WO2012137225A1 - Substituted methylformyl reagents and method of using same to modify physicochemical and/or pharmacokinetic properties of compounds - Google Patents

Substituted methylformyl reagents and method of using same to modify physicochemical and/or pharmacokinetic properties of compounds Download PDF

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Publication number
WO2012137225A1
WO2012137225A1 PCT/IN2012/000248 IN2012000248W WO2012137225A1 WO 2012137225 A1 WO2012137225 A1 WO 2012137225A1 IN 2012000248 W IN2012000248 W IN 2012000248W WO 2012137225 A1 WO2012137225 A1 WO 2012137225A1
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WIPO (PCT)
Prior art keywords
chloromethyl
methyl
oxy
carbonate
ium
Prior art date
Application number
PCT/IN2012/000248
Other languages
French (fr)
Inventor
Sundeep Dugar
Dinesh MAHAJAN
Frank HOLLINGER PETER
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Sphaera Pharma Pvt. Ltd
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Publication date
Application filed by Sphaera Pharma Pvt. Ltd filed Critical Sphaera Pharma Pvt. Ltd
Priority to JP2014503279A priority Critical patent/JP2014514300A/en
Priority to EP12768375.3A priority patent/EP2693876B1/en
Priority to CN201811274102.7A priority patent/CN109608436B/en
Priority to CN201280022913.2A priority patent/CN103607888A/en
Priority to US14/110,373 priority patent/US9359376B2/en
Priority to ES12768375T priority patent/ES2779225T3/en
Publication of WO2012137225A1 publication Critical patent/WO2012137225A1/en

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • 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
    • 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
    • C07D491/22—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 four or more hetero rings

Definitions

  • the present invention relates to the synthesis and application of novel chiral/ achiral substituted methyl formyl reagents to modify pharmaceutical agents and/or biologically active substances to modify the physicochemical, biological and/or pharmacokinetic properties of the resulting compounds from the unmodified original agent.
  • a chemical entity which is potent in activity against its target, is the first step in the drug discovery process.
  • a potent compound is only effective when an appropriate quantity is transported to the site of action at an acceptable rate after it has been administered. Even potent compounds benefit from optimization of these aspects.
  • Many potent chemical entities do not have optimal pharmacokinetic parameters and hence the pharmacodynamic properties of these drugs are also suboptimal.
  • there are several chemical entities that are already available in the market which have restricted pharmacokinetic properties and hence cannot be formulated in a manner convenient for patient administration.
  • the rate and extent of transportation into the blood circulation can be controlled by addition of certain groups to the original molecule, thereby modifying the molecule and its properties.
  • Molecular modification is the chemical modification of a known and previously characterized lead compound for the purpose of enhancing its usefulness as a drug. This could mean enhancing its specificity for a particular target site, increasing its potency, improving its rate and extent of absorption, modifying the time course over which the active components become bio-available in the body (e.g., time release formulation), reducing its toxicity, and/or changing its physical or chemical properties (e.g., solubility) to optimize those aspects for particular applications.
  • the moiety used for molecular modification of the drug must be such that the therapeutic efficacy of the compound is retained and/or enhanced, while causing modification of the pharmacokinetic properties. Further, the modified compound, when administered, must not adversely affect the safety, toxicity and efficacy of the chemical entity beyond a tolerable degree.
  • the present invention aims to provide novel substituted methyl formyl based agents that may be used to modify existing compounds modify in terms of their pharmacokinetic, physical, and/or pharmacodynamic properties.
  • the present invention discloses agents for modification and methods for using them to enhance particular properties while preserving the safety, toxicity, and efficacy of the original compound.
