1 protecting group is t-butyl carbamate (Boc).
In some ments, two adjacent R1 groups come together to form an isopropylidine acetal, benzylidine acetal, l,5-dioxaspiro[5.5]undecane (cyclohexylidene acetal), 6,10— dioxaspiro[4.5]decane (cyclopentylidene acetal), or 2-isobutylmethyl-1,3-dioxane moiety.
For example, the R1 groups at the 4- and 5-positions of the hexose sugar can combine to form one or more of the following protected hexoses: OH OH HO Owe HO 0 Ph O O HO O HO O OH OH HO O HO O O O HO O HO O HO O HO 0 nds of formula (III) may be prepared according to known methods of carbohydrate synthesis. Methods of protecting carbohydrates are also known, as described in The Organic Chemistry rs, Taylor & Francis, 2006, p. 181; and Peturssion, S. et al., J.
Chem. Educ, 74(11), 1297 (1997), each of which is incorporated herein by reference in its entirety.
As will be recognized by persons of ordinary skill in the art, and as discussed, infia, the stereochemistry of the formula (III) structure may govern the stereochemistry of uent intermediates in the synthesis of formula (I) or formula (XIII). er, protection of certain hydroxyl groups can improve solubility of the formula (III) compounds and modulate stereospecificity of successive reaction steps.
Com oundso ormula IV: Another embodiment provided herein relates to the preparation of compounds of formula (IV): 0 CR1 R H OR 1\ 1 N (IV) R1 A 0R1 N \N N O l H is independently H or a or ceutically acceptable salts or hydrates thereof, wherein each R1 protecting group.
As indicated, the amino and hydroxyl groups in the compound of formula (IV) may be in protected or unprotected form. For e, in an unprotected form, the compound for formula (IV) may include the compound o-6,7—dihydroxy—8-(hydroxymethyl)—5a,6,7,8,9a,10- hexahydro—3H—pyrano[3,2-g]pteridin-4(5H)-one: O OH H hi OH )\ | H2N N N o 2-amino—6,7-dihydroxy(hydroxymethyl)- 5a,6,7,8,9a,10-hexahydro-3H—pyrano[3,2—g]pteridin—4(5H)—one or a ceutically acceptable salt, thereof.
Certain amino and/or hydroxyl groups of the formula (IV) structure may be protected with an R1 protecting group. For this purpose, R1 may include any suitable amino or hydroxyl functional group chosen by a person d in the chemical arts. For example, amino protecting disclosure include, but are not limited to, ate, groups Within the scope of the present amide, N—alkyl, or N—aryl-derived protecting groups. Non-limiting examples of hydroxyl protecting groups may e ether, ester, ate, or sulfonate protecting groups. The R1 protecting groups may be the same or different.
In particular, the ate protecting group may include, for example, 9— fluorenylmethyl carbamate (Fmoc), t—butyl carbamate (Boc), carboxybenzyl carbamate (cbz), methyl carbamate, ethyl carbamate, 9—(2-sulfo)fluorenylmethyl ate, 9-(2,7— o)fluorenylmethyl carbamate, l7-tetrabenzo[a,c,g,i]fluorenylmethy1 carbamate (bemoc), 2—chloro-3 -indenylmethyl carbamate (Climoc), 2,7—di-t-butyl[9-(10,10-dioxo-10,10,10,10— tetrahydrothioxanthy1)]methyl carbamate moc), 1 ,1~dioxobenzo[b]thiopheney1methyl carbamate (Bsmoc), 2,2,2-trichloroethy1 carbamate (Troc), 2—trimethylsilylethyl carbamate (Teoc), 2-phenylethy1 ate (hZ), 1,1-dimethyl-2—haloethyl ate, 1,1—dimethyl-2,2— dibromoethyl carbamate (DB-t—boc), 1,1—dimethyl-2,2,2—trichloroethyl carbamate (TCBoc), 1- methyl-1 -(4-biphenylyl)ethy1 carbamate (Bpoc), 1 -(3 t—butylphenyl)methy1ethyl carbamate (t—Bumeoc), N—2—pivaloylamino)—l,l-dimethylethyl carbamate, 2—[(2- nitrophenyl)dithio]—1-phenylethyl carbamate (NpSSPeoc), 2—(N,N— dicyclohexylcarboxamido)ethy1 carbamate, l-adamantyl carbamate (1 -Adoc), Vinyl ate (Voc), l-isopropylallyl carbamate ), 4—nitrocinnamyl carbamate (Noc), 3-(3’pyridyl)prop— 2—enyl carbamate (Paloc), 8—quinolyl carbamate, alkyldithio ate, p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate (Pnz), p—bromobenzyl carbamate, p—chlorobenzyl carbamate, 2,4—dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p- toluenesulfonyl)ethyl carbamate, [2-(1,3-dithiany1)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2- phosphonoethyl carbamate (Peoc), ,1,1-dimethyl—2-cyanoethy1 carbamate, 2—(4-nitrophenyl)ethyl carbamate, 4-phenylacetoxybenzyl carbamate (PhAcOZ), and m-chloro—p-acyloxybenzyl carbamate. In some embodiments, the carbamate protecting group is chosen from 9- WO 12922 2012/025689 fluorenylmethyl carbamate (Fmoc), t—butyl carbamate (Boc), and carboxybenzyl carbamate (cbz) protecting .
The amide protecting group may include, for example, acetarnide, phenylacetamide, 3- phenylpropanamide, pentenarnide, picolinamide, 3-pyridylcarboxamide, benzamide, p— phenylbenzamide, 2—methyl-2—(0-phenylazophenoxy)propanamide), 4-chlorobutanamide, acetoacetamide, 3—(p-hydroxyphenyl)propanamide), and (N’ - dithiobenzyloxycarbonylamino)acetamide.
The ether ting group may include methyl, methoxy methyl (MOM), benzyloxymethyl (BOM), methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl (SEM), methylthiomethyl (MTM), phenylthiomethyl (PTM), azidomethyl, cyanomethyl, 2,2- dichloro-1,1—difluoroethyl, 2-chloroethyl, 2—bromoethyl, tetrahydropyranyl (THP), l—ethoxyethyl (EE), phenacyl, 4—bromophenacyl, cyclopropylmethyl, allyl, propargyl, isopropyl, cyclohexyl, t- butyl, benzyl, 2,6-dimethylbenzyl, 4-methoxybenzyl (MPM-OAr), 0-nitrobenzyl, 2,6- dichlorobenzyl, 3,4-dichlorobenzyl, ethylamino)carbonylbenzyl, 4-methylsulfinylbenzyl (Msib), 9—anthrylmethyl, 4—picolyl, heptafluoro-p-tolyl, tetrafluoro-4—pyridyl, trimethylsilyl (TMS), t—butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl ), and triisopropylsilyl (TIPS) protecting groups.
The ester protecting group may include acetoxy (OAc), aryl formate, aryl acetate, aryl nate, aryl pivaloate, aryl benzoate, and aryl oenecarboxylate. In one embodiment, the ester protecting group is an acetoxy group.
The carbonate protecting group may e aryl methyl carbonate, l—adamantyl ate (Adoc—OAr), t—butyl carbonate (BOC-OAr), 4—methylsulfinylbenzyl carbonate (Msz- OAr), 2,4—dimethylpent-3—yl carbonate (Doc—OAr), aryl 2,2,2—trichloroethyl carbonate, aryl Vinyl carbonate, aryl benzyl carbonate, and aryl carbonate.
The sulfonate protecting groups may include aryl methanesulfonate, aryl toluenesulfonate, and aryl 2—formylbenzenesulfonate.
In some embodiments, the R1 protecting group is t-butyl carbamate (Boc).
In some embodiments, two adjacent R1 groups come together to form an isopropylidine acetal, benzylidine acetal, l,5-dioxaspiro[5.5]undecane (cyclohexylidene ), 6,10— dioxaspiro[4.5]decane (cyclopentylidene acetal), or 2-isobutyl—2-methyl-l,3‘dioxane moiety.
For example, the R1 groups at the 4- and 5—positions of the hexose ring component of formula (IV) can e to form an isopropylidine , benzylidine , 1,5— dioxaspiro[5.5]undecane (cyclohexylidene acetal), 6,10-dioxaspiro[4.5]decane (cyclopentylidene acetal), or 2-isobutylmethy1—1,3—dioxane moiety.
Protection of certain amino and hydroxyl groups can improve solubility of the formula (IV) compounds. For example, preparation of acetyl derivatives of formula (IV) can improve solubility and increase product isolation yield.
A compound of formula (IV) may be prepared by reacting a nd of formula (II): R1\N R1\N with a compound of formula (III): HO 0R1 (III) HO 0 to e a nd of formula (IV): 0 CR1 R H OR 1\ 1 ‘ (1V) R1 A 0R1 \N \N N o l H wherein: each R1 is independently H or a protecting group, as defined above.
In particular, a compound of formula (IV) may be prepared upon reaction of a compound of formula (II) and formula (III) in the presence of any reagent Which would achieve the desired cyclization. Such a reagent can be readily determined by the skilled person and can include, for example, substituted or unsubstituted hydrazines. Non-limiting examples of suitable hydrazine and p- reagents include phenylhydrazines and alkylhydrazines, for e, phenylhydrazine nitrophenylhydrazine.
As will be understood, the isomeric form of the a (IV) structure may govern the stereospecificity of subsequent intermediates in the successive steps of the synthesis of formula (I) or formula (XIII). ingly, a particular isomer may be isolated at this step of the synthesis or, alternatively, isomeric mixtures of formula (IV) may be carried through and isolated at later stages of the synthesis.
In some embodiments, the compound of formula (IV) includes the isomer: O 0R1 R1 \ R1 or pharmaceutically able salts or hydrates thereof.
During the synthesis, the stereochemistry of the formula (IV) product may optionally be lled by lating the stereochemistry of the C—3 and C-4 positions of the formula (III) hexose. For example, formula (III) reactants derived from glucose, mannose, galactose, allose, altrose, gulose, idose, and talose, and tives which differ with respect to the stereochemistry of the C—3 and C-4 positions of the sugar will e different isomer mixtures of the formula (IV) product.
The stereoselectivity of the formula (IV) synthesis can also be controlled by incorporating bulky protecting groups at certain positions of the formula (III) compound. For example, ucing an isopropylidine acetal at any of the C-3, C-4, or C-5 positions of the formula (III) sugar can modulate stereoselectivity of the reaction.
Compounds of formula (If): Another embodiment provided herein s to the preparation of compounds of formula (V): 0 R1 0R1 R N OR 1\N 1 t (V) R1 \ 0R1 \T N T 0 R1 R1 is independently H or a or pharmaceutically acceptable salts or hydrates thereof, wherein each R1 protecting group. For e, the compound of formula (V) includes the compound (V—A), (V- B), and (V-C): 0 R1 OH N CH | (V-A) \ OH H2N N IN‘ 0 0 R1 OH N OH 1 (V-B) R1 OH \N \ N N o . 0 CR1 R1 N 0R1 l (V—C) R1 \ 0R1 \T N T 0 R1 R1 or a pharmaceutically acceptable salt thereof, wherein R1 is H or a protecting group. compound of formula (V) also includes, for e, the compound (9H—fluoren-9—yl)rnethyl 2- amino—6,7-dihydroxy(hydroxymethyl)~4-oxo-Sa,6,7,8,9a, 1 0-hexahydro-3H-pyrano[3 ,2- g]pteridine-5(4H)—carboxylate: o Fmoc OH H N OH X I 0H H2N N M o (9H-fluorenyl)methy| 2—amino-6,7—dihydroxy—8-(hydroxymethyI)—4—oxo- 5a,6,7,8,9a,10-hexahydro—BH-pyrano[3,2~g]pteridine-5(4H)—carboxylate or a pharmaceutically acceptable salt f. In some embodiments, the compound of formula (V) can include, for example, one or more of the following compounds: 0R1 0R1 N 0R1 R \ OR 1\'Il 1 N [I] O R1 R1 0 0R1 R H OR 1\N 1 R OR 1\IIJ \ 1 N III 0 R1 R1 0 0R1 N 0R1 R \ OR 1\III 1 N [I] O 0R1 0R1 H 0R1 X I OR1 HN N N 0 R1 R1 0 0R1 R H OR 1\N 1 X I 0R1 HN N N 0 R1 R1 2012/025689 0R1 OH ZI OH kl OH O OH or a pharmaceutically acceptable salt thereof. For example, a compound of formula (V) can include one or more of: WO 12922 0800 0806 N 0800 \wa I Boc \ OBoc ,r O Boo Boo O OBoc Boc\N N 0800 \wa l Boc \ 0800 v 0 Boc Boc O 0800 N OBoc 1 * Boc \ 0800 \N N N o Boc Boc OBoc 0800 N 0800 x . OBoc HN N N O Boc B00 O 0800 Boc\ N OBoc k I ' OBoc HN N N O Boc Boc O OH N OH Boc\ \ OH .
N N N O 800 Bee 0800 OH N OH x I OH HN N N O Boo Boo or a pharmaceutically acceptableI3salt thereof.
In some embodiments, one or more of the above compounds can be separated by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization” K.F. Blom, et al, J. Coinbi, Chem. 6(6), 874 (2004), which is orated herein by reference in its entirety) and normal phase silica chromatography.
As indicated, n amino and/or hydroxyl groups of the formula (V) structure may be protected with an R1 protecting group. For this purpose, R1 may include any suitable amino or hydroxyl onal group chosen by a person skilled in the al arts. For example, amino protecting groups Within the scope of the present disclosure include, but are not limited to, carbamate, amide, N—alkyl, or N—aryl—derived protecting groups. miting examples of yl protecting groups may e ether, ester, carbonate, or sulfonate protecting groups.
The R1 protecting groups may be the same or different.
In particular, the carbamate protecting group may include, for example, 9— fluorenylmethyl carbamate (Fmoc), t—butyl carbamate (Boc), carboxybenzyl carbamate (cbz), methyl carbamate, ethyl carbamate, 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7- dibromo)fluorenylmethyl carbamate, trabenzo[a,c,g,i]fluorenylmethyl carbamate (bemoc), 2—chloro—3 -indenylmethyl carbamate c), 2,7-di-t—butyl[9—(10,l 0-dioxo-10, l 0,10,10— tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 1,l-dioxobenzo[b]thiophene52~ylmethyl ate (Bsmoc), trichloroethyl carbarnate (Troc), ethylsilylethyl carbamate (Teoc), 2-phenylethy1 carbamate (hZ), 1,1—dimethylhaloethyl carbamate, l,l-dimethyl-2,2- dibromoethyl carbamate (DB—t-boc), 1,1—dimethyl—2,2,2-trichloroethyl carbarnate (TCBoc), 1- methyl- 1 phenylyl)ethyl carbamate (Bpoc), 1 -(3 ,5 -di—t-butylphenyl)— l -methylethyl carbamate eoc), Npivaloylamino)—l,l-dimethylethyl carbamate, 2-[(2— nitrophenyl)dithio]¥1—phenylethyl carbamate (NpSSPeoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, l—adamantyl carbamate (l-Adoc), Vinyl carbamate (Voc), 1-isopropylallyl carbamate (Ipaoc), 4-nitrocinnamyl carbamate (Noc), 3—(3’pyridyl)prop- 2—enyl carbamate (Paloc), 8-quinolyl carbamate, alkyldithio carbamate, p-methoxybenzyl caroamate (Moz), p—nitrobenzyl carbamate (Pnz), p—bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl ate (Msz), diphenylmethyl carbamate, 2—methylthioethyl carbamate, 2—methylsulfonylethyl carbamate, 2-(p— toluenesulfonyl)ethyl carbamate, [2-(1,3-dithiany1)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate , 2- phosphonoethyl carbamate (Peoc), 1,1-dimethylcyanoethyl carbamate, 2—(4-nitrophenyl)ethyl carbamate, 4-phenylacetoxybenzyl ate (PhAcOZ), and m-chloro-p—acyloxybenzyl carbamate. In some embodiments, the carbamate protecting group is chosen from 9- fluorenylmethyl ate (Fmoc), t—butyl carbamate (Boc), and carboxybenzyl carbamate (cbz) ting groups.
The amide protecting group may include, for example, acetamide, acetamide, 3- phenylpropanamide, pent—4-enamide, picolinamide, 3-pyridylcarboxamide, benzamide, p- phenylbenzamide, 2-methyl-2—(0-phenylazophenoxy)propanamide), robutanamide, cetamide, 3-(p-hydroxyphenyl)propanamide), and (N’ - dithiobenzyloxycarbonylamino)acetamide.
The ether protecting group may include methyl, methoxy methyl (MOM), benzyloxymethyl (BOM), methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl (SEM), methylthiomethyl (MTM), phenylthiomethyl (PTM), azidomethyl, cyanomethyl, 2,2- dichloro— 1 ,1 -difluoroethyl, 2—chloroethyl, 2-bromoethyl, tetrahydropyranyl (THP), l—ethoxyethyl (EE), phenacyl, 4—bromophenacyl, cyclopropylmethyl, allyl, propargyl, pyl, cyclohexyl, t— butyl, benzyl, 2,6—dimethylbenzyl, 4-methoxybenzyl (MPM-OAr), o-nitrobenzyl, 2,6- dichlorobenzyl, 3,4-dichlorobenzyl, 4-(dimethylamino)carbonylbenzyl, 4—methylsulfinylbenzyl (Msib), 9-anthrylmethyl, 4—picolyl, uoro-p-tolyl, tetrafluoropyridyl, trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS), t—butyldiphenylsilyl ), and triisopropylsilyl (TIPS) protecting groups.
The ester protecting group may include acetoxy (OAc), aryl formate, aryl acetate, aryl levulinate, aryl pivaloate, aryl benzoate, and aryl 9—fluoroenecarboxylate. In one embodiment, the ester ting group is an y group.
The ate protecting group may include aryl methyl ate, 1—adamantyl carbonate (Adoc-OAr), t-butyl carbonate (BOC-OAr), 4—methylsulfinylbenzyl carbonate (Msz— OAr), 2,4-dimethylpent—3-yl carbonate (Doc-OAr), ary12,2,2—trichloroethyl carbonate, aryl vinyl carbonate, aryl benzyl carbonate, and aryl carbonate.
The ate protecting groups may include aryl methanesulfonate, aryl toluenesulfonate, and aryl 2—formylbenzenesulfonate.
In some embodiments, the R1 protecting group is t—butyl carbamate (Boc).
In some embodiments, two adjacent R1 groups come together to form an isopropylidine acetal, benzylidine acetal, 1,5—dioxaspiro[5.5]undecane (cyclohexylidene acetal), 6,10- dioxaspiro[4.5]decane (cyclopentylidene acetal), or 2-isobutylmethyl-l,3-dioxane moiety.
For e, the R1 groups at the 4- and 5-positions of the hexose ring component of formula (V) can combine to form an an isopropylidine acetal, idine acetal, 1,5- dioxaspiro[5.5]undecane hexylidene acetal), 6,lO—dioxaspiro[4.5]decane (cyclopentylidene acetal), or 2-isobutyl—2—methyl-1 ,3 ne moiety.
Protection of certain amino and hydroxyl groups can improve solubility of the formula (V) compounds. For example, preparation of acetyl derivatives of formula (V) can improve solubility and increase product isolation yield.
A compound of formula (V) may be prepared by selectively protecting a compound of formula (IV): 0 CR1 R H OR 1\ 1 | (IV) R1 /l\ OR1 \N N N o ‘ H to prepare a compound of formula (V): 0 R1 0R1 R1\N N CR1 R1 1 \ 0R1 \T N T 0 R1 R1 wherein: each R1 is independently H or a protecting group, as defined above.
In particular, a compound of formula (V) may be prepared by reacting a compound of formula (IV) with any t and using conditions to achieve selective lation of the R] protecting group at N-5. Suitable reagents and conditions for installing the R1 protecting group can be readily ined by those of ry skill in the art. For example, 9—fluorenylmethyl carbarnate (Fmoc) can be installed using an activated chloride tive, as reported by E.
Atherton et al., “The Fluorenylmethoxycarbonyl Amino ting Group,” in The Peptides, S.
Udenfriend and J. Meienhofer, Eds, Academic Press, New York, 1987, Vol. 9, page 1.
Protection using t—butyl carbamate (Boc) is attained by reacting a compound of formula (IV) with, for example, (Boc)20 in aqueous NaOH as described by D. Tarbell et al., Proc. Natl. Acad.
Sci., USA, 69, 730 (1972). Methyl and ethyl carbamate can be readily introduced as described by E.J. Corey et al., Tetrahedron Lett., 19(12), 1051 (1978).
As will be understood, the isomeric form of the formula (V) ure may govern the stereospecificity of subsequent ediates in the successive steps of the synthesis of formula (I) or formula (XIII). Accordingly, a particular isomer may be isolated at this step of the synthesis or, alternatively, isomeric mixtures of formula (V) may be carried through and isolated at later stages of the synthesis.
In some embodiments, the compound of formula (V) includes the isomer: 0 R1 0R1 \T \ In on, as shown above, the compound of formula (V) also includes the tautomeric structure: 0R1 R1 0R1 til OR1 l (V) R1 \ 0R1 \T N T 0 R1 R1 or a salt f.