  • This invention permits one to achieve one or more of the following: 1) Providing novel substituted methyl formyl based agents for molecular modification of chemical entities;
  • the present invention provides a novel methyl formyl derivatizing reagent of the general formula shown below in Figure 1:
  • FIGURE 1 is a diagrammatic representation of FIGURE 1:
  • Figure 1 represents the structure of a substituted methyl formyl reagent
  • X is selected from CI, Br, I, OTs, OMs;
  • Y is selected from R 2 , OR 2 , or N(R 2 ) 2 ;
  • R and R 1 can independently be H, Ci-Cs straight or branched chain alkyl - optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S0 2 ; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, IM, S, SO, or S0 2 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl;
  • R and R 1 can also be joined to form 3-7 membered carbocyclic ring optionally containing 1- 2 heteroatoms selected from, 0, N, S, SO, S0 2 and also be optionally substituted with alkoxy, F or CI;
  • R 2 can independently be H, Ci-C 8 straight or branch chain alkyl - optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S0 2 ; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S0 2 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl; and
  • R 2 can also be part of a 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from O, N, S, SO, S0 2 and also be optionally substituted with alkoxy, F or CI.
  • methylformyl reagents of the present invention may be present in enantiomerically pure forms or as mixture of enantiomers or diastereomers.
  • This invention provides novel substituted methyl formyl compounds suitable as a reagent for molecular modification, in which the modified entities exhibit improved properties and are suitable for to pharmaceutical use.
  • the resultant modified compounds obtained by using the novel reagents of this invention are suitable for use as drugs and/or pharmaceutical agents with improved pharmacokinetic and/or pharmacodynamic profile(s), while maintaining a desirable safety and toxicity profile.
  • the invention also provides a method for preparation of pharmaceutical agents and other biologically active substances more soluble in saline and/or at biologically useful pHs, a method to affect the pharmacokinetic properties of pharmaceutical agents and other biologically active substances, a method to affect the rate of conversion of the modified pharmaceutical agents and other biologically active substances to the original pharmaceutical agents and biologically active substances by either modification of the structure of the substituted methyl formyl agents or by causing a change in the biological system favored to affect this conversion due to specificity and selectivity, and a method to affect the favored location(s) of conversion of the modified pharmaceutical agents and other biologically active substances to the original pharmaceutical agents and biologically active substances by either modification of the structure of the substituted methyl formyl agents or by causing an change in the biological system favored to affect this conversion due to specificity and selectivity.
  • Process for preparation and isolation of modified compounds are also provided.
  • X is selected from CI, Br, I, OTs, OMs;
  • Y is selected from R 2 , OR 2 , or N(R 2 ) 2 ;
  • R and R 1 are independently H, C C 8 straight or branched chain alkyl — optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S0 2 ; 3-7 membered cycloalkyi optionally containing 1-3 heteroatoms selected from O, N, S, SO, or S0 2 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl;
  • R and R 1 can also be joined to substituted methyl formyl to form a 3-7 membered carbocyclic ring optionally containing 1-2 heteroatoms selected from, 0, N, S, SO, S0 2 and also be optionally substituted with alkoxy, F or CI;
  • R 2 independently is H, Ci-C 8 straight or branch chain alkyl - optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S0 2 ; 3-7 membered cycloalkyi optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S0 2 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl; and
  • R 2 is independently part of a 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from, 0, N, S, SO, S0 2 and also be optionally substituted with alkoxy, F or CI.
  • Figure 1 represents the structure of a substituted methyl formyl reagent
  • X is selected from CI, Br, I, OTs, OMs
  • Y is selected from R 2 , OR 2 , or N(R 2 ) 2 ;
  • R and R 1 can independently be H, C C 8 straight or branched chain alkyl - optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S0 2 ; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S0 2 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl;
  • R and R 1 can also be joined to substituted methyl formyl to form a 3-7 membered carbocyclic ring optionally containing 1-2 heteroatoms selected from, O, N, S, SO, S0 2 and also be optionally substituted with alkoxy, F or CI;
  • R 2 can independently be H, C C 8 straight or branch chain alkyl - optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S0 2 ; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S0 2 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl; and
  • R 2 can also be part of a 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from, 0, N, S, SO, S0 2 and also be optionally substituted with alkoxy, F or CI.
  • alk or “alkyl” refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms.
  • lower alkyl refers to alkyl groups of 1 to 4 carbon atoms.
  • alkenyl refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one double bond. Where an alkenyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a double bond.
  • alkynyl refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4 carbon atoms having at least one triple bond. Where an alkynyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a triple bond.
  • alkylene refers to a straight chain bridge of 1 to 5 carbon atoms connected by single bonds (e. g.,- (CH 2 ) x- wherein x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.
  • alkenylene refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected by single bonds and may be substituted with 1 to 3 lower alkyl groups.
  • alkynylene refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be substituted with 1 to 3 lower alkyl groups.
  • aromatic cyclic groups for example 6 membered monocyclic, 10 membered bicyclic or 14 membered tricyclic ring systems
  • exemplary aryl groups include phenyl, naphthyl, biphenyl and anthracene.
  • cycloalkyl and “cycloalkenyl” refer to cyclic hydrocarbon groups of 3 to 12 carbon atoms.
  • halogen and halo refer to fluorine, chlorine, bromine and iodine.
  • unsaturated ring includes partially unsaturated and aromatic rings.
  • heterocycle refers to fully saturated or unsaturated, including aromatic (i.e. "heteroaryl") cyclic groups, for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom-containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/ or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.
  • Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazoiidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyr
  • bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo [2,3-c] pyridinyl, furo [3,2-b] pyridinyl] or furo [2,3-b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4- oxo-quina
  • Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
  • heteroaryl refers to aromatic heterocyclic groups.
  • exemplary heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, triazinyl, and the like.
  • alkylene and alkyl in this text include both linear and branched, saturated and unsaturated (i.e. containing one double bond) divalent alkylene groups and monovalent alkyl groups, respectively.
  • alkanol in this text likewise includes linear and branched, saturated and unsaturated alkyl components of the alkanol groups, in which the hydroxyl groups may be situated at any position on the alkyl moiety.
  • cycloalkanol includes unsubstituted or substituted (e.g. methyl or ethyl) cyclic alcohols.
  • Pharmaceutical agents include any substance or agent considered to be a medicine, drug, or pharmaceutical agent.
  • Biologically active substances include any substance which exhibits a biological activity as understood by one skilled in the art.
  • Chemical and biological properties include pharmacokinetic and pharmacodynamic properties.
  • novel substituted methyl formyl compounds Reagents of this invention have structures represented by Figure 1.
  • the present invention includes a method of using these novel derivatizing agents to modify one or more of the physicochemical and pharmacokinetic, and pharmacodynamic properties of pharmaceutical compounds.
  • the method of the present invention can readily be applied to a wide variety of compounds to modify their properties in desirable ways.
  • Figure 1 reveals the general structure of the derivatizing agents of the present invention.
  • the methyl formyl reagents (Type I, II, III) can be prepared from respective acids, amines and alcohols directly. An acid with or without activation can be reacted with a corresponding aldehyde in presence of a Lewis acid can provide Type I reagent. An alcohol can be reacted with a halomethylhaloacetate in presence of a base to provide Type III reagent. Similarly, an amine (primary or secondary) can be reacted with halomethyl haloacetate with or without the presence of base can provide Type II reagent.
  • Aldehydes such as paraformaldehyde and acid chlorides, [3] can be reacted under anhydrous conditions and at appropriate temperatures with Lewis acids such as zinc chloride (dry), typically between -10°C and 60°C for a time ranging up to 24 hours.
  • the reaction mixture can be diluted with solvents such as dichloromethane, washed with aqueous dilute base such as a solution of Na 2 HC0 3 . Standard work up and purifications yield the desired substituted methyl formyl Reagents, [4].
  • Metal salt of desired acid such as caesium salt of Acid [2] can be treated with bromoiodomethane in Dry THF at appropriate temperatures,typically between 0°C to RT for 16 hours and if required heating.
  • the reaction mixture can be diluted with solvents such as ethyl acetate, washed with aqueous dilute base such as aqueous solution of Na2HC0 3 .
  • Standard work up and purifications yield the desired substituted methyl formyl Reagents [5].
  • R 2 R 4 can be any of several moieties linking the compound to be modified to the methyl formyl reagent of the present invention.
  • R 2 can independently be H, Ci-Cg straight or branch chain alkyl - optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S0 2 ; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, N, 5, SO, or S0 2 and or lower al kyl, straight or bra nched a lkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl.