Comgounds 0: (ormula (H): In another embodiment, compounds of formula (VI) are prepared: 0 R1 0R1 | OR1' R1 N \N o\Fl[:0 ‘ (V1) R o 1\N \N N 0 l1 FL 3 or pharmaceutically acceptable salts or es thereof, wherein each R1 is independently H or a protecting group. For example, the compound for formula (VI) includes the compound (VI-A): 0 R1 OH | OH N o HN \P/zo ‘ I (VI-A) \ o H2N N u 0 or a ceutically acceptable salt thereof, wherein R1 is H or a protecting group. nd of formula (VI) also includes, for example, the compound: 0 Fmoc OH H N o /OH I \T20 Ax o H2N N m o (9H-fluoren-9—yl)methy| 8—amino—2,12—dihydroxyoxo-4,4a,5a,6,9,10,12,12a- octahydro—[1,3,2]dioxaphosphinino[4',5':5,6]pyrano[3,2—g]pteridine-11(11aH)- carboxylate 2—oxide or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (VI) includes, for example, the compound (VI-B): 0 R1 OH | 0R1 R1 N \ O\T/=O l (VI-B) R A o 1\N \N N o J, J, or a pharmaceutically acceptable salt thereof. In some ments, the compound of formula (VI) includes, for example, the compound (VI-C): 0 CR1 R1 H 0 /0R1 \N \on /l\ I | (VI-C) R O 1\N \N N 0 FL FL or a ceutically acceptable salt thereof. In some embodiments, the compound of formula (VI) can include one or more of: O OH R1\N N O\P=O k i (I) HN N N 0 FL FL 0R1 OH H o\ F“ N / P=O k | (I) HN N N 0 FL FL 0 OH N O /0R1 l \FI’ZO R1\N \N 0 N O FL l1 or a pharmaceutically acceptable salt thereof. For example, a compound of formula (VI) can include one or more of the following: O OH B00 H o /0 T \T—O x 0 HT N T O Boc Boc 0800 OH N o / | \Il3——O )\ 0 HT N T O Boc Boc O OH N o / ‘ \Tzzzo Boc x O \T N T o Boc Boc or a pharmaceutically able salt thereof. In some embodiments, one or more of the above compounds can be separated by those d in the art by a variety of methods, including high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization” K.F. Blom, et al., J. Combi. Chem. 6(6), 874 (2004), which is incorporated herein by reference in its entirety) and normal phase silica chromatography.
As indicated, certain amino and/or hydroxyl groups of the formula (VI) structure may be protected with an R1 protecting group. For this purpose, R1 may include any suitable amino or yl functional group chosen by a person skilled in the chemical arts. For example, amino protecting groups Within the scope of the present disclosure include, but are not limited to, carbamate, amide, N—alkyl, or N—aryl-derived protecting . Non-limiting examples of hydroxyl protecting groups may include ether, ester, carbonate, or sulfonate protecting groups.
The R1 protecting groups may be the same or different.
In particular, the carbamate protecting group may include, for example, 9- ylmethyl carbamate (Fmoc), t—butyl carbamate (Boo), carboxybenzyl carbamate (cbz), methyl carbamate, ethyl carbamate, 9-(2—sulfo)fluorenylmethyl carbamate, 9—(2,7— dibromo)fluorenylmethyl carbamate, l7-tetrabenzo[a,c,g,i]fluorenylmethyl carbamate (bemoc), 2—chloroindenylmethyl carbamate (Climoc), 2,7-di—t—butyl[9-(l0,10-dioxo-10,10,10,10— tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 1,1—dioxobenzo [b]thiopheneylmethyl carbamate (Bsmoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2—phenylethyl carbamate (hZ), 1,1-dimethylhaloethyl carbamate, l,l-dimethyl—2,2- dibromoethyl ate (DB—t—boc), 1,1-dimethyl-2,2,2—trichloroethyl carbamate (TCBoc), 1— methyl— 1 —(4-biphenylyl)ethyl carbamate (Bpoc), l —(3 ,5-di-t—butylphenyl)- 1 lethyl carbamate (t—Bumeoc), N—2-pivaloylamino)-1,l-dimethylethyl carbamate, 2-[(2- nitrophenyl)dithio]-1—phenylethyl carbamate (NpSSPeoc), 2-(N,N— dicyclohexylcarboxamido)ethyl carbamate, l—adamantyl carbamate (l-Adoc), Vinyl carbamate (Voc), l-isopropylallyl carbamate (Ipaoc), 4-nitrocinnamyl carbamate (N00), 3—(3’pyridyl)prop— 2—enyl carbamate (Paloc), S-quinolyl carbamate, ithio ate, p-methoxybenzyl carbamate (Moz), obenzyl carbamate (Pnz), p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4—dichlorobenzyl carbamate, 4—methylsulfinylbenzyl carbamate (Msz), diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p- toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate , 4— thiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2- phosphonoethyl carbamate (Peoc), l,l-dimethyl-Z-cyanoethyl carbamate, 2-(4-nitrophenyl)ethyl carbamate, 4-phenylacetoxybenzyl carbamate Z), and m-chloro—p—acyloxybenzyl carbamate. In some embodiments, a ate protecting group can be chosen from 9— fluorenylmethyl carbamate (Fmoc), t—butyl carbamate (B00), and carboxybenzyl carbamate (cbz) protecting groups.
The amide protecting group may include, for example, acetamide, phenylacetamide, 3- propanamide, pent—4—enamide, picolinamide, 3-pyridylcarboxamide, ide, p— phenylbenzamide, yl-2—(0—pheny1azophenoxy)propanamide), 4-chlorobutanamide, acetoacetamide, 3-(p—hydroxyphenyl)propanamide), and (N’ - dithiobenzyloxycarbonylamino)acetamide.
The ether protecting group may include methyl, methoxy methyl (MOM), benzyloxymethyl (BOM), methoxyethoxymethyl (MEM), 2—(trimethy1silyl)ethoxymethyl (SEM), thiomethyl (MTM), thiomethyl (PTM), azidomethyl, ethyl, 2,2- dichloro—l ,l-difluoroethyl, 2—chloroethyl, 2—bromoethyl, tetrahydropyranyl (THP), l—ethoxyethyl (EE), phenacyl, 4-bromophenacyl, ropylmethyl, allyl, propargyl, isopropyl, cyclohexyl, tbutyl , benzyl, 2,6-dimethylbenzyl, 4—methoxybenzyl (MPM-OAr), o-nitrobenzyl, 2,6- dichlorobenzyl, 3,4-dichlorobenzyl, 4—(dimethylamino)carbonylbenzyl, 4—methylsulfinylbenzyl , 9-anthrylmethyl, 4-picolyl, heptafluoro-p-tolyl, uoro-4—pyridyl, trimethylsilyl (TMS), ldimethylsilyl (TBDMS), t—butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS) protecting groups.
The ester protecting group may include acetoxy (OAc), aryl formate, aryl acetate, aryl levulinate, aryl pivaloate, aryl benzoate, and aryl 9-fluoroenecarboxylate. In one embodiment, the ester protecting group is an acetoxy group.
The carbonate ting group may e aryl methyl carbonate, l—adamantyl carbonate (Adoc-OAr), t—butyl carbonate (BOC—OAr), 4-methylsulfinylbenzyl carbonate (Msz— OAr), 2,4-dimethylpent—3-yl carbonate (Doc-OAr), aryl 2,2,2-trichloroethyl carbonate, aryl vinyl carbonate, aryl benzyl carbonate, and aryl carbonate.
The sulfonate protecting groups may include aryl methanesulfonate, aryl toluenesulfonate, and aryl 2-formylbenzenesulfonate.
In some embodiments, the R1 protecting group is t-butyl carbamate (Boc).
Protection of certain amino and hydroxyl groups can improve solubility of the a (VI) compounds. For example, preparation of acetyl derivatives of formula (VI) can e solubility and increase product isolation yield.
A compound of formula (VI) may be prepared by phosphorylating a compound of formula (V): 0 R1 0R1 R N OR 1\ 1 l (V) R1 \ 0R1 \T N T 0 R1 R1 to prepare a nd of formula (VI): 0 R1 0R1 til OR1 R1 0 / \N \on 1\NI \N o N 0 FL FL or a pharmaceutically acceptable salt form thereof, wherein each R1 is independently H or a protecting group, as defined above.
In particular, a compound of formula (VI) may be prepared by reacting a compound of formula (V) with any phosphorylating agent proper to form a compound of formula (VI).
Suitable phosphorylation reagents and conditions can be readily determined by those of ordinary skill in the art. For example, a compound of formula (VI) may be achieved by treating a compound of formula (V) with a P(V) phosphorylating agent. Suitable P(V) orylating agents include, but are not limited to, POC13, H3PO4, PO(OBn)xC13-X, C13CCH20P(O)C12, PO(OCH3)XC13_X, PO(OCH3)C12, PO(OCH3)XC13.X, PO(OCH3)C12, and (BnO)2P(O)OP(O)(OBn)2.
In some embodiments, the P(V) phosphorylating agent is POCl3.
In one ment, the phosphorylation on is carried out by treating a compound of formula (V) with POC13 at t temperature to afford a compound of formula (VI). In another embodiment, a compound of a (V1) is formed by treating a compound offormula (V) with POCl3 at 60 0C.
The phosphorylation reaction may also involve ng a nd of formula (V) with a P(III) phosphitylating agent to form a phosphite intermediate. Suitable P(III) phosphitylating agents include, for example, P(OCHgCHzCN)2Cl; P(OCHZCH2CN)(NPr2-i)Cl; and cyanoethyl— O-P[N(i-Pr)2)]2. When a P(III) phosphitylating agent is used for phosphorylation, subsequent oxidation may be used to furnish the corresponding ate. When P(III) reagents are employed for the synthesis of a nd of formula (VI), Boc or Cbz groups may be used for R] protection of the N—5 of the compound of formula (IV) due to the basic environment used for phosphitylation.
As will be understood, the isomeric form of the formula (VI) structure may regulate the stereospecificity of successive steps in the synthesis of a (1). Accordingly, a particular isomer may be isolated at this step of the synthesis or, alternatively, isomeric mixtures of a compound of formula (VI) may be carried h and isolated at later stages of the synthesis.
In some embodiments, the compound of formula (VI) includes the : 0 R1 0R1 or a salt thereof.
Com oundso ormula II : In another embodiment, compounds of a (VII) are prepared: 0 R1 HO OH R1\N/uj: frilzoN o /0R1 (VII) R o 1\N \N o ‘ l T each R1 is independently H or a or ceutically acceptable salts or hydrates thereof, wherein protecting group. For example, the compound for formula (VII) includes the compound (VII—A): 0 R1 HO OH N o \ /OH HN P=o | | (VII-A) \ o H2N N {:1 o or a pharmaceutically acceptable salt thereof, wherein R1 is H or a protecting group. The compound of formula (VII) also includes, for example, the compound: Fmoc HO OH mil/LN. o /OH \P__: (9H--f|uoren—9-yl)methy| 8—amino--2, 12,12—Htrihydroxy-1O-0X0——,44a, 5a,69,10,12,12a— octahydro—[-1,3 ,2]dioxaphosphinino[4', 5': 56,]pyrano[3 2-g]pteridine— 11 (11aH)-carboxy|ate e or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (VII) includes the compound (VII—B): 0 R1 HO OH | 0R1 N o HN \P/zo x l | ) \ o HN N N o llR1 A1 or a pharmaceutically acceptable salt thereof. In some embodiments, the nd of formula (VII) includes the compound (VII-C): 0 HO OH R1 N O/OR1 T/LNl |— (VII-C) R1 0 R1 R1 or a pharmaceutically able salt thereof. In some embodiments, a compound of formula (VII) can include one or more of the following: 0 HO OH X 0 HT N T 0 R1 R1 0 HO OH H " I \Tzo R1 k 0 \T N T 0 R1 R1 0R1 HO OH ‘ \llDzo R1 k 0 \T N T o or a pharmaceutically acceptable salt thereof. For example, a compound of formula (VII) can include one or more of the following: Eco N O 2’ \N \PZO A l l HN N N O l l Boc Boc O HO OH ii 0 /0 I \TZO . r0c\N \N .
N O I | Boo Boo OBoc HO OH H 0 /° ‘ \TZO B k 0 °°\N \N N O l|30c | or a pharmaceutically acceptable salt f. In some embodiments, one or more of the above compounds can be separated by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: ed Compound Specific Method Optimization” K.F. Blom, et al., 1 Combi. Chem. 6(6), 874 (2004), which is incorporated herein by reference in its entirety) and normal phase silica chromatography.
As indicated, certain amino and/or hydroxyl groups of the formula (VII) structure may be protected with an R1 protecting group. For this purpose, R1 may include any suitable amino or hydroxyl functional group chosen by a person skilled in the chemical arts. For e, amino ting groups Within the scope of the present disclosure include, but are not limited to, carbamate, amide, N—alkyl, or N—aryl—derived protecting groups. Non-limiting examples of hydroxyl ting groups may include ether, ester, carbonate, or sulfonate protecting .
The R1 protecting groups may be the same or different.
In particular, the carbamate protecting group may e, for e, 9- fluorenylmethyl carbamate (Fmoc), t—butyl carbamate (Boc), carboxybenzyl carbamate (cbz), methyl carbamate, ethyl carbamate, 9-(2-sulfo)fluorenylmethyl carbamate, 9—(2,7— dibromo)fluorenylmethy1 carbamate, 17—tetrabenzo[a,c,g,i]fluorenylmethyl carbamate (bernoc), 2-chloro—3-indenylmethyl carbamate (Climoc), 2,7-di—t-butyl[9-(l0,10-dioxo-10,10,10,10— tetrahydrothioxanthyl)]methyl carbamate ‘(DBD—Tmoc), 1, l -dioxobenzo[b]thiophene—2-ylmethyl carbamate (Bsmoc), 2,2,2—trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1,1-dimethy1-2—haloethyl carbamate, 1,1-dirnethyl-2,2- dibromoethyl carbamate boc), 1,1—dimethyl-2,2,2-trichloroethyl carbamate (TCBoc), 1l—(4—biphenylyl)ethyl ate , l-(3,5—di-t—butylphenyl)—1-methylethyl carbamate (t-Bumeoc), valoylamino)—1,l-dimethylethyl carbamate, 2-[(2- nitrophenyl)dithio]phenylethyl carbamate (NpSSPeoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, l—adamantyl carbamate (1 -Adoc), Vinyl carbamate (Voc), l-isopropylallyl carbamate (Ipaoc), ocinnamyl carbamate (N00), 3-(3’pyridyl)prop—‘ 2—enyl carbamate (Paloc), 8-quinolyl carbamate, alkyldithio carbamate, p—methoxybenzyl carbamate (Moz), p—nitrobenzyl carbamate (Pnz), p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2—methylsulfonylethyl carbamate, 2-(p- toluenesulfonyl)ethyl carbamate, 3—dithianyl)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2- phosphonoethyl carbamate (Peoc), 1,l-dimethyl-Z—cyanoethyl carbamate, 2—(4-nitrophenyl)ethyl carbamate, 4-phenylacetoxybenzyl ate (PhAcOZ), and m-chloro-p-acyloxybenzyl carbamate. In some embodiments, the carbamate protecting group is chosen from 9- fluorenylmethyl ate (Fmoc), t—butyl carbamate (B00), and carboxybenzyl carbamate (cbz) protecting groups.
The amide protecting group may include, for example, acetamide, phenylacetamide, 3— phenylpropanamide, pentenamide, picolinamide, dylcarboxamide, benzamide, p— benzamide, yl—2-(0—phenylazophenoxy)propanamide), 4-chlorobutanamide, acetoacetamide, 3-(p—hydroxyphenyl)propanamide), and (N’ - dithiobenzyloxycarbonylamino)acetamide. 2012/025689 The ether protecting group may include methyl, methoxy methyl (MOM), oxymethyl (BOM), methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl (SEM), methylthiomethyl (MTM), phenylthiomethyl (PTM), azidomethyl, cyanomethyl, 2,2- dichloro—1,1-difluoroethyl, 2-chloroethyl, 2—bromoethyl, tetrahydropyranyl (THP), l-ethoxyethyl (EE), phenacyl, ophenacyl, cyclopropylmethyl, allyl, propargyl, pyl, cyclohexyl, t- butyl, benzyl, 2,6—dimethylbenzyl, 4—methoxybenzyl (MPM-OAr), o-nitrobenzyl, 2,6- dichlorobenzyl, 3,4-dichlorobenzyl, 4-(dimethylamino)carbonylbenzyl, 4—methylsulfinylbenzyl (Msib), rylmethyl, 4—picolyl, heptafluoro-p-tolyl, tetrafluoropyridyl, trimethylsilyl (TMS), t—butyldimethylsilyl ), t-butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS) protecting groups.
The ester protecting group may include acetate, aryl formate, aryl acetate, aryl levulinate, aryl pivaloate, aryl benzoate, and aryl 9—fluoroenecarboxylate.
The carbonate ting group may e aryl methyl carbonate, l-adamantyl ate (Adoc-OAr), t-butyl carbonate (BOC—OAI), 4-methylsulfinylbenzyl carbonate (Msz- OAr), 2,4-dimethylpent-3—yl carbonate (Doc-OAr), aryl 2,2,2—trichloroethyl carbonate, aryl vinyl carbonate, aryl benzyl carbonate, and aryl carbonate.
The sulfonate protecting groups may include aryl esulfonate, aryl toluenesulfonate, and aryl 2-forrnylbenzenesulfonate.
In some embodiments, the R1 protecting group is t—butyl carbamate (Boo).
Protection of certain amino and hydroxyl groups can improve solubility of the formula (VII) compounds. For example, preparation of acetyl derivatives of formula (VII) compounds can improve solubility and increase product isolation yield.
A compound of formula (VII) may be prepared by oxidizing the nd of formula (VI): 0 T1 0R1 R1\ N o\ / l Tzo (V1) R1\ \ o N N T 0 L R, to prepare a compound of formula (VII): 0 R1 HO OH | 0R1 R1\ N N O\P:O i | (W) R o 1\T \N T 0 wherein: each R1 is independently H or a protecting group, as defined above.
In this synthesis, a nd of formula (VII) may be prepared by reacting a compound of formula (V1) with any oxidizing agent proper to selectively form the diol of formula (VII). le oxidizing agents and conditions can be readily determined by those of ordinary skill in the art. For example, a compound of formula (VII) may be formed upon treatment of a compound of formula (V1) with a ruthenium compound, such as RuO4'/NMO. Other oxidants, such as Dess-Martin’s t, DMSO/triflic anhydride, TFAA/DMSO, PDC, hydrogen peroxide, nic peroxides, nitric acid, nitrates, chlorite, chlorate, perchlorate, hypochlorite, peroxide, iodine, ozone, nitrous oxide, silver oxide, permanganate salts, hexavalent chromium compounds, chromic acid, dichromic acids, chromium trioxide, pyridinium chromate, persulfuric acid, sulfoxides, sulfuric acid, Tollens’ reagent, 2,2’-dipyridyldisulf1de (DPS), and osmium tetroxide may also be used. In one ment, the oxidation conditions are performed In some embodiments, the oxidizing so that the pyrazine ring of compound (V1) is not ed. and PDC. agent is chosen from RuO4‘/NMO, Dess-Martin’s reagent, DMSO/triflic anhydride, For example, the oxidation reaction may be carried out by treating a compound of formula (VI) with RuO4'/NMO at ambient temperature to afford a compound of formula (VII).
In r ment, a nd of formula (VII) is formed by treating a compound a (V1) with RuO4'/NMO at a temperature from 20 - 60 °C, or at 20, 25, 30, 35, 40, 45, 50, or 55 °C.
A compound of formula (VII) can be used to prepare a compound of formula (XIV) via ation. Suitable reaction conditions for such a dehydration reaction are readily determined by those of ordinary skill in the art. For example, a compound of formula (VII) can be combined with a concentrated acid or base to prepare a compound of formula (XIV). In some embodiments, any of the oxidation methods provided herein can include the further step of dehydrating the reaction t to obtain the corresponding ketone.
As will be understood, the isomeric form of the a (VII) structure may regulate the stereospecificity of successive steps‘in the synthesis of a (1). Accordingly, a particular isomer may be isolated at this step of the synthesis or, alternatively, isomeric mixtures of a compound of formula (VII) may be carried through and ed at later stages of the synthesis.
In some embodiments, the compound of formula (VII) includes the isomer: 0 R1 the compound of formula (VII) or a ceutically acceptable salt thereof. As shown above, can also include the tautomeric structure: 0R1 R1 Ho OH | 0R1 N o I \TZO R1 O \T \ N T 0 R1 R1 or a pharmaceutically acceptable salt f.
Compound of formula (I): In some embodiments, the preparation of a compound of formula (I): O HO OH N O /OH k . \Tzo i 5 H2N N N g o g H H H and pharmaceutically acceptable salts and hydrates thereof is provided. The compound of formula (I) also includes the tautomeric structure: OH HO OH H2N N N or a pharmaceutically acceptable salt thereof.
The synthesis of the compound of formula (I) is preferably carried out so as to achieve the desired stereochemistry and avoid oxidation due to pyran ring opening during the chemical synthesis.
The compound of formula (I) may be ed, for example, by ecting the compound of formula (VII): 0 R1 HO OH | 0R1 R1\ N o\ / N P20 | | (W) R o 1\T \N T 0 R1 R1 wherein each R1 is ndently H or a protecting group, as defined above, to prepare the compound of formula (I).
In this synthesis, the deprotection may involve, for e, either sequential or one-pot deprotection of certain amino and hydroxyl protecting groups on a compound of formula (VII) to h the compound of formula (1). Suitable ts and conditions for the deprotection of a compound of formula (VII) can be readily determined by those of ordinary skill in the art. For example, nd (I) may be formed upon treatment of a compound of formula (VII) under conditions so that hydroxyl protecting groups, such as acetate, isopropylidine, and benzylidine protecting , are removed from the formula (VII) structure. The acetate group can be cleaved, for example, under Zemplén conditions using catalytic NaOMe as a base in methanol.
The benzylidene and isopropylidene groups Can be cleaved by hydrogenation or using acidic ysis as reported by RM. Hann et al., J. Am. Chem. Soc., 72, 561 (1950). In yet another example, the deprotection can be performed so that amino protecting groups, such as 9- fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (Boc), and carboxybenzyl carbamate (cbz) ting groups are cleaved from the compound of formula (VII). 9-fluorenylmethyl carbamate (Fmoc) can be removed under mild conditions with an amine base (e. g., piperidine) to afford the free amine and dibenzofulvene, as described by E. Atherton et al., “The nylmethoxycarbonyl Amino Protecting Group,” in The Peptides, S. Udenfriend and J. ofer, Academic Press, New York, 1987, p. 1. t—butyl carbamate (Boc) can be removed, as reported by G.L. Stahl et al., J Org. Chem, 43, 2285 (1978), under acidic conditions (e. g., 3 M HCl in EtOAc). Hydrogenation can be used to cleave the carboxybenzyl carbamate (cbz) protecting group as described by J. Meienhofer et al., Tetrahedron Lett, 29, 2983 (1988).
To prevent oxidation of formula (1) during the reaction, the deprotection may be performed under anaerobic conditions. The deprotection may also be performed at ambient temperature or at temperatures of from about 20 - 60 °C (e.g, 25, 30, 35, 40, 45, 50, or 55 °C).
The compound of formula (I) may be isolated in the form of a ceutically acceptable salt. For example, the compound of formula (I) may be llized in the presence of HCl to form the HCl salt form of the compound. In some embodiments, the nd of formula (I) may be crystallized as the HBr salt form of the compound. The compound of a (I) may also be isolated, e. g. , by itation as a sodium salt by treating with NaOH.
The compound of formula (I) is labile under certain reaction and e conditions. In some embodiments, the final solution comprising the compound of formula (I) may be acidified by methods known in the art. For example, the compound of formula (I), if stored in solution, can 2O be stored in an acidic solution.
In some embodiments, the compound of formula (I) may be prepared, for example, by: reacting a compound of formula (II—A): l (II—A) HZN N NH2 with a compound of formula (III—A): HO OH (III-A) HO O in the presence of a hydrazine to produce a compound of a (IV-A): 21 OH HN (IV-A) kl OH H2N N 12 O selectively protecting the nd of a (IV-A) to prepare a compound of formula (V—A): 0 R1 OH N OH | (V—A) \ OH HZN N N o wherein: R1 is a protecting group, as defined above; phosphorylating the compound of formula (V-A) to prepare a compound of formula (VI-A): 0 R1 OH | OH N o HN \P/ZO ‘ I (VI-A) \ o H2N N u o oxidizing the compound of formula (VI-A) to prepare a compound of formula (VII-A): 0 R1 HO OH N o /OH HN \on I | (VII-A) \ o H2N N u o ; and deprotecting the compound of formula (VII—A) to prepare the compound of formula (I). For example, a compound of a (I) can be prepared as shown in Scheme 3.
Scheme 3.
Q on 0 ‘DH it H H NH Hit ll )1 It} J» = CH ~ 5 OH . .‘ 3 ’ "‘ r” m 4» Fm“ 5'v -' R“ / V .
*~ “‘" HE Halal" “‘Ph rm L H + L OH \ L - x .x {3‘3" H..N/ KN; «QMH-r HO” 0.x”; a“! Ha“. \N/ _Na .1130 g ‘tv’ * H H H H p2 .4 "" H234 ‘M’ N E o w - : I H H H H H H SR: Fmoc g Hflk {EH ll [1% w‘ ~ ' xJJ wrw. Mg,» H ?H f “"r Piperidines; 34%} \ng. 34w” x. x \,__— M, rfl «@213 HUI, memo Jm | "x .}g llzl's. é} —-——-'I»' HIM-f N’A .
. MN” 5x0W»- ~V” ,- H “a” 2M0”; “v” H H Ni “N' was:. ‘ ' H H H cw? In another embodiment, the compound of formula (I) is prepared by: reacting a nd of formula (II—A): I (II-A) H2N N NH2 With a compound of formula (III—A): HO OH (III—A) HO 0 in the presence of a hydrazine to e a compound of a (IV-A): 21 OH HN (IV-A) AU OH HZN N IZ O selectively protecting the compound of formula (IV—A) to prepare a compound of formula (VB): 0 R1 OH l OH i (V B) R1 X OH \u N T 0 wherein: each R1 is independently a protecting group, as defined above; phosphorylating the compound of formula (V-B) to prepare a compound of formula (VI-B): 0 R1 OH I 0R1 N o l \T/zo (VI-B) R A o 1\N \N N o H I oxidizing the nd of formula (VI-B) to prepare a compound of formula (VII—B): ‘ R1 HO OH N o /0R1 HN \on ‘ | (VII—B) R o 1\u \N T 0 ; and deprotecting the nd of formula (VII-B) to prepare the compound of formula (I). For example, a compound of formula (I) can be prepared as shown in Scheme 4.
Scheme 4. a 3mm. MAP,W a: bask: Mp 13 {muypgw:gja, dfi-dfimmlrréflaméa '2} twine. lutidino .H ’ R l a Ma 0" . _"’ “R M: no 0% A» .3 ' .5 HM fl 0 r 5 Ft ft ““x\ {83:63:36) mfifi'mmmlhan . I A?“ E n max . A. mg. , “Mm fl lama? Hh'l E43"“Ag2 N Alternatively, a compound of formula (I) can be formed as shown in Scheme 5. A opyrimidinone compound of formula (II) can be coupled with a phosphorylated hexose of formula (IX). The piperizine ring nitrogen sugar of formula (VIII), to give a compound atoms can be protected to give a compound of formula (X) which can be oxidized to give a diol of formula (XI). The diol of formula (XI) can then be deprotected using appropriate ions and converted to the compound of formula (1).
Scheme 5 O 0R1 O QR1 H CH2 0R2 H - Rlng ion R1 N o R1 NH HO O \N 2 \tho (8.9., with hydrazine) \N \T/zo ‘ + ——.——-—————> R1 \ 0 R1 /LN‘ \T \N 0 N NHz HO 0 n R1 (II) (V111) R1 (1X) R1 = H or R2 = H or protecting group protecting group R3 R3 0 0 l 0R1 ‘ HO OH R1 N O 2 R N O \N \on 1\N \P/=O Piperizine V nng protection I I [O] ‘ I _—'* o ———-—-> R1 \ O R1 \ \T 0 N N o \T N N R1 Ii? R1 IL4 R3 = protecting group (X) (XI) R4 = H or protecting group 0 HO OH H OH N o\ / Deprotection HN P=O ———> t l \ O 3 5 HzN N M g o g H H In this embodiment, the phosphate may be introduced at the beginning of the synthesis avoid rable equilibrium n the pyrano and furano isomers during subsequent steps the synthesis. For example, a compound of formula (I) can be prepared as shown in Scheme Scheme 6.
‘ UH OH .1 id fi :i H LB § .' Q mNH"‘5 Hat 5 0“», J' / \T(352.1 Fng‘4? HM“ fl: ‘ “r" T—OEE. HZH” “Ph F—N A + —-+ - 0 k“‘H 2 . H” , . L “2“ MR2 HO “‘0'”; “I HEN”; N Gji- ”M ‘ gifé .4 H H R1=¥H Rf=8r§ D H: CH a? HQ HH fl 5| H lH :3 lhé—lfllr’ifi am’ . '5 ,1 '5 so“ ,H. I y. ';,N ”‘x3,, o 1;; j / EPWQR \ W . .,, Pipe-radian”: HM Ru‘DdiNMF’ 24M" ‘P—O ‘—”_‘*” 1% A | a c; rL « _.._+ i | | ,«w mN ~ I . 2‘ ,'0 HEH’ 2 ,M— a. «an (a .
, ., =‘V N MN 2 a HH“ N“ \‘N’IEKOMEEV” H ‘ H H H H :-| R3=Fma~1 Q {pH i; t H. {FR‘ PHtCin: .[L It: U . .
Hal/r \u: ("at.e '5 "wT=U5 HE}, :tGH;H£0‘. F, [lg —————-——.‘ ' 0 ~ xiv - - H”; .x- 0’5\l: 4” H_H *4 a H H; H A compound of formula (I) can also be formed as shown in Scheme 7. diaminopyrimidinone compound of formula (II) can be coupled to a compound of formula (III) atoms of the to afford the piperizine derivative of formula (IV). The piperizine ring nitrogen nd of a (IV) can be protected under standard conditions to give a derivative formula (XII). formula (V). The a (V) structure can be oxidized to afford compounds of Global Phosphorylation of a compound of formula (XII) gives a compound of formula (VII). deprotection of the compound of formula (VII) can afford the compound of formula (I).
Scheme 7 0 0R1 . H Rlng formation. R1 N 0R1 Plperlzme.
R1 NH; OR1 \N HO ‘ (e.g., WIth hydrazme) \N ring protection ‘ 4 + 1 R1 X OR R1 X 0R1 \hll 1 N NH2 HO 0 \N N u R1 (II) (III) R1 av) R1 = H of protecting group R1 O 0 0R1 i HO OH R1 N 0R1 R1 0R1 \N [01 \N ‘ Phosphorylation R1 0R1 R1 \ \ 0R1 \l\|l N N N o \T N o I R1 I R1 R1 (V) (x11) 0 Ho OH R1 N O /OR‘ \N \PZO Deprotection l I __..
R1 \ O ___.
\T N N O R1 l (VII) WO 12922 For example, a compound of formula (I) can be prepared as shown in Scheme 8.
Scheme 8.
O H C2 H H H H; ' if i 2.1-; HO. ; .0. PH. .2ii i . 2*” xF’h . .24, 2 , I a HM” .2 .
‘ ' I “2*“ “J ' *T” 122:2" K“ 2W “29mph Fmoxzwm I + I ————* I I —* I” . w“ x/MM "“25 I s. «in»! = .r" :"H “*2“ r2 “HHS, H0 .x" 0’5 *2" 22.21" "‘22 H“ ,“D v-2 ”W ' H H H H: o a H R HQ: L 52'1HTH I 2:: PH IL : N High;" = GHQ/P“ H6190“!: 'J ”g N” . ”r "" ~ w = “.3 HM" *” " MP RN» H/ “t l A | E c I ———s- | 2 am" H 2:? H: «. G Hfif MN \é‘l'fli ”” H1321} 2:222?” ‘HN.«“:=‘-.QF; . ' 2| H H R H H R=Fmsm . . . o g R W" PH ('2 Pi: A/I‘L XIV] :1 . 2H2 jg: E. EJF‘ {i-P{}2Ng1 xii“... 0H E: grin g we" (I ‘3' . 220252024510 “‘ “N HT all» j: "22:9 I H]: l ‘Tzo ————- I 3:5.» "xix >0 .«r’ 32‘“‘24”" -. ,.’ = “0 - «I 3‘“:" HHr2’ 4.» H. - ,,.—v. ., “r2" “r2" a w“ HEN - 23 9o H3 . l-é H H H 2220! «cF‘M‘EP‘ In an alternative ment, the compound of formula (I) can be formed as shown in Scheme 9. A diaminopyrimidinone compound of formula (II) can be condensed with a 2- carbonyl hexose building block of formula (XVIII) to e an imine of formula (XX) with good regioselectivity. Further activation of a functional group at the anomeric position (such as of formula an acetate) by a Lewis acid (LA) (e. g., TMSOTf) will furnish a cyclized compound (XXI). The newly generated glycosidic bond may be in an equatorial position. Hydrogenation of a compound of formula (XXI) can produce a compound of formula (IV). Selective protection of a compound of a (IV) gives a compound or formula (V) which is oxidized to give a compound of formula (XII). A compound of formula (XII) can then be treated as described herein to furnish the compound of formula (I).
Scheme 9 0 0R1 INH2 0 OR R1 N 0R1 LA \N \ LA -———-—-> _________> I + R1 \ OR R1 \ 0R1 \T 1 N NH2 R10 0 \T N R10 R1 (11) (XVIII) R1 (XX) R1 = H or protecting group 0 CR1 0 0R1 N 0R1 Piperizine R1 N 0R1 R1\ \N \ N ring tion I [H] —————-> ——————> 1 R1\ \ \ 0R1 R1\ N N N O N N N O I H l H R1 (IV) R1 (XXI) R1 R O ‘ OR‘ 0 ‘1 HO OH R1 N 0R1 R N OR1 \N 1\N . [01 —» OR X l OR Formula I R \ 1 , , R \N 1 , ( ) 1 \T N N o 1\N N o R1 | FL 1 | R1 R1 (V) (m) For example, a compound of formula (I) can be prepared as shown in Scheme Scheme 10.
U 83W- H B " ?11:;V J ’XPR N L if 0 Fifi _.&NH: 0;“; £1»;ka h:__, ,y- EKG Nx’" "xv,” HM” New“ LA HN" m I + -——~ I I —- ’0' 0 '~ 5' “(W -.:/" a?L ' 4- ‘L .A 4:“ . o N” Am ”‘0 ’1; V” Hi4" ”rsé “NH, Aefl’ “a“; V HM I .- H ENHI H fi' ~ ’5"fag-I LL H {‘3chv N, Y x o 9.6% ”59”“ : ‘: 802315}; ”My“ HN ~12: {1/ “r {H} l m“;,1 HNK 3f 'x=«*"0"v’% Base A B B‘ 5' .3“ xix a” -‘u fix ME) J Ll :3 H2“ g“ {3 ‘3‘ f4 g H‘N’Wfia" "N” 5‘53“”; “xx ‘ H H H foam 5345:; 0 on: GH D @3113“ W EH H \4 H .
Alternatively, the compound of formula (I) can be formed as shown in Scheme 11. In this synthesis, the cyclization of a diaminopyrimidinone of formula (II) with a hexose building block can be carried out in the presence of base. Activation with a Lewis Acid (LA) affords a cyclic product, which can be deprotected to form an unprotected ketone. The ketone may be phosphorylated and/or globally deprotected as described herein to e the compound of formula (I) or a compound of formula (XIII).
Scheme 11 0 0 R10 0R1 R10 0R1 R1\N NH N HO 0R1 R1\ 0R1 Base N ‘ LA ——————-—> —-—> R1 0R1 \NkNi OR R1 \ 1 \N N 0 R1X o RX 1 NH; R1 (II) R1 R1=Hor X=O,NorS protecting group 0 R10 0R1 0 0 R N OR1 R H OH 1\N Deprotection 1\N Formula I I or R1\ \ 0R1 OH Formula XIII T N INI O Nl N O R1R1 For example, a compound of formula (I) can be prepared as shown in Scheme 12.
Scheme 12.
I | fig: «- Mt »k w, 513/35 JO MLK‘X- ”q ”N" M? wk H551 M NH: Pm 9M»! $4 ?h3 0 5 h- " NEH: 3:H {a D O a : I r!t U H; H [1L H x“ I}: E J » E rig—1 ‘ 0 m N. X xxx—f x .. ,/‘- /“ XL“.
:L/ j3/?11 H‘- H34“ 3:0ng W 7' "4" L I I I —4- cFMP‘xHS OH. _ . if ,3», "“2 “KN v“, _:. f ”aw”, f :1“? WM “WM-1“ "CI; EW‘V’EU ‘34:” N 5x0 E l 3305!? = H H {4; H 5-! In an alternative ment, the compound of formula (I) can be prepared from a cyclization on ofcompound Z, as shown in scheme 13.
Scheme 13 O HO OH Cyclization HN > x ‘ H2N N Compound Z In some embodiments, the compound of formula (I) can be prepared as shown in Scheme 14. A diaminopyrimidinone compound of formula (II) can be coupled to a compound of formula (XXII) to afford the piperizine derivative of formula (IV). The zine ring nitrogen atoms of the compound of formula (IV) can be protected under standard conditions to give a tive of formula (V). In some embodiments, the compound of formula (V) can undergo selective deprotection prior to phosphorylation. For example, one or more of the yl moieties can be deprotected prior to phosphorylation. Phosphorylation of a compound of formula (V) affords a compound of formula (VI). The formula (VI) structure can be oxidized to prepare a compound of formula (VII). Global deprotection of the compound of formula (VII) affords the nd of formula (1).
Scheme 14 0 CR1 0 0R1 H . . .
R1\ NH2 HO 0R1 N 0R1 Piperlzme N Base R1\ N ring protection l + \ 1 R OR1 T N NHz PhHNN/ HO 1\N \N N o R1 (II) (XXII) J21 (IV) R1 = H or protecting group R o 0R1 o ‘1 l1 0R1 R N o 1 /0R1 \N \P=0 R N OR 1\ 1 N orylationt I l I R1\N \N 0 N o R1 \ 0R1 \N N N o | l l R‘ I R1 (W) R1 ‘ 0 l HO OH R1 N O W __[___.0] \N ‘ \Tr—O Deprotection ___., Formula (I) R1\ \ 0 T N N O R1 l (V11) For example, a compound of formula (I), or a pharrnaceutically acceptable salt thereof, can be prepared by reacting a compound of formula (II-A): k ' (II-A) H2N N NH2 with a nd of formula (XXII-A): HO OH PhHNN H0 in the presence of a base to produce a compound of formula (IV-A): O OH N OH HN (IV-A) k . OH H2N N u o of formula The compound of formula (IV—A) can be selectively protected to e a compound (V-C): o 0R1 R1 N 0R1 R1 \ 0R1 \T N T o 5 wherein each R1 is H or a protecting group, as bed herein. The compound of (V-C) can then be phosphorylated to afford a compound of formula (VI—C): R1\N 1 (VI—C) R1\T R1 R1 The compound of formula (VI-C) can then be oxidized to prepare a compound of formula (VII- R‘\N °\|/__ ) R1\T R1 R1 Finally, the compound of formula (VII-C) is deprotected to prepare the compound of a (I).
In some embodiments, both nitrogens on the piperazine ring of compounds (V-C), (VI-C) (VII-C) may be bound to R1.
Alternatively, the compound of formula (I) can be prepared as shown in Scheme 15. A compound of formula (XXIII) can undergo epoxidation to provide a nd of formula (XXIV). The compound of formula (XXIV) can be coupled to a compound of formula (II) to The compound of formula (XXV) can undergo a ring prepare a compound of formula (XXV). e reaction to afford the piperizine derivative of formula (IV). The piperizine ring nitrogen conditions to give a atoms of the compound of formula (IV) can be protected under standard derivative of formula (V). Phosphorylation of a nd of formula (V) affords a compound of formula of formula (VI). The formula (VI) structure can be ed to provide a compound (VII). Global deprotection of the compound of formula (VII) affords the compound of formula (1).
Scheme 15 0R1 R\1 0R1 Epoxide ring N N\ NHZ 0R1 ion R1/ \ H R1\/l\/| _-__> 0R1 'l‘ \N NHZ NH OR l 1 (xxm R1 (11) 2 o o (XXIII) ‘ (XXV) R1: H or i protecting group R4 = H or leaving group 0 R1 OR OR1 N N 1 0R1 N M )1“ 0R1 PiperiZine N/ N ‘ tection o 0 ML. R OR 1 ————> R1\/K| 0R1 1\N)\N i N 0 N N N o 1 l H R I R1 R1 (IV) (V) OR 0R1 11HO OH OR 1 N/ [01 N / o/ N P=0 P h It I ———> Deprotection hosp oryalonR | _" ’ RN“ 0 l R1\ x O a“) N N N 0 (V11) R1 FL W11) For example, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be prepared by reacting a compound of a (XXIII—A): (XXIII-A) I 5 wherein each R1 is independently H or a protecting group and R4 is H or a leaving group, to produce a compound of formula (XXIV): o 0 (XXIV) Reacting the compound of formula OCXIV) with a compound of formula (II—A): I (II-A) H2N N NH2 to produce a compound of a (XXV—A): H2N%N\ OH (XXV—A) NH2 0R1 0 0 Catalyzing ring formation of the compound of formula (XXV-A) to produce a compound of a (IV—D): 0R1 OH 21 0R1 N/ (IV-D) r ' IMZ 2 I2 0 Selectively protecting the compound of formula (IV-D) to prepare a compound of formula (V- 0R1 0R1 H OR1 R1 \ OR1 \T N T 0 R1 R1 wherein each R1 is H or a ting group.
Phosphorylating the compound of formula (V—D) to prepare a compound of formula (VI-D): 0R1 0R1 N o\ N / P=o ‘ | (VI-D) R1 \ o \T N T 0 R1 R1 Oxidizing the compound of formula (VI—D) to prepare a compound of formula ): 0R1 HO OH N o /OR1 N / \on ‘ I (VII-D) R1 O \T \ N T 0 R1 R1 Finally, deprotecting the compound of formula (VII—D) to prepare the compound of a (1).
Com oundso ormula XII : In another ment, compounds of formula (XII) are ed: 0 R1 HO OH R1 N 0R1 \jfij: (x11) R1\T \N 0R1 T o R1 R1 each R1 is independently H or a or pharmaceutically acceptable salts or hydrates thereof, wherein protecting group.
As indicated, certain amino and/or hydroxyl groups of the formula (XII) structure may be protected with an R1 protecting group. For this e, R1 may include any suitable amino or hydroxyl functional group chosen by a person skilled in the chemical arts. For example, amino protecting groups within the scope of the present disclosure include, but are not limited to, 2012/025689 carbamate, amide, N—alkyl, or N—aryl—derived protecting . Non-limiting examples of hydroxyl protecting groups may include ether, ester, carbonate, or sulfonate protecting groups.
The R1 protecting groups may be the same or different.