  • R 2 can also be part of 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from, O, N, S, SO, S0 2 and also be optionally substituted with alkoxy, F or CI.
  • Corresponding primary or secondary amines can be reacted with substituted or unsubstituted chloro methylchloroformate, [6], in a solvent such as hexane or DCM at 0° C.
  • the reaction mixture can be filtered and the filtrate can be washed with 1.0 N HCI.
  • the organics can be evaporated to get the desired reagent, [7]. If required, further purification ca n be achieved using any general purification method practiced in organic chemistry laboratory such as precipitation or crystallization or preparative column purification.
  • R and R 1 ca n independently be H, Ci-C 8 straight or branched alkyl chain - optionally containing 1-3 heteroatoms selected from O, N, S, SO, or S0 2 ; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S0 2 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl.
  • R and R 1 can also be joined to substituted methyl formyl to form a 3-7 membered carbocyclic ring optionally containing 1-2 heteroatoms selected from, 0, N, S, SO, S0 2 and also be optionally substituted with alkoxy, F or CI.
  • R 2 can independently be H, Ci-C 8 straight or branch chain alkyl - optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S0 2 ; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S0 2 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl.
  • R 2 can also be part of a 3-7 membered ring optionally containing an additional 1-2 heteroatoms selected from, 0, N, S, SO, S0 2 and also be optionally substituted with alkoxy, F or CI.
  • R 2 can be any of several moieties linking the compound to be modified to the methyl formyl reagent of the present invention.
  • R 2 can independently be H, C C 8 straight or branch alkyl chain - optionally containing 1-3 heteroatoms selected from O, N, S, SO, or S0 2 ; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S0 2 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl.
  • R 2 can also be part of a 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from, 0, N, S, SO, S0 2 and also be optionally substituted with alkoxy, F or CI.
  • Scheme 4 General Synthetic Scheme for halide exchange: Scheme 4.1:
  • Chloromethyl formyl Reagents [4] when treated with bromide suitable reagent such as lithium bromide or sodium bromide at appropriate temperatures, typically in the range of 40 -80°C for a time ranging up to 24 hours followed by standard work up and purification, yields desired bromo methyl formyl Reagents, [5].
  • bromide suitable reagent such as lithium bromide or sodium bromide
  • Chloromethyl formyl Reagents when treated with a reagent such as sodium iodide at appropriate temperatures, typically ranging from room temperature to 60°C for a time ranging up to 24 hours followed by a standard work up and purification, yields desired iodo methyl formyl Reagents, [10].
  • a reagent such as sodium iodide at appropriate temperatures, typically ranging from room temperature to 60°C for a time ranging up to 24 hours followed by a standard work up and purification, yields desired iodo methyl formyl Reagents, [10].
  • Chloromethyl formyl Reagents when treated with silver salt of methane sulfonic acid at appropriate temperatures, typically ranging from room temperature to 60°C to 90°C for a time ranging up to 24 hours followed by standard work up and purification, yield desired ((methylsulfonyl)oxy) methyl formyl Reagents, [11].
  • Fig 1 Some non limiting examples of type I Reagents.
  • Type II reagents are listed herein below and represented at Figure 2.
  • Fig 2 A non limiting set of compounds of Type II reagents.
  • Fig 3 List of Type III compounds.
  • novel substituted methyl formyl Reagents of the present invention are used to modify the properties of any chemical molecule that may be used for pharmaceutical, nutraceutical or other purposes. Such modification may be carried out on a wide variety of substrates to modify several parameters. This modification may be carried out by reacting a functional group of the chemical molecule, with the substituted methyl formyl reagents of the present invention. The modification may also be carried out by effecting a chemical reaction of the substituted methyl formyl reagents of the present invention with a heteroatom of a heterocyclic ring system.
  • the modification may be carried out by converting any functional group present in the chemical molecule of interest of type I, II or III and then reacting with an suitable external quaternization agent, or by reaction of the reagent on a heteroatom present on molecule of interest to make a quart.