In particular, the carbamate protecting group may include, for example, 9- fluorenylmethyl carbamate (Fmoc), t—butyl carbamate (Boc), carboxybenzyl carbamate (cbz), methyl carbamate, ethyl carbamate, 9—(2-sulfo)fluorenylmethyl carbamate, 9-(2,7— dibromo)fluorenylmethyl carbamate, l7-tetrabenzo[a,c,g,i]fluorenylrnethyl carbamate (bemoc), 2-chloro-3—indeny1methyl carbamate (Climoc), -t—butyl[9—(10,l0—dioxo-10,10,10,10— tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 1,1-dioxobenzo[b]thiophene-2—ylmethyl carbamate (Bsmoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate , 2—pheny1ethy1 carbamate (hZ), 1,1—dimethyl-2—haloethy1 ate, l,1-dimethyl—2,2- dibromoethyl carbamate boc), l,1—dimethyl-2,2,2-trichloroethyl carbamate (TCBoc), 1- methyl—l -(4—bipheny1yl)ethy1 carbamate (Bpoc), 1 —(3,5-di—t-buty1phenyl)— l -methylethy1 carbamate (t—Bumeoc), Npivaloy1amino)-l,l-dimethylethyl carbamate, 2-[(2- nitropheny1)dithio]— 1 -phenylethyl carbamate (NpS , 2-(N,N- ohexylcarboxamido)ethyl carbamate, l-adamantyl carbamate (l-Adoc), vinyl carbamate (Voc), 1-isopropy1allyl carbamate (Ipaoc), 4-nitrocinnamyl carbamate (Noc), 3-(3’pyridy1)prop— 2-eny1 carbamate (Paloc), 8—quinolyl carbamate, alkyldithio carbamate, p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate (Pnz), p-bromobenzyl carbamate, p-chlorobenzyl carbamate, chlorobenzyl carbamate, 4—methylsulfinylbenzyl carbamate (Msz), diphenylmethyl carbamate, 2-methylthioethy1 carbamate, 2—methylsulfonylethyl carbamate, 2-(p- toluenesulfony1)ethylcarbamate, [2—(1,3-dithianyl)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), methy1thiopheny1 carbamate (Bmpc), 2— onoethyl ate (Peoc), 1,1—dimethyl-2—cyanoethyl carbamate, 2—(4-nitrophenyl)ethy1 carbamate, 4-phenylacetoxybenzyl ate (PhAcOZ), and m-chloro-p-acyloxybenzyl carbamate. In some embodiments, a carbamate protecting group is chosen from 9- fluorenylmethyl carbamate (Fmoc), l ate (Boc), and carboxybenzyl carbamate (cbz) protecting groups.
The amide protecting group may include, for example, acetamide, phenylacetamide, 3- » phenylpropanamide, pent—4—enamide, picolinamide, 3—pyridylcarboxamide, benzamide, p— benzamide, 2-methyl—2-(0-pheny1azophenoxy)propanamide), 4—chlorobutanamide, acetoacetamide, 3 —(p-hydroxyphenyl)propanamide), and (N’ - dithiobenzyloxycarbonylamino)acetamide.
The ether protecting group may include methyl, methoxy methyl (MOM), benzyloxymethyl (BOM), methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl (SEM), methylthiomethyl (MTM), phenylthiomethyl (PTM), ethyl, cyanomethyl, 2,2- dichloro-l,l-difluoroethyl, roethyl, 2-bromoethyl, tetrahydropyranyl (THP), l-ethoxyethyl (EE), phenacyl, 4-bromophenacyl, cyclopropylmethyl, allyl, propargyl, isopropyl, cyclohexyl, [- butyl, benzyl, 2,6-dimethylbenzyl, 4—methoxybenzyl (MPM-OAr), 0~nitrobenzyl, 2,6— dichlorobenzyl, 3,4—dichlorobenzyl, 4—(dimethylamino)carbonylbenzyl, 4—methylsulfinylbenzyl (Msib), 9—anthrylmethyl, 4-picolyl, heptafluoro-p-tolyl, tetrafluoro-4—pyridyl, trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS), t—butyldiphenylsilyl ), and triisopropylsilyl (TIPS) protecting groups.
The ester protecting group may include acetoxy (OAc), aryl formate, aryl acetate, aryl levulinate, aryl pivaloate, aryl benzoate, and aryl 9—fluoroenecarboxylate. In one embodiment, the ester protecting group is an y group.
The carbonate ting group may include aryl methyl carbonate, l-adamantyl carbonate (Adoc-OAr), t-butyl carbonate (BOC—OAr), 4-methylsulfinylbenzyl carbonate (Msz— OAr), 2,4-dimethylpentyl ate (Doc-OAr), aryl 2,2,2-trichloroethyl carbonate, aryl vinyl carbonate, aryl benzyl ate, and aryl carbonate.
The ate protecting groups may include aryl methanesulfonate, aryl toluenesulfonate, and aryl 2-formylbenzenesulfonate.
In some embodiments, the R1 protecting group is t-butyl carbamate (Boc).
Protection of certain amino and hydroxyl groups can improve solubility of the a (XII) compounds. For example, preparation of acetyl derivatives of a compound of formula (XII) can e solubility and increase t isolation yield.
A compound of formula (XII) may be prepared by oxidizing a compound of formula (V): WO 12922 0 R1 0R1 R N OR 1\ 1 R1 \ 0R1 \T N T 0 R1 R1 wherein: each R1 is independently H or a protecting group, as defined above, to prepare a compound of formula (X11): 0 T1 HO OH R N OR 1\ 1 | (x11) R1 \ 0R1 \N N T 0 R1 R1 In this synthesis, a compound of formula (XII) may be prepared by reacting a compound of formula (V) with any oxidizing agent proper to selectively form the diol of formula (XII). le oxidizing agents and conditions can be readily determined by those of ordinary skill in the art. For example, a compound of formula (XII) may be formed upon treatment of a compound of a (V) With a ium compound, such as RuO4'/NMO. Other oxidants, such as Dess-Martin’s reagent, DMSO/triflic anhydride, TFAA/DMSO, PDC, hydrogen peroxide, inorganic peroxides, nitric acid, nitrates, chlorite, chlorate, perchlorate, hypochlorite, peroxide, iodine, ozone, nitrous oxide, silver oxide, permanganate salts, hexavalent chromium compounds, chromic acid, dichromic acids, chromium trioxide, nium chlorochromate, persulfuric acid, sulfoxides, sulfuric acid, s’ reagent, 2,2’-dipyridy1disulf1de (DPS), and osmium tetroxide may also be used. In one embodiment, the oxidation conditions are performed In some embodiments, the oxidizing so that the pyrazine ring of compound (XII) is not oxidized. agent is chosen from RuO4'/NMO, Dess-Martin’s t, DMSO/triflic anhydride, TFAA/DMSO, and PDC.
For example, the oxidation on may be carried out by treating a compound of formula (V) with RuO4'/NMO at ambient temperature to afford a nd of formula (XII). In another embodiment, a compound of formula (XII) is formed by treating a compound of formula (V) with RuO4'/NMO at a temperature from about 20 — 60 °C (e. g, at about 20, 25, 30, 35, 40, 45, 50, or 55 °C).
As will be understood, the isomeric form of the a (XII) structure may regulate the stereospecificity of subsequent intermediates in the successive steps in the synthesis of formula (I) or formula . Accordingly, a particular isomer may be isolated at this step of the synthesis or, alternatively, isomeric mixtures of a compound of formula (XII) may be carried through and ed at later stages of the synthesis.
Com ouna’s 0 ormula XIII .' In another embodiment, a compound ofthe formula (XIII) is prepared: 0 O IZ Illlll O Iilllam or ceutically acceptable salts or hydrates thereof. A compound of formula (XIII) also includes the tautomeric structure: OH 0 H OH N / k = = O H2N N N g 0 g H H H or pharmaceutically able salts or hydrates thereof.
The compound of formula (I) can be a on product of a compound of formula (XIII) and water. Alternatively, the compound of formula (XIII) can be a dehydration product of a compound of formula (I). Given the equilibrium created between these two products, at certain pHs and conditions, both species may be present in an aqueous solution. One of skill in the art can control tic conditions (e. g. , working in the e of water) to isolate the ketone species of a (XIII) to reduce or eliminate the presence of the compound of formula (1).
While the methods described above for producing a compound of formula (I) give rise to a gem- diol following oxidation (e. g., a compound of formula (VII)), the methods can include an additional step involving le dehydration conditions (e. g., concentrated acid or base) to produce a ketone (e. g., a compound of formula (XIV)). For example, the conversion can occur as shown in Scheme 16.
Scheme 16.
R1 R1 0 0 o HO OH I R1 l o f“ R N o F“ \N 1\N \P=O l \T=o +120 v——_~———-'— I + H20 R1\ \ O R1\ \ A N N 0 N N o | {\II R l R l 1 1 R1 R1 (VII) (XIV) Following formation of the , the remaining steps of the methods described below may used to produce a compound of a (XIII).
The compound of a (XIII) may be ed by deprotecting the compound of formula (XIV): 0 R1 0 R N O /OR1 1\N . l \T=o R O 1\T \N T 0 wherein: each R1 is independently H or a protecting group, as defined above, to e the compound formula .
In this synthesis, the deprotection may involve, for example, either sequential or one—pot deprotection of certain amino and hydroxyl protecting groups of formula (XIV) to furnish the compound of formula (XIII). Suitable reagents and conditions for the deprotection of the compound of formula (XIV) can be readily determined by those of ordinary skill in the art. For e, compound (XIII) may be formed upon treatment of the compound of formula (XIV) under conditions so that hydroxyl protecting groups, such as acetate, isopropylidine, and benzylidine protecting groups, are removed from formula (XIV). The acetate group can be cleaved, for example, under Zemplén conditions using catalytic NaOMe as a base in methanol. acidic The benzylidene and isopropylidene groups can be cleaved by hydrogenation or using hydrolysis as ed by RM. Hann et al., J Am. Chem. 800., 72, 561 (1950). In yet another example, the ection can be performed so that amino protecting groups, such as 9- fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (Boc), and ybenzyl carbamate (cbz) protecting groups are cleaved from the compound of formula (XIV). 9—fluorenylmethyl carbamate (Fmoc) can be removed under mild conditions With an amine base (eg. , piperidine) afford the free amine and dibenzofulvene, as described by E. Atherton et al., “The and J.
Fluorenylmethoxycarbonyl Amino Protecting Group,” in The Peptides, S. Udenfriend ofer, Academic Press, New York, 1987, p. 1. t-butyl carbamate (Boc) can be removed, as reported by G.L. Stahl et al., J. Org. Chem, 43, 2285 (1978), under acidic conditions (e. g., 3 HCl in EtOAc). Hydrogenation can be used to cleave the carboxybenzyl carbamate (cbz) protecting group as described by J. Meienhofer et al., edron Lett, 29, 2983 (1988).
To prevent oxidation of a (XIII) during the reaction, the deprotection may performed under anaerobic conditions. The deprotection may also be performed at ambient 55 °C. temperature or at temperatures of from 20—60 °C, or 25, 30, 35, 40, 45, 50, or Alternatively, compounds of formula (XIII) can be formed as shown in Scheme 17. A diaminopyrimidinone compound of formula (II) can be d with a phosphorylated hexose of formula (IX). The piperizine ring en sugar of formula (VIII), to give a compound oxidized to give a diol atoms can be protected to give a compound of formula (X) which can be of formula (XV). The diol of a (XV) can then be deprotected using appropriate conditions and converted to the compound of formula (XIII).
Scheme 17 0 0R1 o on1 0R2 . H 0R2 R NH formation N o 1\N 2 HO 0\p{:o mg R1 (eg, with hydrazine) \N l + | ———» | \pé-o R1 \ 0 R1 k 0 \T N NH2 HO 0 \T N m 0 R1 (II) (V111) R1 (IX) R1 = H or R2 = H or protecting group protecting group R R o '3 0R1 o ’3 0 OR 2 R N o 2 R1 N o Piperizine 1\N \P{——O \N \P/=O ring protection ‘ | [0] ‘ I R1 \ 0 O , R1 \ \T N N o \T N N o R I R 1 1 l R4 R4 R3 = protecting group (X) (XV) R4 = H or protecting group Deprotection In another embodiment, a compound of formula (XIII) may be formed as shown in Scheme 18. For example, a diaminopyrimidinone compound of formula (II) can be reacted with a protected or unprotected hexose sugar of formula (III) to give a nd of formula (IV).
The ring nitrogen atoms of the piperizine ring of formula (IV) can then be ively protected using standard conditions to give a derivative of formula (V). Phosphorylation of the compound of formula (V) can furnish a phosphate intermediate of formula (VI). The ate of formula (VI) can be converted to a ketone of formula (XIV) under riate oxidation conditions. y, the compound of formula (XIV) can be deprotected to give the compound of formula (XIII).
Scheme 18.
PCT/U82012/025689 o 0R1, H . . .
Ring formatlon. N QR1 Pipenzme R1 NHz H0 OR R1 \N 1 . (e.g.. wuth hydrazme) \N ring protection ‘ ——————> + —————-——> I R1\ \ 0R1 R1\ \ ORI I]! N NHZ HO 0 T N u (11) (111) R1 (IV) R1 = H or protecting group R1 0 OR1 0 OR1 l R1\N)&Ni 0R1 Phosphorylation R1\N O\F‘/=O [O] —’—’ i ____, l l R1 0R1 R1 \ \T \N \rxli N N o N o i R 1 R1 1 R1 (V) (VI) 0 i 0 R1 N O /0R1 \N \P=O ection i I ——» R1\ 0 \ —-—> a IT N N O H2N N n 0 a g H H R. I R1 (XIII) (XIV) Alternatively, the compound of formula (XIII) can be prepared as shown in Scheme 19. of formula A diaminopyrimidinone nd of formula (II) can be coupled to a compound atoms of (XXII) to afford the piperizine derivative of formula (IV). The piperizine ring nitrogen derivative of the nd of formula (IV) can be protected under standard conditions to give a formula (V). In some ments, the compound of formula (V) can undergo selective deprotection prior to phosphorylation. For example, one or more of the yl moieties can be deprotected prior to phosphorylation. Phosphorylation of a compound of formula (V) affords afford compounds of compounds of formula (VI). The formula (VI) structure can be oxidized to formula (XIV). Global deprotection of the compound of a (XIV) can afford the compound of formula (XIII).
Scheme 19 0 0R1 o 0R1 R1\ NHz HO 0R1 R1\ u 0R1 Piperizine N Base N ring protection | + —————-> _—————> 1 R1\ \ 0R1 R OR1 N NHZ PhHNN/ HO 1\N \N T E o R1 (11) (XXII) ;1 (m R1 = H or protecting group R1 o 0R1 R‘ 0R1 o 0R1 R1\ N o\ / N P=0 R N OR 1\ 1 Phosphorylatlon. N I | t 0 .._.._-—> R1\ \ N N N o R1\ \ 0R1 N N o l N I l I R1 R1 (VI) 0 O R1\ N O __-_> i \ll’zo Deprotection -———> Formula (XIII) R1\ 0 T N N O R1 l (XIV) atively, the compound of formula (XIII) can be prepared as shown in Scheme 20. of formula A compound of formula (XXIII) can undergo epoxidation to provide a compound formula (II) to (XXIV). The compound of formula (XXIV) can be coupled to a compound of The compound of formula (XXV) can undergo a ring prepare a compound of formula (XXV). closure on to afford the piperizine derivative of formula (IV). The zine ring nitrogen ions to give a atoms of the compound of formula (IV) can be protected under rd derivative of formula (V). Phosphorylation of a compound of formula (V) affords compounds of of formula formula (VI). The formula (VI) structure can be oxidized to afford compounds (XIV). Global deprotection of the compound of formula (XIV) can afford the compound a (XIII).
Scheme 20 O 0R1 R1 OR1 Epoxide ring 0R1 N\ / NH2 N 0R1 formation + N l R1/ \ kl OR 0R1 —-———> N / 1 O O R1\NJ\N NH2 I NH 0R1 RI 2 (XXIV) R1 (11) o 0 (XXIII) I (XXV) =Hor l protecting group R4: Hor leaving group \N/lkN/ 0R1 0R1 M H QR1 Piperizine N/ O 0 I ringprotection ‘——" R1\ X 0R1 R1\N N N N O I H . l1 (IV) (V) l1 O IR‘ 0R1 N/ \P=O __[.l__.O N 0 ’ N/ Deprotection- I \I?=O ——" __>PhosphoryiationR )1 R1\N 0 l R1 \ O Formula(XIlI) \N N N o R1 l (VI) (XIV) The compound of formula (XIII) may be isolated in the form a pharmaceutically acceptable salt. For example, the compound of formula (XIII) may be crystallized in the of the compound. In some embodiments, the presence of HCl to form the HCl salt form compound of a (XIII) may be crystallized as the HBr salt form of the compound. The compound of formula (XIII) may also be isolated, e. g., by itation as a sodium salt by treating with NaOH. The compound of formula (XIII) is labile under certain reaction and storage conditions. In some embodiments, the final solution comprising the compound of formula (XIII) may be acidified by methods known in the art. For example, the compound of formula , if stored in solution, can be stored in an acidic solution.
Com oundso ormula XIV In another ment, cognpounds of formula (XIV) are ed: R1\R1llN ONE/(:0 (XIV) T I R1 R1 wherein each R1 is independently H or a or pharmaceutically acceptable salts or hydrates thereof, includes the compound (XIV- protecting group. For example, the compound for a (XIV) 0 R1 0 | ' OH N o HN \P/-—"—“O l | (VII—A) H2N N o p u n R1 is H or a ting group. The or a pharmaceutically acceptable salt thereof, compound of formula (XIV) also includes, for example, the compound: O Fmoc O H N O /OH l \T20 X 0 H2N N a o (9H-fluoren-9—yl)methy| 8-amino—2—hydroxy—10,12-dioxo—4,4a,5a,6,9,10,12,12a-octahydro- [1,3,2]dioxaphosphinino[4',5'25,6]pyrano[3,2-g]pteridine-11(11aH)-carboxylate 2-oxide In some embodiments, the compound of formula or a pharmaceutically acceptable salt thereof.
(XIV) includes the compound ): 0 R1 0 I OR1 N o HN \P/:0 /l\ l l (VII-B) HN N N 0 FL l, In some embodiments, the compound of formula or a pharmaceutically acceptable salt thereof.
(XIV) includes the compound (XIV—C): R‘\N/Uj:" 0R1 H °\P/:O l | (VII C) R1\N \N N O FL FL In some embodiments, a compound of formula or a pharmaceutically acceptable salt thereof.
(XIV) can include one or more of the following: R1 R1 0 0 N o\ / . TZO R1 k \T N T 0 R1 R1 O\P—0 R1 /T;Nl O R1 R1 For e, a compound of formula (XIV) can or a pharmaceutically acceptable salt thereof. include one or more of the following: O O Boc n 0 /° ‘ \T:—0 k 0 HT N T O Boc Boc O O ' O N o / Boc X 0 \T N T o Boc Boc OBoc O n o f ‘ \TZO Boc k 0 \T N T o Boc Boc or a pharmaceutically acceptable salt thereof. In some embodiments, one or more of the above compounds can be separated by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) (“Preparative LC—MS Purification: Improved Compound Specific Method Optimization” K.F. Blom, et al., J Combi. Chem. 6(6), 874 (2004), which is incorporated herein by reference in its entirety) and normal phase silica chromatography.
As ted, certain amino and/or hydroxyl groups of the formula (XIV) ure may be protected with an R1 protecting group. For this purpose, R1 may include any suitable amino arts. For example, or hydroxyl onal group chosen by a person skilled in the chemical amino protecting groups within the scope of the present disclosure include, but are not limited to, carbamate, amide, l, or N-aryl-derived protecting . miting examples of hydroxyl protecting groups may include ether, ester, carbonate, or sulfonate protecting groups.
The R1 protecting groups may be the same or different.
In particular, the carbamate protecting group may include, for example, 9- fluorenylmethyl carbamate (Fmoc), t—butyl carbamate (Boc), carboxybenzyl carbamate (cbz), methyl carbamate, ethyl carbamate, 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7— dibromo)fluorenylmethyl carbamate, 17—tetrabenzo[a,c,g,i]fluorenylmethyl carbamate (bemoc), 2-chloro-3—indenylmethyl carbamate (Climoc), 2,7-di—t—butyl[9—(1 0,1 o-10,10,10,10- ydrothioxanthyl)]methyl carbamate (DBD—Tmoc), oxobenzo[b]thiopheneylmethy1 carbamate (Bsmoc), 2,2,2—trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2—phenylethyl carbamate (hZ), 1,1-dimethyl-2—haloethyl carbamate, methyl-2,2- dibromoethyl carbamate boc), l,1-dimethyl—2,2,2-trichloroethyl carbamate (TCBoc), 1- methyl(4—biphenylyl)ethyl carbamate (Bpoc), l -(3 ,5-di—t-butylphenyl)— l —methylethyl carbamate (t-Bumeoc), N-2—pivaloylamino)-1,l—dimethylethyl carbamate, 2-[(2- nitrophenyl)dithio]-1—pheny1ethyl ate (NpS SPeoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, 1 -adamanty1 carbamate (1 -Adoc), Vinyl carbamate (Voc), l-isopropylallyl carbamate ), 4—nitrocinnamyl carbamate (Noc), 3-(3’pyridyl)prop— 2-enyl carbamate (Paloc), 8-quinolyl carbamate, alkyldithio carbamate, p—methoxybenzyl carbamate (Moz), p—nitrobenzyl carbamate (Pnz), p—bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), diphenylmethyl carbamate, ylthioethyl carbamate, ylsulfonylethyl carbamate, 2—(p- toluenesulfonyl)ethyl carbamate, [2-(1,3—dithianyl)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate , 2,4—dimethylthiophenyl carbamate , 2— phosphonoethyl carbamate (Peoc), 1,l—dimethyl-Z-cyanoethyl carbamate, 2-(4—nitrophenyl)ethyl carbamate, 4-phenylacetoxybenzyl carbamate Z), and m—chloro-p-acyloxybenzyl carbamate. In particular, 9—fluorenylmethyl carbamate (Fmoc), t—butyl carbamate (Boc), and carboxybenzyl carbamate (cbz) protecting groups may be used.
The amide protecting group may include, for example, acetamide, phenylacetamide, 3- phenylpropanamide, pent-4—enamide, picolinamide, 3—pyridylcarboxamide, benzamide, pphenylbenzamide , 2-methyl—2—(o-phenylazophenoxy)propanarnide), robutanamide, and (N’ — , acetoacetamide, 3-(p-hydroxyphenyl)propanamide), dithiobenzyloxycarbonylamino)acetamide.
The ether ting group may include methyl, methoxy methyl (MOM), benzyloxymethyl (BOM), methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl (SEM), methylthiomethyl (MTM), thiomethyl (PTM), azidomethyl, cyanomethyl, 2,2- dichloro- 1 , 1 roethyl, 2—chloroethyl, 2-bromoethyl, ydropyranyl (THP), l —ethoxyethyl (EE), phenacyl, 4—bromophenacyl, cyclopropylmethyl, allyl, gyl, isopropyl, cyclohexyl, t- butyl, benzyl, 2,6-dimethylbenzyl, 4-methoxybenzyl (MPM-OAr), o—nitrobenzyl, 2,6— dichlorobenzyl, 3,4-dichlorobenzyl, 4-(dimethylamino)carbonylbenzyl, 4-methylsulf1nylbenzyl (Msib), 9-anthrylmethyl, 4-picolyl, heptafluoro-p-tolyl, tetrafluoropyridyl, trimethylsilyl (TMS), t—butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS) protecting groups.
The ester protecting group may include acetoxy (OAc), aryl e, aryl acetate, aryl levulinate, aryl pivaloate, aryl benzoate, and aryl 9—fluoroenecarboxylate. In one embodiment, the ester protecting group is an acetoxy group.
The carbonate ting group may include aryl methyl ate, l—adamantyl carbonate (Adoc—OAr), t—butyl carbonate (BOC—OAr), 4-methylsulfinylbenzyl ate (Msz— OAr), 2,4-dimethylpent—3-yl carbonate (Doc-OAr), ary12,2,2—trichloroethyl carbonate, aryl vinyl carbonate, aryl benzyl carbonate, and aryl carbonate.
The sulfonate protecting groups may include aryl methanesulfonate, aryl toluenesulfonate, and aryl 2—formylbenzenesulfonate.
In some embodiments, the R1 protecting group is t—butyl carbamate (Boc).
Protection of certain amino and hydroxyl groups can improve solubility of the formula (XIV) compounds. For example, preparation of acetyl derivatives of formula (XIV) can improve solubility and se t isolation yield.
The compound of formula (XIV) may be prepared by oxidizing the compound of formula (VI): 0 R1 0R1 l 0R1 R1 N o \N \on i I l R1 \ o \T N T 0 R1 R1 to prepare a compound of formula (XIV): O |T1 O R N O R 1\N/uj: mun/=0O 1\[\|] \N T 0 R1 R1 wherein: each R1 is independently H or a protecting group, as defined above.
In this sis, the compound of formula (XIV) may be prepared by reacting the compound of formula (V1) with any oxidizing agent proper to selectively form the ketone of formula (XIV). Suitable oxidizing agents and ions can be readily determined by those of ordinary skill in the art. For example, compound (XIV) may be formed upon treatment of the compound of formula (V1) with a ruthenium compound, such as RuO4'/NMO. Other oxidants, such as Dess-Martin’s reagent, DMSO/triflic anhydride, TFAA/DMSO, PDC, hydrogen peroxide, inorganic peroxides, nitric acid, nitrates, te, chlorate, perchlorate, hypochlorite, peroxide, iodine, ozone, nitrous oxide, silver oxide, permanganate salts, hexavalent chromium compounds, chromic acid, dichromic acids, chromium trioxide, pyridinium chlorochromate, furic acid, sulfoxides, sulfuric acid, Tollens’ t, 2,2’—dipyridyldisulfide (DPS), and osmium ide may also be used. In one embodiment, the oxidation conditions are performed In particular, the oxidizing agents so that the pyrazine ring of compound (XIV) is not oxidized.
RuO4'/NMO, Dess-Martin’s reagent, riflic anhydride and PDC may be used.
For example, the oxidation on may be carried out by treating the compound of formula (V1) with RuO4'/NMO at ambient ature to afford the compound of formula (XIV). In another embodiment, the compound of formula (XIV) is formed by treating the compound of formula (VI) with RuO4'/NMO at a temperature from 20 - 60 °C, or at 20, 25, 30, , 40, 45, 50, or 55 °C.
A nd of formula (XIV) can also be prepared by dehydrating a compound of formula (VII). Suitable reaction conditions for such a dehydration reaction are readily determined by those of ordinary skill in the art. For example, a compound of formula (VII) can be combined with a concentrated acid or base to e a compound of a (XIV).
As will be understood, the isomeric form of the formula (XIV) structure may regulate stereospecificity of subsequent intermediates in the successive steps of the synthesis of formula (XIII). Accordingly, a ular isomer may be isolated at this step of the synthesis or, alternatively, isomeric mixtures of formula (XIV) may be carried through and isolated at later stages of the synthesis.
In one embodiment, the compound of formula (XIV) includes the isomer: 0R1 R1 0 or a pharmaceutically acceptable salt thereof.
Com ounds 0 ormula XXII Another embodiment relates to a compound of a (XXII): HO 0R1 (XXII) / 0R1 PhHNN HO wherein each R1 is independently H or a or pharmaceutically acceptable salts or hydrates f, protecting group.
As indicated, the hydroxyl groups in the compound of formula (XXII) may be protected or unprotected form. For e, in an unprotected form, the compound for formula (XXII) may include the compound (XXII—A): HO OH PhHNN/ OH 6-(2-phenylhydrazono)hexane-l,2,3,4,5-pentaol or a pharmaceutically acceptable salt, thereof.
Certain hydroxyl groups of the formula (XXII) structure may be protected with an R1 protecting group. For this purpose, R1 may include any le hydroxyl functional group chosen by a person skilled in the al arts. For e, non—limiting examples of hydroxyl The R1 protecting groups may include ether, ester, carbonate, or sulfonate protecting . protecting groups may be the same or different.
The ether protecting group may include methyl, methoxy methyl (MOM), benzyloxymethyl (BOM), methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl 2,2- (SEM), methylthiomethyl (MTM), phenylthiomethyl (PTM), azidomethyl, cyanomethyl, dichloro-l ,l-difluoroethyl, 2-chloroethyl, 2—bromoethyl, tetrahydropyranyl (THP), l-ethoxyethyl (EE), phenacyl, 4-bromophenacyl, cyclopropylmethyl, allyl, propargyl, pyl, exyl, butyl, , 2,6—dimethylbenzyl, 4-methoxybenzyl (MPM-OAr), o-nitrobenzyl, 2,6- dichlorobenzyl, 3,4-dichlorobenzyl, 4-(dimethylamino)carbonylbenzyl, 4—methylsulfinylbenzyl (Msib), 9-anthrylmethyl, 4-picolyl, heptafluoro-p—tolyl, tetrafluoropyridyl, trimethylsilyl and triisopropylsilyl (TMS), t—butyldimethylsilyl (TBDMS), t—butyldiphenylsilyl (TBDPS), (TIPS) protecting groups.
The ester protecting group may include acetoxy (OAc), aryl formate, aryl acetate, aryl In one embodiment, levulinate, aryl pivaloate, aryl benzoate, and aryl 9—fluoroenecarboxylate. the ester ting group is an acetoxy group.
The carbonate protecting group may include aryl methyl carbonate, l—adamantyl ate (Mszcarbonate (Adoc-OAr), t—butyl carbonate (BOC—OAr), 4-methylsulfinylbenzyl Vinyl OAr), 2,4—dimethylpentyl carbonate (Doc-OAr), aryl trichloroethyl carbonate, aryl carbonate, aryl benzyl carbonate, and aryl ate.
The sulfonate protecting groups may include aryl methanesulfonate, aryl toluenesulfonate, and aryl 2-formylbenzenesulfonate.
In some embodiments, the R1 protecting group is t-butyl carbamate (B00).
In some embodiments, two adjacent R1 groups come together to form an isopropylidine acetal, benzylidine acetal, l,5—dioxaspiro[5.5]undecane (cyclohexylidene acetal), 6,10- dioxaspiro[4.5]decane (cyclopentylidene acetal), or 2—isobutyl-2—methyl-1,3-dioxane moiety. of formula For example, the R1 groups at the 4- and 5~positions of the hexose ring component (XXII) can combine to form an pylidine acetal, benzylidine , 1,5- dioxaspiro[5.5]undecane (cyclohexylidene acetal), 6,10-dioxaspiro[4.5]decane (cyclopentylidene acetal), or 2-isobutyl—2-methyl—1,3-dioxane moiety. formula Protection of n amino and hydroxyl groups can e solubility of the (XXII) compounds. For example, preparation of acetyl derivatives of formula (XXII) can improve solubility and increase product isolation yield.
A compound of formula (XXII) may be prepared by known methods (see, 6. g, Goswami, S.; Adak, A.K. Tetrahedron Lett. (2005), 46, 221—224) or purchased cially.
As will be understood, the ic form of the formula (XXII) structure may govern of formula stereospecificity of subsequent intermediates in the successive steps of the synthesis (I) or formula (XIII). Accordingly, a ular isomer may be isolated at this step of the synthesis or, atively, isomeric mixtures of formula (XXII) may be d through isolated at later stages of the synthesis. isomer: In some embodiments, the compound of formula (XXII) includes the Home, 0R1 / 0R1 PhHNN H0 thereof. or pharmaceutically acceptable salts or hydrates Compounds of formula (XXIII) Another embodiment relates to a nd of formula (XXIII): 2012/025689 R10 0R1 (XXIII) o 0 K 9 wherein each R1 is independently H or a or ceutically acceptable salts or es thereof, protecting group and R4 is H or a leaving group. be in As indicated, the hydroxyl groups in the compound of formula (XXIII) may protected or unprotected form. For example, in an unprotected form, the compound for formula (XXIII) may include the compound 2-(allyloxy)(hydroxymethyl)tetrahydro—2H—pyran-3,4,5- triol: HO OH O O 2—(allyloxy)(hydroxymethy1)tetrahydro-2H- pyran—3 ,4,5 -triol or a pharmaceutically acceptable salt, thereof.
Certain hydroxyl groups of the formula (XXIII) ure may be protected with an R1 protecting group. For this e, R1 may include any suitable hydroxyl functional group chosen by a person skilled in the chemical arts. For example, non-limiting examples of hydroxyl The R1 protecting groups may include ether, ester, carbonate, or sulfonate protecting groups. protecting groups may be the same or different.
The ether protecting group may include methyl, methoxy methyl (MOM), benzyloxymethyl (BOM), methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl (SEM), methylthiomethyl (MTM), phenylthiomethyl (PTM), azidomethyl, cyanomethyl, 2,2— dichloro—l ,1 -difluoroethyl, roethyl, 2—bromoethyl, ydropyranyl (THP), l-ethoxyethyl (EE), phenacyl, 4—bromophenacyl, cyclopropylmethyl, allyl, propargyl, isopropyl, cyclohexyl, butyl, benzyl, 2,6-dimethylbenzyl, 4-methoxybenzyl (MPM-OAr), o-nitrobenzyl, 2,6— dichlorobenzyl, 3,4—dichlorobenzyl, 4-(dimethylamino)carbonylbenzyl, 4—methylsulfinylbenzyl (Msib), 9-anthrylmethyl, 4—picolyl, heptafluoro-p-tolyl, tetrafluoropyridyl, trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS), t—butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS) protecting groups.
The ester ting group may include acetoxy (OAc), aryl formate, aryl acetate, aryl levulinate, aryl pivaloate, aryl benzoate, and aryl 9—fluoroenecarboxylate. In one embodiment, the ester protecting group is an acetoxy group.
The carbonate protecting group may include aryl methyl carbonate, antyl carbonate (Adoc—OAr), t-butyl carbonate (BOC—OAr), 4—methylsulfinylbenzyl carbonate (Msz- OAr), 2,4—dimethylpentyl carbonate Ar), aryl 2,2,2-trichloroethyl carbonate, aryl Vinyl carbonate, aryl benzyl carbonate, and aryl carbonate.
The sulfonate protecting groups may include aryl methanesulfonate, aryl toluenesulfonate, and aryl 2-formylbenzenesulfonate.
In some embodiments, the R1 ting group is t-butyl carbamate (Boc).
In some embodiments, two adjacent R1 groups come together to form an isopropylidine acetal, benzylidine , 1,5—dioxaspiro[5.5]undecane (cyclohexylidene acetal), 6,10— dioxaspiro[4.5]decane (cyclopentylidene acetal), or 2—isobutyl—2-methyl-l xane moiety. formula For example, the R1 groups at the 4- and 5—positions of the hexose ring component of (XXIII) can combine to form an isopropylidine acetal, benzylidine acetal, 1,5— dioxaspiro[5.5]undecane (cyclohexylidene acetal), 6,lO-dioxaspiro[4.5]decane (cyclopentylidene acetal), or 2-isobutyl—2-methy1-l,3—dioxane . For example, a compound of formula (XXIII) can be a compound of a (XXIII-B): R10 0 O O or a pharmaceutically acceptable salt thereof. For example, a compound of (XXIII) can include a compound: HO O O O W or HO O O 0 or a pharmaceutically able salt thereof.
Protection of n amino and hydroxyl groups can improve solubility of the formula (XXIII) compounds. For e, preparation of acetyl derivatives of formula (XXIII) can improve solubility and increase product isolation yield.
As indicated above, R4 can be a leaving group. For this purpose, R4 may include any suitable yl leaving group chosen by a person d in the chemical arts. For example, non—limiting examples of hydroxyl protecting groups may include tosylates, brosylates, nosylates, mesylates, ms, triflates, nonaflates, and tresylates.
A compound of a (XXIII) may be prepared by known methods or purchased commercially.
As will be understood, the isomeric form of the formula (XXIII) structure may govern stereospecificity of subsequent intermediates in the sive steps of the synthesis of formula (I) or formula (XIII). Accordingly, a particular isomer may be isolated at this step of the synthesis or, alternatively, isomeric mixtures of formula (XXIII) may be carried through isolated at later stages of the synthesis.
In one embodiment, the compound of formula (XXIII) includes the isomer: R10 0R1 o 0 or pharmaceutically acceptable salts or hydrates Compounds of a (XXIV) Another embodiment relates to a compound of formula (XXIV): o o (XXIV) 1H , wherein each R1 is independently H or a or pharmaceutically acceptable salts or hydrates thereof, protecting group. be in As indicated, the hydroxyl groups in the compound of formula (XXIV) may protected or unprotected form. For example, in an unprotected form, the compound for formula (XXIV) may include the compound 2—(allyloxy)-4—(hydroxymethyl)—3,7— dioxabicyclo [4. l .0]heptanol: O O 2—(allyloxy)-4—(hydroxymethyl)—3,7—dioxabicyclo[4.l tan—5-ol or a pharmaceutically acceptable salt thereof. with an R1 n hydroxyl groups of the formula (XXIV) structure may be protected protecting group. For this e, R1 may include any suitable hydroxyl functional group chosen by a person skilled in the chemical arts. For example, non—limiting examples of hydroxyl protecting groups may include ether, ester, carbonate, or sulfonate protecting groups. The R1 protecting groups may be the same or different.
The ether protecting group may include , methoxy methyl (MOM), benzyloxymethyl (BOM), methoxyethoxymethyl (MEM), 2-(trimethylsily1)ethoxymethy1 (SEM), methylthiomethyl (MTM), phenylthiomethyl (PTM), azidomethyl, ethyl, 2,2- dichloro-l,1-difluoroethy1, 2-chloroethy1, 2-bromoethyl, tetrahydropyranyl (THP), l-ethoxyethyl (EE), phenacyl, ophenacyl, cyclopropylmethyl, allyl, propargyl, pyl, cyclohexyl, t— butyl, , 2,6~dimethylbenzyl, 4—methoxybenzyl (MPM—OAr), o—nitrobenzyl, 2,6- dichlorobenzyl, 3,4-dichlorobenzy1, 4-(dimethylamino)carbonylbenzyl, ylsulf1ny1benzy1 (Msib), 9—anthrylmethyl, 4—picoly1, heptafluoro—p-tolyl, tetrafluoropyridy1, trimethylsilyl (TMS), t—butyldimethylsilyl (TBDMS), t—butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS) protecting groups.
The ester protecting group may include acetoxy (OAc), aryl formate, aryl acetate, aryl levulinate, aryl pivaloate, aryl te, and aryl 9-fluoroenecarboxylate. In one embodiment, the ester protecting group is an y group.
The carbonate protecting group may include aryl methyl carbonate, 1-adamanty1 carbonate (Adoc—OAr), t-butyl carbonate (BOC—OAr), 4-methylsulf1nylbenzyl carbonate (Msz— OAr), 2,4-dimethylpent—3-yl carbonate (Doc-OAr), aryl 2,2,2—trichloroethy1 carbonate, aryl Vinyl carbonate, aryl benzyl carbonate, and aryl carbonate.
The sulfonate protecting groups may include aryl methanesulfonate, aryl toluenesulfonate, and aryl 2-formy1benzenesulfonate.
In some embodiments, the R1 protecting group is t-butyl carbamate (Boc).
In some embodiments, two adjacent R1 groups come together to form an isopropylidine acetal, benzylidine acetal, 1,5-dioxaspiro[5.5]undecane (cyclohexylidene acetal), 6,10- dioxaspiro[4.5]decane (cyclopentylidene ), or utylmethyl-1,3—dioxane .
For example, the R1 groups at the 4- and 5-positions of the hexose ring component of formula (XXIV) can combine to form an isopropylidine acetal, benzylidine acetal, 1,5— dioxaspiro[5.5]undecane (cyclohexylidene acetal), 6,10-dioxaspiro[4.5]decane (cyclopentylidene acetal), or 2-isobutyl—2-methy1—1,3-dioxane moiety. For example, a compound of formula (XXIV) can include a compound: or a pharmaceutically acceptable salt thereof.
Protection of certain amino and hydroxyl groups can improve lity of the formula (XXIV) compounds. For e, preparation of acetyl derivatives of formula (XXIV) can improve solubility and increase product isolation yield.
A compound of formula (XXIV) may be prepared by reacting a compound of a R10 0R1 o o with a base to prepare a compound of formula (XXIV): o 0 K wherein R1 is independently H or a protecting group, and R4 is H or a leaving group, as defined above.
In this synthesis, a compound of formula (XXIV) may be prepared by reacting a compound of formula (XXIII) with any base proper to selectively form the e of formula (XXIV). Suitable bases and conditions can be readily determined by those of ordinary skill in the art. For example, a compound of formula (XXIV) may be formed upon treatment of a compound of formula (XXIII) with a strong base, such as sodium hydroxide. Other bases, such calcium as potassium hydroxide, barium hydroxide, cesium hydroxide, strontium hydroxide, hydroxide, magnesium hydroxide, lithium hydroxide, rubidium hydroxide, butyl lithium, lithium diisopropylamide, lithium diethylamide, sodium amide, sodium hydride, and lithium imethylsilyl)amide may also be used.
For e, the reaction may be carried out by treating a compound of formula (XXIII) with sodium hydroxide in organic solvent at about 0° C then warming to room temperature overnight to afford a compound of formula (XXIV).
As will be understood, the isomeric form of the formula (XXIV) structure may govern the stereospecificity of uent intermediates in the successive steps of the synthesis of formula (I) or formula (XIII). Accordingly, a particular isomer may be ed at this step of the synthesis or, alternatively, ic mixtures of formula (XXIV) may be carried through and isolated at later stages of the synthesis.
In one ment, the compound of formula (XXIV) includes the isomer: (CI/0R10R1 HO O or pharmaceutically acceptable salts or es thereof.
Compounds Qfiormula w) Another embodiment relates to a compound of formula (XXV): i1! 0R1 N\ OR 1 R1/ \« H OR N / 1 . (XXV) NH2 0R1 O 0 is independently H or a or pharmaceutically acceptable salts or es thereof, wherein each R1 protecting group. 2012/025689 As indicated, the hydroxyl groups in the compound of formula (XXV) may be in protected or unprotected form. For example, in unprotected form, the compound for formula (XXV) may include the compound 6—(allyloxy)-5—((2,4-diamino—6-hydroxypyrimidin-5— yl)amino)—2-(hydroxymethyl)tetrahydro-2H-pyran-3 ,4-diol: H2N OH \“/N\ OH ” / 731 NH2 0 0 yloxy)—5—((2,4—diaminohydr0xypyrimidin—5-yl)amino)—2— xymethyl)tctrahydro—ZH-pyran-3,4-diol or a pharmaceutically acceptable salt thereof. Alternatively, one or more of the hydroxyl groups may be protected. For example, the compound of formula (XXV) may include a compound of formula (XXV—A): HzN N\ OR1 \f OH such as the compound 6—(allyloxy)((2,4-diamino(benzyloxy)pyrimidin—5-yl)amino)~2- phenylhexahydropyrano[[3,2-d][1,3]dioxin-8——o:l #18181$ 6—(allyloxy)—7—((2,4-diamino—6—(benzyloxy)pyrimidinyl)amino)—2— phenylhexahydropyrano[3,2—d][1,3]dioxin—8-ol or a pharmaceutically able salt thereof.
As indicated, certain amino and/or hydroxyl groups of the formula (XXV) ure may be protected with an R1 protecting group. For this purpose, R1 may include any suitable amino For example, or hydroxyl functional group chosen by a person skilled in the chemical arts. amino protecting groups within the scope of the present disclosure include, but are not d to, carbamate, amide, N—alkyl, or N—aryl-derived protecting groups. Non—limiting examples of hydroxyl ting groups may include ether, ester, carbonate, or sulfonate protecting groups.
The R1 protecting groups may be the same or different.