  • the term 'Chemical compound' includes within its scope, all molecules that are currently present in the market as drugs, including antibiotics and orphan drugs, molecules currently undergoing clinical trials, molecules awaiting approval, molecules meant for use as nutraceuticals or as nutrients, molecules meant for agricultural purposes as pesticide, herbicide, insecticide, fungicide and other similar applications.
  • the term 'functional group' includes the specific groups of atoms and/or bonds within molecules that are responsible for the characteristic chemical reactions of those molecules and include hydrocarbons, groups containing halogens, groups containing oxygen, groups containing nitrogen, groups containing sulfur, groups containing phosphorus, groups containing boron.
  • the functional groups may be aliphatic or aromatic in nature.
  • Preferred groups for modification by the substituted methyl formyl reagents which may be termed as sites of translation are the carboxylic group, amino group, the heteroatom of the ring, alcoholic group, amide, etc.
  • the heteroatom of the'heterocyclic ring system may be any heteroatom, but is preferably 0, N, S or P.
  • R 3 and R 4 can independently be H, Ci-C 8 straight or branched alkyl chain - optionally containing 1- 3 heteroatoms selected from 0, N, S, SO, or S0 2 ; 3-7 membered cycloalkyl optionally containing 1- 3 heteroatoms selected from 0, N, S, SO, or S0 2 and/ or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl.
  • R 3 and/ or R 4 can also be part of 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from, 0, N, S, SO, S0 2 and also be optionally substituted with alkoxy, F or CI.
  • R 3 and R 4 may be connected to form 3-8 membered aliphatic or aromatic ring fused to the hetero-aromatic ring.
  • rings would be appropriately aliphatic and which would be aromatic.
  • Drugs or biological active molecules with nitrogen containing aromatic rings such as [234] can be reacted with a Type I reagent such as [235] using a solvent such as DCM or ACN under anhydrous conditions at room temperature for a time ranging up to 24 hours.
  • the reaction mixture can be evaporated to dryness and triturated with ether. The standard work up yields desired product
  • R 3 and R 4 can independently be H, Ci-C 8 straight or branched chain alkyl - optionally containing 1-
  • heteroatoms selected from 0, N, S, SO, or S0 2 ; 3-7 membered cycloalkyl optionally containing 1- 3 heteroatoms selected from O, N, S, SO, or S0 2 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl.
  • R 3 and/ or R 4 can also be part of 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from, O, N, S, SO, S0 2 and also be optionally substituted with alkoxy, F or CI.
  • R 3 and R 4 may be connected to form 3-8 membered aliphatic or aromatic ring fused to the hetero-alicyclic ring.
  • One skilled in the art would know which rings would be appropriately aliphatic and which would be aromatic.
  • Drugs or biologically active molecules with aliphatic tertiary amines such as [234] can be reacted with a Type I reagent such as [237] using acetonitrile/ tetrahydrofuran/ dichloromethane as solvents under anhydrous conditions at room temperature for a time ranging up to 24 hours.
  • the reaction mixture can be evaporated to dryness and triturated with ether.
  • the standard work up yields the desired product such as [238].
  • a solvent such as ACN
  • Drugs or biologically active molecules with alcohols and/ or phenols and/ or amines can also be modifyed by conversion to a respective methyl formyl reagent followed by making a quaternary ammonium cation using amines such as pyridine, for example nicotinamide is a preferred embodiment.
  • Non-limiting examples of such conversions with drugs or biologically active molecules with alcohols and/ or phenols are shown in Schemes below .
  • Non-limiting examples of such conversions of drugs or biologically active molecules with primary or secondary amines are shown in Schemes 7 and8.
  • Rx/Ry H or alkyl
  • Rx/Ry H or alkyl
  • drugs or biological active molecules with a primary or secondary amino group [239] can be reacted first with a suitable halo actetyl chloride such as bromo acetylchloride [244] using DCM as solvent. Standard workup of the reaction mixture yields the intermediate [245].
  • This intermediate [245] can be further reacted with a quaternization reagent such as nicotinamide [243] using a solvent such as DCM at room temperature.
  • the reaction mixture can be evaporated to yield the desired final modified drug or biological active molecule [246].