In particular, the carbamate protecting group may include, for example, 9- fluorenylmethyl carbamate (Fmoc), t—butyl carbamate (Boc), carboxybenzyl carbamate (cbz), methyl carbamate, ethyl carbamate, 9—(2-su1fo)fluorenylmethyl carbamate, 9—(2,7- o)fluorenylmethyl carbamate, l7-tetrabenzo[a,c,g,i]fluorenylmethyl carbamate (bemoc), 2—chloro-3—indenylmethy1 carbamate (Climoc), 2,7-di-t—butyl[9-(10,lO—dioxo—10,l 0,10,10— tetrahydrothioxanthyl)]methyl carbamate (DBD—Tmoc), 1,1—diox0benzo[b]thiophene—2-ylmethyl carbamate (Bsmoc), 2,2,2-trichloroethyl carbamate , 2—trimethylsilylethyl carbamate (Teoc), ylethyl carbamate (hZ), 1,1-dirnethyl—2—haloethyl carbamate, 1,1-dimethyl—2,2— dibromoethyl carbamate boc), 1,1—dimethyl-2,2,2—trichloroethyl carbamate (TCBoc), 1- methyl-l-(4—biphenylyl)ethy1 carbamate (Bpoc), l—(3 ,5-di—t—butylphenyl)—l -methylethyl carbamate (t—Bumeoc), N—2—pivaloylarnino)-1,1—dimethy1ethyl carbamate, 2-[(2- nitropheny1)dithio]phenylethyl carbamate (NpSSPeoc), - dicyclohexylcarboxamido)ethyl carbamate, 1-adamantyl ate (l-Adoc), Vinyl carbamate (Voc), l-isopropylallyl carbamate ), 4—nitrocinnamyl carbamate (Noe), 3-(3 ’pyridy1)prop— 2-eny1carbamate (Paloc), 8-quinolyl carbamate, alkyldithio carbamate, p-methoxybenzyl ate (Moz), p—nitrobenzyl carbamate (Pnz), p—bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), diphenylmethyl carbamate, 2—methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p- toluenesulfonyl)ethyl carbamate, [2—(1,3—dithianyl)]methyl carbamate (Dmoc), 4— methylthiophenyl carbamate (Mtpc), 2,4-dimethy1thiophenyl carbamate , 2— phosphonoethyl carbamate (Peoc), 1,l-dimethylcyanoethyl carbamate, 2—(4—nitrophenyl)ethyl ate, 4-phenylacetoxybenzyl carbamate (PhAcOZ), and ro-p—acyloxybenzyl carbamate. In some embodiments, a carbamate protecting group is chosen from 9- 2012/025689 fluorenylrnethyl ate (Fmoc), t—butyl carbamate (Boc), and carboxybenzyl ate (cbz) protecting groups.
The amide protecting group may e, for example, acetamide, phenylacetamide, phenylpropanamide, pent—4—enamide, picolinamide, 3-pyridylcarboxamide, benzamide, p— phenylbenzamide, 2-methyl-2—(0-pheny1azophenoxy)propanamide), 4-chlorobutanamide, acetoacctamide, ydroxyphenyl)propanamide), and (N’ - dithiobenzy1oxycarbonylamino)acetamidc.
The ether protecting group may include methyl, methoxy methyl (MOM), benzyloxymethyl (BOM), methoxyethoxymethyl (MEM), 2-(trimethylsi1yl)ethoxyrnethyl (SEM), methylthiomethyl (MTM), phenylthiomethyl (PTM), azidomethyl, cyanomethyl, 2,2— 1 —ethoxyethyl ro— 1 , 1 -difluoroethyl, roethyl, 2-bromoethy1, tetrahydropyranyl (THP), (EE), phenacyl, 4—bromophenacyl, cyclopropylmethyl, allyl, propargyl, isopropyl, cyclohexyl, butyl, , 2,6—dimethylbenzyl, 4-methoxybenzyl (MPM-OAr), o—nitrobenzyl, 2,6— robenzyl, 3,4—dichlorobenzyl, 4-(dimethylamino)carbonylbenzyl, 4—methylsulfinylbenzy1 (Msib), 9-anthrylmethy1, 4—picolyl, heptafluoro—p—tolyl, tetrafluoropyridyl, trimethylsilyl (TMS), t—butyldimethylsilyl (TBDMS), t—butyldiphenylsilyl (TBDPS), and triisopropylsilyl (TIPS) protecting groups.
The ester protecting group may include acetoxy (OAc), aryl formate, aryl acetate, aryl levulinate, aryl pivaloate, aryl benzoate, and aryl 9-fluoroenecarboxylate. In one embodiment, the ester protecting group is an y group.
The carbonate protecting group may e aryl methyl carbonate, l—adamantyl carbonate (Msz- carbonate OAr), t—butyl carbonate (BOC-OAr), 4-methylsulfinylbenzyl OAr), 2,4—dimethylpent—3-yl carbonate (Doc—OAr), aryl 2,2,2—trichloroethyl carbonate, aryl Vinyl carbonate, aryl benzyl carbonate, and aryl carbonate.
The sulfonate protecting groups may include aryl esulfonate, aryl toluenesulfonate, and aryl 2-formylbenzenesulfonate.
In some embodiments, the R1 protecting group is t—butyl carbamate (Boo). form an isopropylidine In some embodiments, two adjacent R1 groups come together to acetal, benzylidine acetal, 1,5-dioxaspiro[5.5]undecane (cyclohexylidene acetal), 6,10— dioxaspiro[4.5]decane (cyclopentylidene acetal), or 2-isobuty1-2—methyl—1,3—dioxane moiety. of formula For example, the R1 groups at the 4- and 5-positions of the hexose ring component 2012/025689 (XXV) can combine to form an isopropylidine acetal, idine acetal, 1,5— dioxaspiro[5.5]undecane (cyclohexylidene acetal), 6,10—dioxaspiro[4.5]decane (cyclopentylidene acetal), or 2-isobutyl—2-methyl-1,3-dioxane moiety. For example, a nd of formula (XXV) can e a compound: N N 0R1 N / 763; ”“2 o o or a pharmaceutically acceptable salt thereof.
Protection of certain amino and yl groups can improve solubility of the formula (XXV) compounds. For example, preparation of acetyl derivatives of formula (XXV) can improve solubility and increase product isolation yield.
A compound of formula (XXV) may be prepared by reacting a compound of formula (XXIV): HO O with a compound of formula (II): R1 A \T \N NH2 to afford a compound of formula (XXV): R\1 OR1 R1 \ H OR1 NH2 OR1 0 O wherein R1 is independently H or a protecting group, as defined above.
In this synthesis, a compound of formula (XXV) may be prepared by coupling a compound of a (XXIV) With a compound of formula (II) to form the compound of formula (XXV). le reaction conditions can be y ined by those of ordinary skill in the art. For example, a compound of formula 0(XV) may be formed upon treatment of a compound of formula (XXIV) and (II) in the presence of an oxidant, such as lithium perchlorate.
Other oxidants, such as RuO4'/NMO, Dess—Martin’s reagent, DMSO/triflic anhydride, TFAA/DMSO, PDC, hydrogen peroxide, inorganic peroxides, nitric acid, nitrates, chlorite, chlorate, perchlorate, hypochlorite, peroxide, iodine, ozone, nitrous oxide, silver oxide, chromium permanganate salts, hexavalent chromium compounds, chromic acid, dichromic acids, trioxide, pyridinium chlorochromate, persulfuric acid, ides, sulfuric acid, Tollens’ reagent, 2,2’-dipyridyldisulfide (DPS), and osmium tetroxide may also be used.
For example, the ion reaction may be carried out by treating a mixture of a compound of formula (XXIV) and (II) with m perchlorate in organic solvent while heating (e. g., at about 90° C) to afford a compound of formula (XXV).
As will be understood, the isomeric form of the formula (XXV) structure may govern stereospecificity of subsequent intermediates in the successive steps of the synthesis of formula (I) or formula (XIII). ingly, a ular isomer may be isolated at this step of the synthesis or, alternatively, isomeric mixtures of formula (XXV) may be d through and isolated at later stages of the synthesis.
In one embodiment, the nd of formula (XXV) includes the isomer: R1 0R1 /N \ 0R1 R1 \ H OR N / 1 NH2 OR1 0 O or pharmaceutically acceptable salts or hydrates thereof.
The compound of formula (XXV) can then be used to produce a compound of formula (IV). A compound of formula (IV) may be prepared by reacting a nd of formula (XXV): R\1 0R1 R1 \ ii OR N / 1 NH2 OR1 OH O with methylbarbituric acid to afford a compound of formula (IV), wherein each R1 is independently H or a protecting group, as defined above.
In this synthesis, a compound of formula (IV) may be prepared by reacting a compound of formula (XXV) with 1,3—dimethylbarbituric acid in the presence of a catalyst to form the compound of formula (IV). Suitable catalysts and reaction conditions can be readily determined by those of ordinary skill in the art. For example, a compound of formula (XXV) may be formed and (II) in the ce of a catalyst, such as upon treatment of a nd of formula (XXIV) tetrakis(triphenylphosphine)palladium(0). Other catalysts may also be used.
Pharmaceutical Formulations and Dosage Forms When employed as pharmaceuticals, the compounds provided herein can be stered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of , depending is desired and upon the area to be treated. upon whether local or ic treatment Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous WO 12922 membranes ing asal, vaginal and rectal delivery), ary (e. g., by inhalation or insufflation of powders or aerosols, including by zer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, eritoneal, intramuscular or injection or infusion; or intracranial, e. g. intrathecal or entricular, administration. eral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, Conventional pharmaceutical creams, gels, drops, suppositories, sprays, liquids and powders. carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
This disclosure also provides pharmaceutical compositions which contain, as the active ingredient, a compound provided herein or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable rs (excipients). In some embodiments, the composition is suitable for topical administration. In making the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or liquid or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, s, s, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, e injectable solutions, and sterile packaged powders.
In preparing a formulation, an active compound can be milled to provide the riate particle size prior to combining with the other ingredients. If an active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If an active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially m distribution in the formulation, e. g. about 40 mesh.
The compounds provided herein may be milled using known milling procedures such as wet milling to obtain a particle size riate for tablet formation and for other formulation herein can be types. Finely d (nanoparticulate) preparations of the compounds provided prepared by processes known in the art, 6. g. see International App. No. .
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl ose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and ding ; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions provided herein can be formulated so as to provide quick, sustained or delayed e of the active ingredient after administration to the patient by employing procedures known in the art.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound provided herein. When referring to these mulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the ition so that the composition can be readily subdivided into equally ive unit dosage forms such as tablets, pills and capsules. This solid preformulation is then ided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient ed herein.
The tablets or pills provided herein can be coated or otherwise compounded to provide a dosage form affording the age of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an pe over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A y of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the compounds and compositions provided herein can be incorporated for administration orally or by injection include aqueous solutions, suitably d syrups, s or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
In some embodiments, the compounds provided herein are formulated for intravenous stration. Pharmaceutical compositions suitable for injectable use can include sterile and sterile powders for the aqueous solutions (where water soluble) or sions For intravenous oraneous preparation of sterile injectable solutions or dispersion. administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition exists. It should be stable must be sterile and should be fluid to the extent that easy syringability under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, thereof. propylene , and liquid polyethylene glycol, and the like), and suitable es The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of sion and by the use tants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, ol, sodium chloride in the composition. Prolonged absorption of the inj ectable compositions can be brought about by ing in the composition monostearate and gelatin. an agent that delays absorption, for example, aluminum Sterile inj ectable solutions can be prepared by incorporating the active compound in enumerated required amount in an appropriate t with one or a combination of ingredients above, as required, followed by filter sterilization. Generally, sions are prepared by incorporating the active compound into a sterile e, which contains a basic dispersion medium and the ed other ients from those enumerated above. In the case of e powders for the preparation of sterile inj ectable solutions, the preferred methods of preparation a powder of the active ingredient plus any are vacuum drying and freeze-drying, which yield additional desired ient from a previously sterile—filtered on thereof.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic ts, or mixtures thereof, and powders. liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as nasal described supra. In some embodiments, the compositions are administered by the oral or of inert respiratory route for local or systemic effect. Compositions can be nebulized by use be breathed directly from the nebulizing device or the nebulizing gases. Nebulized solutions may machine. device can be attached to a face mask, tent, or ittent ve pressure breathing devices Solution, suspension, or powder compositions can be administered orally or nasally from which r the formulation in an appropriate .
Topical formulations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for e, liquid paraffin, polyoxyethylene alkyl ether, propylene , white Vaseline, the like. Carrier compositions of creams can be based on water in combination with glycerol one or more other components, e.g. glycerinemonostearate, PEG-glycerinemonostearate cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, ly in combination with other components such as, for example, glycerol, hydroxyethyl cellulose, and the like. In some embodiments, topical ations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt % of the compound provided herein. The topical formulations can be suitably packaged in tubes of, for example, 100 g which are optionally associated with instructions for the ent of the select indication.
In one ment, the compounds provided herein are prepared with carriers that will controlled release t the compounds t rapid elimination from the body, such as a formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, thoesters, and polylactic acid. Such formulations can be prepared using standard techniques, or obtained commercially, e. g., from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to selected cells with monoclonal antibodies to cellular antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.
The compositions administered to a t can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more usually about 100 to about 500 mg, of the active ingredient. The term “unit dosage forms”" refers to physically discrete units suitable as unitary dosages for human subjects and other s, each unit containing a ermined quantity of active al calculated to produce the desired therapeutic effect, in association with a suitable ceutical excipient.
In some embodiments, the compositions provided herein contain from about 5 to about 50 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compositions containing about 5 to about 10, about 10 to about 15, about 15 to about , about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, or about 45 to about 50 mg of the active ingredient.
In some embodiments, the compositions provided herein contain from about 50 to about 500 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compositions containing about 50 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 250, about 250 to about 300, about 350 to about 400, or about 450 to about 500 mg of the active ingredient.
In some embodiments, the compositions provided herein n from about 500 to about 1000 mg of the active ingredient. One having ordinary skill in the art will iate that this es compositions containing about 500 to about 550, about 550 to about 600, about 600 to about 650, about 650 to about 700, about 700 to about 750, about 750 to about 800, about 800 to about 850, about 850 to about 900, about 900 to about 950, or about 950 to about 1000 mg of the active ingredient.
Similar s may be used of the compounds described herein in the methods and uses provided .
The active compound can be effective over a Wide dosage range and is generally administered in a pharrnaceutically effective amount. It will be understood, however, that the amount ofthe compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of WO 12922 administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
The amount of compound or composition administered to a patient will vary depending the purpose of the administration, such as prophylaxis or upon what is being administered, therapy, the state of the t, the manner of administration, and the like. In therapeutic disease in an applications, itions can be administered to a patient already suffering from a of the e and its amount ent to cure or at least partially arrest the symptoms well as by complications. Effective doses will depend on the disease ion being treated as of the the judgment of the attending clinician ing upon factors such as the severity disease, the age, weight and general condition of the patient, and the like.
The eutic dosage of a compound provided herein can vary according to, of the example, the particular use for which the treatment is made, the manner of administration compound, the health and condition of the patient, and the judgment of the prescribing physician.
The proportion or concentration of a compound provided herein in a pharmaceutical composition chemical characteristics (e.g, can vary depending upon a number of factors including dosage, hydrophobicity), and the route of administration. For example, the compounds provided herein solution ning about 0.1 to about 10% can be provided in an s physiological buffer from about 1 w/v of the compound for parenteral administration. Some typical dose ranges are is from mg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on overall health such variables as the type and extent of progression of the disease or disorder, the status of the particular patient, the relative biological efficacy of the compound selected, ation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
EXAMPLES Example 1. Preparation of precursor Z (cPMP) Scheme 21. 0 1) MeOH—HZO 110 CC HO OH + ““2 *3: | 2 HCI 2) Et3N PhHNN OH HO H2N \N NH2 Boc20,DMAP ONJEEE‘OBocH Boc Boc‘NJLNI N O BOG 3a 800 Boc\NBIA OBoc BoRO_ " OBocN HOBoc HE/K/Nl OBoc silica gel BocFl 3b O 0800 flN/li HOBoc 08°C Boc\NAN‘ 0800 B00 B05 8°C WW::OMe/Me0f\5.5 eq. /4 eq. NaOMe/MeOH O OH OBoc|_I H OH H H N : OH N ? OH HN ‘N HEJLN | A ‘ \ . 0H OH BORN N N i O N '31 O é H Boc Boc B00 06 2012/025689 CIZPO(OMe) 4a, b or c 3°C CHZClz-pyridine )INOBocN 5c 0//O F"OMe BocF! 1) DMSO, TFAA, DCM 2) DIPEA gOOH OBoc HO OH H HOOH H _ o N O// N _ O Boc\N O ‘ Ox // HN \P\ / P‘OMe BoctN/KN i ' 0 k | o o N ; o NHBoc HN N NHO é | R 0C Boc Boc Boc 6a 6b 1) TMSBr, MeCN 2) HCI HN 0T5: A ' ' OH . O HZN N 0 mental.
Air sensitive reactions were performed under argon. Organic solutions were dried over anhydrous MgSO4 and the solvents were evaporated under reduced pressure. Anhydrous and chromatography solvents were obtained commercially (anhydrous grade solvent from Sigma— Aldrich Fine Chemicals) and used without any further purification. Thin layer chromatography (t.l.c.) was performed on glass or aluminum sheets coated with 60 F254 silica gel. c compounds were visualized under UV light or with use of a dip of ammonium molybdate (5 wt%) and (lV) sulfate‘4H20 (0.2 wt%) in aq. H2804 (2M), one of 12 (0.2 %) and K1 (7 %) WO 12922 in H2S04 (1M), or 0.1 % ninhydrin in EtOH. tography (flash column) was performed on silica gel (40 — 63 um) or on an automated system with continuous gradient facility. Optical cm2 g'l; rotations were recorded at a path length of 1 dm and are in units of 10'1deg concentrations are in g/100 mL. 1H NMR spectra were measured in CDC13, CD30D (internal 13C NMR Me4Si, 5 0 ppm) or D20 (HOD, 6 4.79 ppm), and spectra in CDC13 (center line, 5 8 39.7 ppm), D20 (no 77.0 ppm), CD30D (center line, 8 49.0 ppm) or DMSO d6 (center line internal reference or internal CH3CN, 5 1.47 ppm where stated). ments of 1H and 13C 1H-13C HSQC, HMBC) and DEPT resonances were based on 2D (‘H—‘H DQF-COSY, reference. High experiments. 31P NMR were run at 202.3 MHZ and are reported without Tandem Mass resolution electrospray mass spectra (ESI-HRMS) were recorded on a Q-TOF Spectrometer. nalyses were performed by the Campbell Microanalytical ment, University of Otago, Dunedin, New Zealand.
A. Preparation of (5aS, 6R, 7R, 8R, 9aR)-2—amin0-6, 7-dihydr0xy(hydroxymethyD- 3H, 4H, 5H, 5aH, 6H, 7H, 8H, 9aH, 1 0H—pyran0[3, 2-g]pteridin—4—0ne mono e (I). 2,5,6-Triamino—3,4—dihydropyrimidin—4—one dihydrochloride (Pfleiderer, W.; Chem. Ber. 1957, 90, 2272; Org. Synth. 1952, 32, 45; Org Synth. 1963, Call. Vol. 4, 245, 10.0 g, 46.7 mmol), D—galactose phenylhydrazone mi, S.; Adak, A.K. Tetrahedron Lett. 2005, 46, 4, heated to reflux (bath temp .78 g, 58.4 mmol) and 2-mercaptoethanol (1 mL) were stirred and 110 0C) in a 1:1 mixture of MeOH-H20 (400 mL) for 2 h. After cooling to ambient temperature, ed off diethyl ether (500 mL) was added, the flask was shaken and the diethyl ether layer ether (500 mL) and and discarded. The process was repeated with two further portions of diethyl then the remaining les were evaporated. Methanol (40 mL), H20 (40 mL) seeded with a few triethylamine (39.4 mL, 280 mmol) were successively added and the mixture milligrams of 1. After 5 min a yellow solid was filtered off, washed with a little MeOH An analytical dried to give 1 as a monohydrate (5.05 g, 36 %) of suitable purity for further use. dec. portion was recrystallized from DMSO—EtOH or boiling H20. MPt 226 [0L]12)0 +1356 (01.13, DMSO). 1H NMR (DMSO d6): 5 10.19 (bs, exchanged D20, 1H), 7.29 (d, J= 5.0 Hz, D20, slowly exchanged D20, 1H), 5.90 (s, exchanged D20, 2H), 5.33 (d, J= 5.4 Hz, exchanged 4.39 (d, J: 1H), 4.66 (ddd, J~5.0, ~1.3, ~1.3 Hz, 1H), 4.59 (t, J: 5.6 Hz, exchanged D20, 1H), 3.70 (m, 1H), 3.58 (dd, .3 Hz, exchanged D20, 1H), 3.80 (bt, J~1.8 Hz, exchanged D20, 1H), 3.35 J: 10.3, 3.0 Hz, 1H), 3.53 (dt, J: 10.7, 6.4 Hz, 1H), 3.43 (ddd, J: 11.2, 5.9, 5.9 Hz, 1H), (t, J: 6.4 Hz, 1H), 3.04 (br m, 1H). 13C NMR (DMSO d6 center line 5 39.7): 5 156.3 (C), 150.4 53.9 (CH).
(C), 148.4 (C), 99.0 (C), 79.4 (CH), 76.5 (CH), 68.9 (CH), 68.6 (CH), 60.6 (CH2), Anal. calcd. for C10H15N505'H20 39.60 C, 5.65 H, 23.09 N, found 39.64 C, 5.71 H, 22.83 B. Preparation ofcompounds 2 (a or b) and 3 (a, b or c).
Di-tert-butyl dicarbonate (10.33 g, 47.3 mmol) and DMAP (0.321 g, 2.63 mmol) were under added to a stirred suspension of 1 (1.5 g, 5.26 mmol) in anhydrous THF (90 mL) at 50 0C Ar. After 20 h a clear solution resulted. The solvent was evaporated and the residue chromatographed on silica gel (gradient of 0 to 40 % EtOAc in hexanes) to give two product fractions. The first product to elute was a yellow foam (1.46 g). The product was observed to a t with seven Boc groups a mixture of two compounds by 1H NMR containing mainly (23 or 2b). A sample was crystallized from EtOAc-hexanes to give 2a or 2b as a fine crystalline solid. MPt 189 — 191 0C. [or]? —43.6 (c 0.99, MeOH). 1H NMR (500 MHz, Z 5 5.71 (t, J = 1.7 Hz,1H), 5.15 (dt, J: 3.5, ~ 1.0, 1H), 4.97 (t, J: 3.8, 1H), 4.35 (br t, J: ~1.7,1H),4.09— 3.97 (m, 3H), 3.91 (m,1H), 1.55,1.52,1.51,1.50, 1.45 (5s, 45H), 1.40 (s, 18H). 13C NMR (125.7 MHZ, : 8 152.84 (C), 152.78 (C), 151.5 (C), 150.9 (C), 150.7 (2 X C), 150.3 (C), 82.6 (C), 149.1 (C), 144.8 (C), 144.7 (C), 118.0 (C), 84.6 (C), 83.6 (C), 83.5 (C), 82.7 (3 X C), 76.3 (CH), 73.0 (CH), 71.4 (CH), 67.2 (CH), 64.0 (CH2), 51.4 (CH), 28.1 (CH3), 27.8 (2 X CH3), found 27.7 (CH3), 27.6 (3 X CH3). MS-ESI+ for C45H72N5019+, (M+H)+, Calcd. 986.4817 986.4818. Anal. calcd. for N5019 H20 54.39 C, 7.39 H, 6.34 N; found 54.66 C, 7.17 H, 7.05 N. A second fraction was obtained as a yellow foam (2.68 g) which by 1H NMR was a from product with six Boc groups present (321, 3b or 3c). A small amount was llized EtOAc-hexanes to give colorless crystals. [0.]? —47.6 (c, 1.17, CHC13). 1H NMR (500 MHz, CDC13): 5 11.10 (br s, ged D20, 1H), 5.58 (t, J: 1.8 Hz, 1H), 5.17 (d, J: 3.4 Hz, 1H), 4.12 (dd, 4.97 (t, J: 3.9 Hz, 1H), 4.62 (s, exchanged D20, 1H), 4.16 (dd, J: 11.3, 5.9 Hz, 1H), 1.46 J: 11.3, 6.4 Hz, 1H), 3.95 (dt,J= 6.1,1.1Hz,1H),3.76(m,1H),1.51,1.50,1.49,1.48, (5s, 54H). 13C NMR (125.7 MHz, CDC13): 8 156.6 (C), 153.0 (C), 152.9 (C), 151.9 (C), 150.6 82.49 (C), (C), 149.4 (2 x C), 136.2 (C), 131.8 (C), 116.9 (C), 85.0 (2 x C), 83.3 (C), 82.8 (C), 27.6 (4 >< 82.46 (C), 73.3 (CH), 71.5 (CH), 67.2 (CH), 64.5 (CH2), 51.3 (CH), 28.0, 27.72, 27.68, CH3). MS-ESI+ for C40H64N5017+, (M+H)+ calcd. 886.4287, found 886.4289.
C. ation ofcompound 4a, 417 0r 4c.
Sip—1 - The first fraction from B above containing mainly compounds 2a or 2b (1.46 g, 1.481 mmol) was dissolved in MeOH (29 mL) and sodium methoxide in MeOH (1M, 8.14 mL, 8.14 mmol) added. After leaving at ambient temperature for 20 h'the solution was neutralized with Dowex 50WX8 (H+) resin then the solids filtered off and the solvent evaporated. $122 - The second on from B above containing mainly 3a, 3b or 3c (2.68 g, 3.02 mmol) was dissolved in MeOH (54 mL) and sodium ide in MeOH (1M, 12.10 mL, 12.10 mmol) added. After leaving at t temperature for 20 h the solution was neutralized with Dowex 50WX8 (H+) resin then the solids filtered off and the solvent evaporated.
The ts from st_ep_l and st_ep_2 above were combined and chromatographed on silica gel (gradient of 0 to 15 % MeOH in CHC13) to give 421, 4b 0r 4c as a cream colored solid (1.97 g). 1H NMR (500 MHz, DMSO d6):5 12.67 (br s, exchanged D20, 1H), 5.48 (d, J: 5.2 Hz, exchanged D20, 1H), 5.43 (t, J = ~1.9 Hz, after D20 exchange became a d, J = 1.9 Hz, 1H), 5.00 (br s, exchanged D20, 1H), 4.62 (d, J= 5.7 Hz, ged D20, 1H), 4.27 (d, J= 6.0 Hz, exchanged D20, 1H), 3.89 (dt, J: 5.2, 3.8 Hz, after D20 became a t, J: 3.9 Hz, 1H), 3.62 (dd, J = 6.0, 3.7 Hz, after D20 exchange became a d, J= 3.7 Hz, 1H), 3.52 — 3.39 (m, 4H), 1.42 (s, 9H), 1.41 (s, 18H). 13C NMR (125.7 MHZ, DMSO d6): 8 157.9 (C), 151.1, (C), 149.8 (2 X C), 134.6 (C), 131.4 (C), 118.8 (C), 83.5 (2 X C), 81.3 (C), 78.2 (CH), 76.5 (CH), 68.1 (CH), 66.8 (CH), 60.6 (CH2), 54.4 (CH), 27.9 (CH3), 27.6 (2 X CH3). MS—ESI+ for C25H40N5011+, (M+H)+ calcd. 586.2719, found 586.2717.
D. Preparation ofcompound 5a, 5b or 50 Compound 4a, 4b or 4c (992 mg, 1.69 mmol) was dissolved in anhydrous pyridine and concentrated. The residue was dissolved in anhydrous CH2C12 (10 mL) and pyridine (5 mL) under a nitrogen atmosphere and the solution was cooled to ~42 °C in an acetonitrile/dry ice bath. Methyl dichlorophosphate (187 uL, 1.86 mmol) was added dropwise and the mixture was stirred for 2 h 20 min. Water (10 mL) was added to the cold solution which was then removed from the cold bath and diluted with ethyl e (50 mL) and saturated NaCl solution (30 mL).
The organic portion was separated and washed with saturated NaCl solution. The combined and the combined c aqueous portions were extracted twice further with ethyl acetate 2012/025689 portions were dried over MgSO4 and concentrated. Purification by silica gel flash column chromatography (eluting with 2 — 20 % methanol in ethyl acetate) gave the cyclic methyl phosphate 5a, 5b or SC (731 mg, 65%). 1H NMR (500 MHZ, CDC13,):8 11.72 (bs, exchanged D20, 1H), 5.63 (t, J: 1.8 HZ, 1H), 5.41 (s, exchanged D20, 1H), 4.95 (d, J: 3.2 HZ, 1H), 4.70 (dt, J=12.4,1.8 HZ, 1H), 4.42 (dd, J= 22.1, 12.1 HZ, 1H). 4.15 (q, J: 3.7 HZ, 1H), 3.82 (s, 1H), 3.75 (s, 1H), 3.58 (d, J= 11.7 HZ, 3H), 2.10 (bs, exchanged D20, 1H + H2O), 1.50 (s, 9H), 1.46 (s, 18H). 13C NMR (125.7 MHZ, CDC13, centre line 5 77.0): 5 157.5 (C), 151.2 (C), 149.6 (2 x C), 134.5 (C), 132.3 (C), 117.6 (C), 84.7 (2 x C), 82.8 (C), 77.3 (CH), 74.8 (d, J: 4.1 HZ, CH), 69.7 (CH2), 68.8 (d, J: 4.1 HZ, CH), 68.6 (d, J= 5.9 HZ, CH), 56.0 (d, J= 7.4 HZ, CH3), 51.8 ‘10 (CH), 28.1 (CH3), 27.8 (CH3). MS-ESI+ for C26H40N5Na013P+ (M+Na)+, calcd. 684.2252, found 684.2251.
E. Preparation ofcompound 6a, 6b or 60 Compound 5a, 5b or So (223 mg, 0.34 mmol) was ved in anhydrous CH2C12 (7 mL) under a nitrogen atmosphere. Anhydrous DMSO (104 ”L, 1.46 mmol) was added and the solution was cooled to —78 °C. roacetic anhydride (104 pL, 0.74 mmol) was added dropwise and the mixture was stirred for 40 min. N,N—diisopropylethylamine (513 pL, 2.94 mmol) was added and the ng was continued for 50 min at —78 °C. Saturated NaCl solution (20 mL) was added and the mixture removed from the cold bath and diluted with CH2C12 (30 mL). Glacial acetic acid (170 ”L, 8.75 mmol) was added and the mixture was stirred for 10 min. The layers were separated and the aqueous phase was washed with CH2C12 (10 mL) The combined c phases were washed with 5 % aqueous HCl, 3 :1 saturated NaCl solution: 10 % NaHC03 solution and saturated NaCl solution successively, dried over MgSO4, and concentrated to give nd 6a, 6b or 60 (228 mg, quant.) of suitable purity for further use. 1H NMR (500 MHZ,CDC13): 5 5.86 (m, 1 H), 5.07 (m, 1 H), 4.70 ~ 4.64 (m, 2 H), 4.49 — 4.40 (m, 1 H), 4.27 (m, 1 H), 3.56, m, 4 H), 1.49 (s, 9 H), 1.46 (s, 18 H) ppm. 13C NMR (500 MHZ, CDC13): 6 157.5 (C), 151.1 (C), 150.6 (2 C), 134.6 (C), 132.7 (C), 116.6 (C), 92.0 (C), 84.6 (2 C), 83.6 (C), 78.0 (CH), 76.0 (CH), 70.4 (CH2), 67.9 (CH), 56.2 (CH3) 56.0 (CH), 28.2 (3 CH3), 26.8 (6 CH3) ppm. 31P NMR (500 MHZ, CDC13): 6 — 6.3 ppm.
‘ F. Preparation ofcompound 7: (4aR,5aR,IIaR,12aS)-1,3,2- Dioxaphosphorino[4 ’, 5 ’.‘ 5, 6]pyran0[3, 2—g]pteridin—1 0(4H)—0ne, 8-amino- 4a, 5a, 6, 9, 1 1, I 1a, 1 2, 12a-octahydr0—2, 12, 12-trihydroxy—2—0xide Compound 6a, 6b or Go (10 mg, 14.8 umol) was dissolved in dry acetonitrile (0.2 mL) and the and cooled to 0 °C. Bromotrimethylsilane (19.2 ul, 148 umol) was added dropwise which time a mixture was allowed to warm to ambient ature and stirred for 5 h during for a further 15 precipitate formed. HCl<aq) (10 pl, 37 %) was added and the mixture was stirred collected. min. The mixture was centrifuged for 15 min (3000 g) and the ing precipitate min. The Acetonitrile (0.5 mL) was added and the mixture was centrifuged for a further 15 solid was acetonitrile wash and centrifugation was repeated a further two times and the resulting 5.22 dried under high vacuum to give compound 7 (4 mg, 75 %). 1H NMR (500 MHZ, D20): 4.18 (m, 1H), 3.94 (d, J: 1.6 Hz, 1H), 4.34 (dt, J: 13, 1.6 Hz, 1H), 4.29 — 4.27 (m, 1H), 4.24 — MS-ESI+ for (br m, 1H), 3.44 (t, J: 1.4 Hz, 1H). 31P NMR (500 MHz, D20): 8 —4.8 C10H15N508P+, (M+H)+ calcd. 53, found 364.0652. that prepared Example 2. Comparison of precursor Z (cPMP) prepared synthetically to from E. coli in the in vitro synthesis of Moco Z (cPMP) In vitro synthesis of Moco was compared using samples of synthetic precursor and cPMP purified from E. coli. Moco synthesis also involved the use of the purified and apo-sulfite oxidase. See U.S. components E. coli MPT synthase, gephyrin, molybdate, ATP, cofactor Patent No. 7,504,095 and “Biosynthesis and molecular biology of the molybdenum Informa (Moc0)” in Metal Ions in Biological Systems, Mendel, Ralf R. and Schwarz, Gunter, cPMP into MPT, the Plc, 2002, Vol. 39, pages . The assay is based on the conversion of subsequent ate insertion using recombinant gephyrin and ATP, and finally reconstitution of human apo-sulfite oxidase.
As shown in Moco synthesis from synthetic cPMP was confirmed, and no cPMP. differences in Moco sion were found in comparison to E. col1' purified that prepared e 3. Comparison of sor Z (cPMP) prepared synthetically to from E. coli in the in vitro synthesis of MPT WO 12922 In vitro synthesis of MPT was compared using samples of synthetic precursor Z (cPMP) and cPMP purified from E. coli. MPT synthesis also ed the use of in vitro assembled MPT synthase from E. 0011'. ‘See US. Patent No. 7,504,095 and “Biosynthesis and molecular biology of the molybdenum cofactor (Moco)” in Metal Ions in Biological Systems, Mendel, Ralf R. and Schwarz, , Informa Plc, 2002, Vol. 39, pages 317—68. Three repetitions of each experiment were performed and are shown in FIGS. 2 and 3.
As shown in FIGS. 2 and 3, MPT synthesis from synthetic cPMP confirmed, and no cPMP. A apparent differences in MPT conversion were found when compared to E. coli purified linear conversion of cPMP into MPT is seen in all samples confirming the identity of synthetic cPMP (see . Slight ences between the repetitions are ed to be due to an inaccurate concentration determination of synthetic cPMP given the presence of interfering chromophores.
Example 4. Preparation of precursor Z (cPMP) A. Preparation ofstarting materials Scheme 22. 2012/025689 MeCN, CSA, rt, o/n, 74% TsCI, A920, KI, rt, 24h NaH, DMF, 0°C —> r1.
O ‘ 65—95% o o LiCIo4 MeCN, 90°C )LNJXNHZ/ HZN N NH2 H N CH 2 / \ H g B. Introduction ofthe protectedphosphate Scheme 23.
HZN / \ H C:)H OBn QH N = o 2 N\ N O Pd(Ph3)4 N/ 0 | NH2 MeOH 50°C. \ o 0 O o W O HZNXN H6 \NJKN/ [7] Boc20,DMAP, 45-49% over 2 steps OBn OBoc OBn OH H : H E N O N O bonate l l k o MeOH k 0 N o 96% BocZN N O BoczN N I l boc boc [9] [8] H2,Pd/C MeOH, 50°C OH OH OH H o H 9” Pyr.,DCM g N = OH __.___. N/ oxH/‘K I 1 IE; A ' ' \ O \ OH “L 0 N o BOCZN N _O/P 016M BoczN I?! o N
[11] The formation of the cyclic phosphate using intermediate [10] (630mg) gave the desired product as a 1:1 mixture of diastereoisomers (494 mg, 69%).
Scheme 24.
HHo 0HO Bocsz 30‘:sz
[13] OH OH OH OH H H i O i TMSBr(10e ) (I) N 0|. N N/ N/ O\H3|/OH )\\ | O\II|3|/O\ MeCN o X 1 0 BoczN N N o HZN N H o
[14] Lifiggggflfeo Dess-Martin . Ion -78°C, DCM HHo OH 0H 9H 0IPI/\o N o (I)! OH IN' N/ I mI \ / O BocZN HZN/kN N H0 [16l [15] TMSBr (1o eq.) MeCN HHo OH 0 OO\%/OHO cPMP C. Oxidation and overall deprotection 0fthe molecule Oxidation of the ary alcohol to the gem-diol did prove successful on intermediate be purified. For , but the oxidized product [13] did Show significant instability and could not this reason, deprotection of the phosphate was attempted before the oxidation. However, molecule giving on of intermediate [11] with TMSBr led to complete deprotection of the intermediate [14]. An attempt to oxidize the alcohol to the gem-diol using Dess-Martin periodinane gave the ized pteridine [15].
Oxidation of ediate [11] with Dess-Martin periodinane gave a mixture of starting al, oxidized product and several by—products. Finally, intermediate [11] was oxidized using the method described Example 1. Upon treatment, only partial oxidation was observed, leaving a 2:1 mixture of [11]/[16]. The crude mixture was submitted to the final deprotection. off white solid was obtained and analyzed by 1H-NMR and HPLC-MS. These analyses suggest that cPMP has been produced along with the ected sor [11]. the major Because the analytical HPLC conditions gave a good separation of cPMP from material. impurities, this method will be repeated on a prep—HPLC in order to isolate the final

Claims (109)

WHAT IS CLAIMED IS:
1. A process for preparing a compound of formula (I): 5 or a pharmaceutically acceptable salt thereof, the process comprising: (a) reacting a compound of formula (II): each R1 is independently H or a protecting group, 10 with a nd of formula (III): to produce a compound of formula (IV): (b) selectively protecting the compound of formula (IV) to prepare a compound of formula (V): 5 (c) phosphorylating the compound of formula (V) to prepare a compound of formula (VI): (d) oxidizing the compound of formula (VI) to prepare a nd of formula (VII): ; and (e) deprotecting the compound of formula (VII) to prepare the compound of formula (I). 5
2. The process of claim 1, wherein the pharmaceutically acceptable salt is an HCl salt.
3. The process of any one of claims 1-2, wherein the compound of formula (II) is: 10
4. The process of any one of claims 1-3, n the compound of formula (III) is a protected or unprotected galactose, mannose, glucose, or gulose.
5. The process of any one of claims 1-4, wherein the compound of formula (III) is:
6. The process of any one of claims 1-5, wherein two adjacent R1 groups come er to form an isopropylidine acetal or idine acetal moiety.
7. The s of any one of claims 1-6, wherein step (a) comprises reacting the compound of formula (II) and the compound of formula (III) in the presence of a hydrazine. 5
8. The process of claim 7, wherein the hydrazine is selected from the group consisting of phenylhydrazines and alkylhydrazines.
9. The process of claim 8, n the hydrazine is phenylhydrazine.
10 10. The process of any one of claims 1-9, wherein the phosphorylation of step (c) comprises reacting the compound of formula (V) with a P(V) phosphorylating agent.
11. The process of claim 10, wherein the P(V) phosphorylating agent is selected from the group consisting of: POCl3; H3PO4; PO(OBn)xCl3-x; Cl3CCH2OP(O)Cl2; and 15 (BnO)2P(O)OP(O)(OBn)2.
12. The process of claim 10, wherein the P(V) phosphorylating agent is POCl3.
13. The process of any one of claims 1-9, wherein the phosphorylation of step (c) 20 comprises reacting the compound of formula (V) with a P(III) phosphitylating agent.
14. The process of claim 13, wherein the P(III) phosphitylating agent is selected from the group consisting of: P(OCH2CH2CN)2Cl; P(OCH2CH2CN)(NPr2-i)Cl; and cyanoethyl- O-P[N(i-Pr)2)]2.
15. The process of claim 13, wherein step (c) further comprises oxidizing the resulting phosphite to prepare the ate of compound (VI).
16. The process of any one of claims 1-15, wherein step (d) comprises ng the 30 compound of formula (VI) with an ing agent ed from the group consisting of: RuO4; artin; DMSO/triflic anhydride; and PDC.
17. The process of any one of claims 1-16, wherein the deprotection of the compound of formula (VII) is performed under anaerobic ions. 5
18. The process of any one of claims 1-17, wherein the compound of formula (IV) is:
19. The process of any one of claims 1-18, wherein the compound of formula (V) is:
20. The s of any one of claims 1-19, wherein the compound formula (VI) is:
21. The process of any one of claims 1-20, wherein the compound of formula (VII) is:
22. The process of any one of claims 1-21, wherein the process r comprises formulating the compound of formula (I) as a pharmaceutical composition.
23. A process for preparing a compound of formula (I): or a pharmaceutically able salt thereof, the process comprising: (a) reacting a compound of formula (II-A): with a compound of formula ): in the presence of a hydrazine to produce a compound of formula (IV-A): (b) selectively protecting the compound of formula (IV-A) to prepare a compound of formula (V-A): 5 wherein R1 is a protecting group; (c) phosphorylating the compound of formula (V-A) to prepare a nd of formula (VIA 10 (d) oxidizing the compound of formula (VI-A) to prepare a compound of formula (VII-A): ; and (e) deprotecting the compound of a (VII-A) to prepare the compound of formula (I).
24. A process for preparing a compound of formula (I): 5 or a ceutically acceptable salt f, the process comprising: (a) reacting a compound of formula (II-A): with a compound of formula (III-A): in the presence of a hydrazine to produce a compound of formula (IV-A): (b) selectively protecting the compound of formula (IV-A) to prepare a compound of formula 15 (V-B): wherein: each R1 is independently a protecting group; (c) phosphorylating the compound of formula (V-B) to prepare a compound of formula (VI- 5 B): (d) oxidizing the compound of formula (VI-B) to prepare a compound of formula ): ; and 10 (e) deprotecting the compound of formula (VII-B) to prepare the compound of formula (I).
25. A process for preparing a nd of formula (I): or a pharmaceutically acceptable salt thereof comprising: (a) reacting a compound of a (II): 5 wherein each R1 is ndently H or a protecting group; with a compound of formula (VIII): wherein R2 is H or a protecting group; to produce a compound of formula (IX): (b) selectively protecting the compound of formula (IX) to prepare a compound of formula (X): wherein R3 is a protecting group and R4 is H or a protecting group; (c) ing the compound of formula (X) to prepare a compound of formula (XI): 5 ; and (d) deprotecting the compound of formula (XI) to prepare the compound of formula (I).
26. A process for preparing a compound of formula (I): or a pharmaceutically acceptable salt f, the process comprising: (a) reacting a compound of formula (II): with a compound of formula (III): 5 to produce a compound of formula (IV): wherein each R1 is independently H or a protecting group; (b) ively protecting the nd of formula (IV) to prepare a compound of formula 10 (V): (c) oxidizing the compound of formula (V) to prepare a compound of formula (XII): (d) phosphorylating the compound of formula (XII) to prepare a nd of formula (VII): ; and deprotecting the compound of formula (VII) to prepare the compound of formula (I).
27. A compound of formula (IV): or a pharmaceutically acceptable salt form f, wherein: each R1 is independently H or a protecting group.
28. The compound of claim 27, wherein the compound of formula (IV) is: or a ceutically acceptable salt form thereof.
29. A compound of formula (V): 5 , or a pharmaceutically acceptable salt form thereof, wherein: each R1 is independently H or a protecting group.
30. The compound of claim 29, wherein the compound of formula (V) is selected from 10 the group consisting of: , and or a pharmaceutically acceptable salt form thereof.
31. The compound of claim 29, n the compound of formula (V) is selected from 5 the group consisting of: 0800 0800 N 0806 Boc\ \ 0800 N N N O B oo B ee 0 OB H 00 Boc\ N 08 Boc\ \ 0800 N N N O Boo Boo O 0800 N 0800 Boc\ \ OBOC N N N O 800 Bee 0800 OBoc N OBoc x l 00 HN N N O Boo 800 153 153 or a pharmaceutically acceptable salt thereof.
32. A compound of formula (VI): or a pharmaceutically acceptable salt form thereof, wherein: each R1 is independently H or a protecting group.
33. The compound of claim 32, wherein the compound of formula (VI) is ed from 10 the group consisting of: , and or a ceutically acceptable salt form thereof.
34. The compound of claim 32, whrein the compound of formula (VI) is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
35. A compound of formula (VII): or a pharmaceutically acceptable salt form thereof, wherein: each R1 is ndently H or a protecting group, and at least one R1 is a protecting group.
36. The compound of claim 35, wherein the compound of formula (VII) is selected from the group consisting of: , and 5 , or a pharmaceutically acceptable salt form thereof.
37. The compound of claim 35, wherein the nd of formula (VII) is selected from the group consisting of: or a pharmaceutically able salt form thereof.
38. A process for preparing a compound of formula (XIII): or a pharmaceutically acceptable salt form thereof, the process comprising: (a) reacting a compound of formula (II): with a compound of formula (III): 5 to produce a compound of formula (IV): wherein: each R1 is independently H or a protecting group; 10 (b) selectively protecting the compound of a (IV) to prepare a compound of formula (V): (c) phosphorylating the compound of formula (V) to prepare a compound of formula (VI): (d) oxidizing the compound of formula (VI) to prepare a compound of a (XIV): ; and (e) deprotecting the compound of formula (XIV) to prepare the compound of a (XIII).
39. A process for preparing a compound of formula (XIII): or a ceutically acceptable salt thereof, the process comprising: (a) reacting a compound of formula (II): wherein: 5 each R1 is independently H or a protecting group, with a compound of formula (VIII): wherein: R1 and R2 are each independently H or a protecting group, 10 to produce a compound of formula (IX): (b) selectively protecting the compound of formula (IX) to prepare a nd of formula 15 (X): wherein: R3 is a protecting group and R4 is H or a protecting group; (c) oxidizing the compound of formula (X) to e a compound of formula (XV): ; and (d) deprotecting the compound of formula (XV) to prepare the compound of formula (XIII).
40. A process for preparing a compound of a (XIII): or a pharmaceutically acceptable salt thereof, the process sing: (a) reacting a compound of formula (II): wherein: each R1 is independently H or a protecting group; with a compound of formula (III): to produce a compound of formula (IV): (b) selectively protecting the nd of formula (IV) to prepare a compound of formula 10 (V): (c) orylating the compound of formula (V) to prepare a compound of formula (VI): (d) oxidizing the compound of formula (VI) to prepare a compound of formula (XIV): ; and (e) deprotecting the compound of formula (XIV) to prepare the nd of formula (XIII).
41. A process for preparing a compound of formula (I): 10 or a pharmaceutically acceptable salt thereof, the s comprising: (a) oxidizing the compound of formula (VI): wherein: each R1 is independently H or a protecting group; to prepare a compound of formula (VII): 5 ; and (b) deprotecting the compound of formula (VII) to prepare the compound of formula (I).
42. A process for preparing a nd of formula (I): or a pharmaceutically acceptable salt thereof, the process comprising: (a) orylating the compound of formula (V): wherein: each R1 is independently H or a protecting group; to prepare a compound of a (VI): (b) ing the compound of formula (VI) to prepare a compound of formula (VII): 10 ; and (c) deprotecting the compound of formula (VII) to prepare the compound of formula (I).
43. A process for preparing a compound of formula (I): or a pharmaceutically acceptable salt thereof, the s comprising: (a) selectively protecting the compound of formula (IV): wherein: each R1 is independently H or a protecting group; to prepare a compound of formula (V): 10 (b) phosphorylating the compound of formula (V) to e a compound of formula (VI): (c) oxidizing the compound of formula (VI) to prepare a compound of a (VII): 5 ; and (d) deprotecting the compound of formula (VII) to prepare the compound of formula (I).
44. A process for preparing a compound of formula : or a ceutically acceptable salt form thereof, the process comprising: (a) oxidizing the compound of formula (VI): wherein: 15 each R1 is independently H or a protecting group; to prepare a compound of formula (XIV): ; and (b) deprotecting the compound of a (XIV) to prepare the compound of formula (XIII).
45. A process for preparing a compound of formula (XIII): or a pharmaceutically acceptable salt form thereof, the process sing: (a) phosphorylating the compound of formula (V): wherein: 10 each R1 is independently H or a protecting group; to prepare a compound of formula (VI): (b) oxidizing the compound of formula (VI) to prepare a compound of formula (XIV): ; and 5 (c) deprotecting the compound of formula (XIV) to e the compound of formula (XIII).
46. A process for preparing a compound of a (XIII): or a ceutically acceptable salt form thereof, the process comprising: 10 (a) selectively protecting the compound of formula (IV): wherein: 15 each R1 is independently H or a protecting group; to prepare a compound of formula (V): (b) orylating the compound of formula (V) to prepare a compound of formula (VI): (c) ing the compound of formula (VI) to prepare a compound of formula (XIV): ; and (d) deprotecting the compound of formu la (XIV) to prepare the compound of formula (XIII).
47. A compound of formula (I): or a pharmaceutically acceptable salt thereof, prepared by the process comprising: (a) reacting a compound of formula (II): 5 wherein: each R1 is ndently H or a protecting group, with a compound of formula (III): 10 to e a compound of formula (IV): (b) selectively protecting the compound of formula (IV) to prepare a compound of formula (V): (c) phosphorylating the compound of formula (V) to e a compound of formula (VI): 5 (d) oxidizing the compound of formula (VI) to e a compound of formula (VII): ; and (e) deprotecting the compound of formula (VII) to prepare the compound of formula (I).
48. A compound of formula (I): or a pharmaceutically acceptable salt thereof, prepared by the process comprising: (a) oxidizing the compound of formula (VI): wherein: each R1 is independently H or a protecting group; to prepare a compound of formula (VII): ; and (b) deprotecting the compound of formula (VII) to e the nd of formula (I). 15
49. A compound of formula (I): or a pharmaceutically acceptable salt thereof, prepared by the process comprising: (a) phosphorylating the compound of formula (V): wherein: 5 each R1 is independently H or a protecting group, to prepare a compound of formula (VI): (b) oxidizing the compound of formula (VI) to prepare a compound of formula (VII): ; and (c) deprotecting the compound of formula (VII) to prepare the compound of a (I). 15
50. A nd of formula (I): or a pharmaceutically acceptable salt f, ed by the process comprising: (a) selectively protecting the compound of formula (IV): wherein: each R1 is independently H or a protecting group; to prepare a compound of formula (V): 10 (b) phosphorylating the compound of formula (V) to prepare a compound of formula (VI): (c) oxidizing the compound of a (VI) to e a compound of formula (VII): 5 ; and (d) deprotecting the compound of formula (VII) to prepare the compound of formula (I).
51. A compound of formula (XIII): or a pharmaceutically acceptable salt thereof, prepared by the process comprising: (a) reacting a compound of formula (II): wherein: 15 each R1 is independently H or a protecting group, with a nd of formula (VIII): wherein: R1 and R2 are each independently H or a protecting group, to produce a compound of formula (IX): 5 , (b) selectively ting the compound of formula (IX) to e a nd of formula (X): 10 wherein R3 is a protecting group and R4 is H or a protecting group; (c) oxidizing the compound of formula (X) to prepare a compound of formula (XV): ; and (d) deprotecting the compound of formula (XV) to prepare the compound of formula (XIII). 15
52. A compound of formula (XIII): or a pharmaceutically able salt form f, ed by the process comprising: (a) oxidizing the compound of formula (VI): 5 wherein: each R1 is independently H or a protecting group, to prepare a compound of formula (XIV): ; and 10 (b) deprotecting the compound of formula (XIV) to prepare the compound of formula (XIII).
53. A compound of formula (XIII): or a pharmaceutically acceptable salt form thereof, prepared by the process comprising: (a) phosphorylating the compound of formula (V): wherein: each R1 is independently H or a protecting group; 5 to prepare a compound of formula (VI): (b) oxidizing the compound of a (VI) to prepare a compound of formula (XIV): ; and (c) deprotecting the nd of formula (XIV) to prepare the compound of formula (XIII).
54. A compound of formula (XIII): or a pharmaceutically acceptable salt form thereof, prepared by the process comprising: (a) selectively protecting the compound of formula (IV): 5 wherein: each R1 is ndently H or a protecting group; to prepare a compound of formula (V): 10 (b) phosphorylating the compound of formula (V) to prepare a nd of formula (VI): (c) oxidizing the compound of formula (VI) to prepare a compound of formula (XIV): ; and 5 (d) deprotecting the nd of formula (XIV) to prepare the compound of formula (XIII).
55. A process for preparing a compound of formula (I): or a pharmaceutically acceptable salt f, the process comprising: (a) reacting a compound of formula (II): 15 n: each R1 is independently H or a protecting group, with a compound of formula (XXII): to produce a compound of a (IV): 5 , wherein: each R1 is independently H or a protecting group; (b) selectively protecting the compound of formula (IV) to prepare a compound of formula (V): 10 ; (c) phosphorylating the compound of formula (V) to prepare a compound of formula (VI): (d) oxidizing the compound of a (VI) to prepare a compound of a (VII): ; and (e) deprotecting the compound of formula (VII) to prepare the compound of formula (I). 10
56. The process of claim 55, wherein the compound of formula (II) is:
57. The process of any one of claims 55-56, wherein the compound of formula (XXII) is:
58. The process of any one of claims 55-57, wherein the orylation of step (c) comprises reacting the compound of formula (V) with a P(V) phosphorylating agent.
59. The process of claim 58, wherein the P(V) phosphorylating agent is selected from the group consisting of: POCl3; 3)xCl3-x; H3PO4; PO(OBn)xCl3-x; Cl3CCH2OP(O)Cl2; and P(O)OP(O)(OBn)2. 10
60. The process of claim 58, wherein the P(V) phosphorylating agent is Cl2PO(OCH3).
61. The process of any one of claims 55-60, wherein step (d) comprises reacting the compound of formula (VI) with an oxidizing agent selected from the group consisting of: TFAA/DMSO; RuO4; Dess-Martin; riflic anhydride; and PDC.
62. The process of any one of claims 55-61, wherein the deprotection of the compound of formula (VII) is performed under anaerobic conditions.
63. The process of any one of claims 55-62, wherein the compound of formula (IV) is: 20 .
64. The process of any one of claims 55-63, wherein the nd of formula (V) is:
65. The process of any one of claims 55-64, wherein the compound formula (VI) is:
66. The process of any one of claims 55-65, wherein the compound of formula (VII) is:
67. The process of any one of claims 55-66, n the process r comprises 10 formulating the compound of formula (I) as a pharmaceutical composition.
68. A process for preparing a compound of formula (I): or a pharmaceutically acceptable salt thereof, the process comprising: (a) reacting a compound of formula (II-A): 5 with a compound of formula (XXII-A): in the presence of a base to produce a compound of formula (IV-A): (b) selectively protecting the compound of formula (IV-A) to e a compound of formula 10 (V-C): each R1 is independently H or a protecting group; (c) orylating the compound of formula (V-C) to prepare a compound of formula (VIC (d) oxidizing the compound of formula (VI-C) to prepare a compound of formula (VII-C): 5 ; and (e) ecting the compound of formula (VII-C) to prepare the nd of formula (I).
69. A process for preparing a compound of formula (I): or a pharmaceutically acceptable salt thereof, the process comprising: (a) reacting a compound of formula (XXIII): wherein: each R1 is independently H or a protecting group, and R4 is H or a leaving group; 5 to produce a compound of formula (XXIV): (b) reacting a compound of a (XXIV) with a compound of formula (II): 10 to produce a compound of formula (XXV): (c) zing ring formation of the compound of formula (XXV) to produce a compound of formula (IV): (d) selectively protecting the compound of formula (IV) to prepare a compound of formula 5 (V): (e) phosphorylating the compound of formula (V) to prepare a compound of formula (VI): (f) oxidizing the compound of formula (VI) to e a compound of formula (VII): ; and (g) deprotecting the compound of formula (VII) to prepare the compound of a (I). 5
70. The process of claim 69, wherein the compound of formula (XXIII) is selected from the group consisting of:
71. The process of any one of claims 69-70, wherein the compound of formula (XXIV) 10 is:
72. The process of any one of claims 69-71, wherein the compound of formula (II) is:
73. The s of any one of claims 69-72, wherein the compound of a (XXV) is: 5 .
74. The process of any one of claims 69-73, wherein the phosphorylation of step (e) comprises reacting the compound of formula (V) with a P(V) phosphorylating agent. 10
75. The process of claim 74, wherein the P(V) phosphorylating agent is selected from the group consisting of: POCl3; PO(OCH3)xCl3-x; H3PO4; PO(OBn)xCl3-x; Cl3CCH2OP(O)Cl2; and P(O)OP(O)(OBn)2.
76. The process of claim 74, n the P(V) phosphorylating agent is Cl2PO(OCH3).
77. The process of any one of claims 69-76, wherein step (f) ses reacting the compound of formula (VI) with an oxidizing agent selected from the group consisting of: TFAA/DMSO; RuO4; Dess-Martin; DMSO/triflic anhydride; and PDC. 20
78. The process of any one of claims 69-77, wherein the deprotection of the compound of formula (VII) is performed under anaerobic conditions.
79. The process of any one of claims 69-78, wherein the compound of a (XXIII) 5
80. The process of any one of claims 69-79, wherein the compound of formula (XXIV)
81. The process of any one of claims 69-80, wherein the compound formula (XXV) is: 10 .
82. The process of any one of claims 69-81, wherein the compound of formula (IV) is:
83. The s of any one of claims 69-82, wherein the compound of formula (V) is:
84. The process of any one of claims 69-83, wherein the compound formula (VI) is:
85. The process of any one of claims 69-84, wherein the compound of formula (VII) is: 10 .
86. The process of any one of claims 69-85, wherein the process further ses formulating the compound of formula (I) as a pharmaceutical composition.
87. The process of any one of claims 69-86, wherein a leaving group is selected from the 5 group consisting of: tosylates, ates, nosylates, mesylates, oxoniums, triflates, nonaflates, and tresylates.
88. A process for preparing a compound of formula (I): or a pharmaceutically acceptable salt thereof, the process sing: (a) reacting a compound of formula -A): 15 wherein: each R1 is independently H or a protecting group, and R4 is H or a leaving group, to produce a compound of formula (XXIV): (b) reacting a nd of a (XXIV) with a compound of formula (II-A): to produce a compound of formula (XXV-A): 5 ; (c) catalyzing ring formation of the compound of formula (XXV-A) to produce a compound of formula (IV-D): (d) selectively protecting the compound of formula (IV-D) to prepare a compound of formula 10 (V-D): (e) phosphorylating the compound of formula (V-D) to prepare a compound of formula (VID (f) ing the compound of formula (VI-D) to prepare a compound of formula (VII-D): 5 ; and (g) deprotecting the nd of formula (VII-D) to prepare the compound of formula (I).
89. A compound of a (I): or a pharmaceutically acceptable salt thereof, prepared by the process comprising: (a) reacting a compound of formula (II): each R1 is independently H or a protecting group, with a compound of formula (XXII): to produce a compound of formula (IV): 10 (b) selectively protecting the compound of formula (IV) to prepare a compound of formula (V): (c) phosphorylating the compound of formula (V) to prepare a nd of formula (VI): 5 (d) ing the compound of formula (VI) to prepare a compound of formula (VII): ; and 10 (e) ecting the compound of formula (VII) to prepare the compound of formula (I).
90. A compound of formula (I): or a pharmaceutically acceptable salt thereof, prepared by the process comprising: (a) reacting a compound of formula (XXIII): wherein: each R1 is independently H or a protecting group and R4 is H or a leaving group; 5 to produce a compound of a (XXIV): (b) reacting a compound of formula (XXIV) with a compound of formula (II): 10 to produce a compound of formula (XXV): (c) catalyzing ring formation of the nd of formula (XXV) to produce a compound of formula (IV): (d) ively protecting the compound of formula (IV) to prepare a compound of formula 5 (V): (e) phosphorylating the compound of formula (V) to prepare a compound of formula (VI): (f) oxidizing the compound of formula (VI) to prepare a compound of formula (VII): ; and (g) deprotecting the compound of formula (VII) to prepare the compound of formula (I). 5
91. A process for preparing a compound of formula (XIII): or a pharmaceutically acceptable salt thereof, the process sing: (a) reacting a compound of a (II): 10 wherein: each R1 is independently H or a protecting group, with a compound of formula (XXII): to produce a nd of formula (IV): (b) selectively protecting the compound of a (IV) to prepare a compound of formula 5 (V): (c) phosphorylating the compound of formula (V) to prepare a compound of formula (VI): 10 (d) oxidizing the compound of formula (VI) to prepare a compound of formula (XIV): ; and (e) deprotecting the compound of formula (XIV) to prepare the compound of formula .
92. A process for preparing a compound of formula : or a pharmaceutically acceptable salt thereof, the process comprising: (a) reacting a compound of formula (XXIII): wherein: each R1 is independently H or a protecting group and R4 is H or a leaving group; to produce a compound of formula (XXIV): (b) reacting a compound of formula (XXIV) with a compound of formula (II): 5 to produce a compound of a (XXV): (c) catalyzing ring formation of the compound of formula (XXV) to produce a compound of formula (IV): (d) ively protecting the compound of formula (IV) to prepare a compound of formula (V): (e) phosphorylating the compound of formula (V) to prepare a compound of formula (VI): (f) oxidizing the compound of formula (VI) to prepare a compound of formula (XIV): ; and (g) deprotecting the compound of formula (XIV) to e the compound of formula (XIII).
93. A pharmaceutical composition comprising i) a compound of formula (I), or a pharmaceutically able salt thereof, prepared by the process of claim 1 and ii) a 15 pharmaceutically acceptable excipient.
94. A pharmaceutical composition comprising i) a compound of formula (I), or a pharmaceutically acceptable salt thereof, prepared by the process of claim 23 and ii) a pharmaceutically acceptable ent.
95. A pharmaceutical composition comprising i) a compound of formula (I), or a pharmaceutically acceptable salt thereof, prepared by the process of claim 24 and ii) a pharmaceutically acceptable ent. 10
96. A pharmaceutical composition comprising i) a compound of formula (I), or a pharmaceutically acceptable salt thereof, prepared by the process of claim 25 and ii) a pharmaceutically acceptable excipient.
97. A pharmaceutical composition sing i) a compound of formula (I), or a 15 pharmaceutically acceptable salt thereof, prepared by the process of claim 26 and ii) a pharmaceutically acceptable excipient.
98. A pharmaceutical composition comprising i) a compound of formula (I), or a pharmaceutically acceptable salt thereof, prepared by the process of claim 55 and ii) a 20 pharmaceutically acceptable excipient.
99. A pharmaceutical composition comprising i) a compound of formula (I), or a pharmaceutically acceptable salt thereof, prepared by the process of claim 68 and ii) a ceutically able excipient.
100. A pharmaceutical composition comprising i) a compound of formula (I), or a ceutically acceptable salt thereof, prepared by the process of claim 69 and ii) a pharmaceutically acceptable excipient. 30
101. A ceutical composition comprising i) a compound of formula (I), or a pharmaceutically able salt thereof, ed by the process of claim 88 and ii) a pharmaceutically acceptable excipient.
102. A pharmaceutical composition comprising i) a nd of formula (XIII), or a ceutically acceptable salt thereof, prepared by the process of claim 39 and ii) a pharmaceutically acceptable excipient.
103. A pharmaceutical composition comprising i) a compound of formula (XIII), or a pharmaceutically acceptable salt thereof, prepared by the process of claim 40 and ii) a pharmaceutically acceptable excipient. 10
104. A pharmaceutical composition sing i) a compound of formula (XIII), or a pharmaceutically able salt thereof, prepared by the process of claim 44 and ii) a pharmaceutically acceptable excipient.
105. A pharmaceutical composition comprising i) a compound of formula , or a 15 pharmaceutically able salt thereof, prepared by the process of claim 45 and ii) a pharmaceutically acceptable excipient.
106. A pharmaceutical composition comprising i) a compound of formula (XIII), or a pharmaceutically acceptable salt thereof, prepared by the process of claim 46 and ii) a 20 pharmaceutically acceptable excipient.
107. A pharmaceutical composition comprising i) a compound of formula (XIII), or a pharmaceutically acceptable salt thereof, ed by the process of claim 91 and ii) a ceutically acceptable excipient.
108. A pharmaceutical ition comprising i) a compound of formula (XIII), or a pharmaceutically acceptable salt thereof, prepared by the process of claim 92 and ii) a pharmaceutically acceptable excipient. 30
109. A process of preparing a compound of formula (XXIV): or a pharmaceutically acceptable salt thereof, wherein: each R1 is H or a ting group, 5 the method comprising: reacting a compound of formula (XXIII): wherein: R4 is H or a leaving group, with a base to prepare a compound of formula (XXIV).
NZ614009A 2011-02-18 2012-02-17 Methods for synthesizing molybdopterin precursor z derivatives NZ614009B2 (en)

Applications Claiming Priority (13)

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US201161444280P 2011-02-18 2011-02-18
US201161444389P 2011-02-18 2011-02-18
US201161444399P 2011-02-18 2011-02-18
US61/444,399 2011-02-18
US61/444,389 2011-02-18
US61/444,280 2011-02-18
US201161498801P 2011-06-20 2011-06-20
US201161498808P 2011-06-20 2011-06-20
US61/498,808 2011-06-20
US61/498,801 2011-06-20
US201261599314P 2012-02-15 2012-02-15
US61/599,314 2012-02-15
PCT/US2012/025689 WO2012112922A1 (en) 2011-02-18 2012-02-17 Methods for synthesizing molybdopterin precursor z derivatives

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