  • Drugs or biological active molecules containing alcohol such as [250] can be reacted with chloromethyl chloroformate [8] in presence of a base such as pyridine and a solvent such as DCM. Standard workup of the reaction mixture yields an intermediate [251].
  • Drugs or biological active molecules containing alcohol such as [250] can be reacted first with a suitable haloacetylhalides such as bromoacetylchloride [244] in a solvent such as DCM at a desired temperature followed by a standard workup yield compound [257].
  • Compound [257] can be further reacted with a suitable quaternizing agent such as nicotinamide [243] using solvent such as ACN at desired temperature.
  • a suitable quaternizing agent such as nicotinamide [243] using solvent such as ACN at desired temperature.
  • the corresponding drug or biological active molecule [250] can be reacted with suitable halomethyl reagents such as chloromethyl nicotinate [259] in a solvent such as DCM at a desired temperature ranging from ambient to refluxing.
  • suitable halomethyl reagents such as chloromethyl nicotinate [259]
  • DCM a solvent
  • a similar work up yields the desired modified biological active molecule [261].
  • a suitable halomethyl reagent such as chloromethyl nicotinate [259]
  • a solvent such as DCM at desired temperature.
  • the corresponding drug or biological active molecule with a carboxylic acid group [262] can be reacted with Lewis acids such as Zinc chloride (dry) and aldehydes such as paraformaldehyde at temperatures ranging from -10 °C to 60 °C for a time ranging up to 20-24 hours.
  • Lewis acids such as Zinc chloride (dry)
  • aldehydes such as paraformaldehyde at temperatures ranging from -10 °C to 60 °C for a time ranging up to 20-24 hours.
  • Standard work up of the reaction mixture yields the intermediate [265], which can be further reacted with nicotinamide [322] using DCM or ACN as a solvent at room temperature.
  • the reaction mixture can be evaporated to yield the desired final modified drug or biological active molecule [266].
  • the corresponding drug or biological active molecule with a carboxylic acid group [262] in dichloromethane can be treated with a base such as sodium bicarbonate and tetrabutylammonium bisulfate followed by dropwise addition of chloromethyl chlorosulfate in solvent such as dichloromethane.
  • a base such as sodium bicarbonate and tetrabutylammonium bisulfate
  • chloromethyl chlorosulfate in solvent such as dichloromethane.
  • the organic layer was washed with aqueous Na2C0 3
  • a quaternization reagent such as nicotinamide [243] in solvent such as ACN.
  • the reaction mixture on evaporation provides modified drug or biological active molecule [267].
  • the corresponding drug or biological active molecule with a carboxylic acid group [262] can be reacted with a base such as cesium carbonate followed by the addition of a reagent such as bromo iodomethane in a solvent such as THF.
  • a reagent such as bromo iodomethane in a solvent such as THF.
  • THF a solvent
  • substituted methyl formyl Reagents [268]
  • a quaternization reagent such as nicotinamide [243] in a solvent such as ACN.
  • the reaction mixture on evaporation yields desired products [269].
  • a quaternary salt such as [273] can be prepared by the method describe above with a suitable halomethyl formyl reagent such as iodo methyl formyl (Type I or Type II or Type III).
  • the quat [272] can be treated with a suitable metal salt such as silver mesylate in a solvent such as acetonitrile at a desired temperature ranging from ambient to refluxing which results in the precipitation of silver iodide and formation of desired product.
  • the insoluble silver halide can be filtered out to get reasonably pure desired product [273].
  • the above method is applicable to do anion exchange on all type of quat salts having any halide such as chloride, bromide or iodide as the counter ion.
  • the various types of silver salts can be used such as silver acetate, silver mesylate or silver tosylate etc.
  • Substituted methyl formyl reagents of the present invention are used to generate New Chemical Entities (NCEs) so that the rate and site of conversion of these NCEs to the parent drugs/biologically active compounds can be controlled. This can be achieved, due to the presence of the converting enzyme(s) or other converting parameters and reagents that are involved in the transformation of the NCEs to the parent drugs/biologically active substances which may only (or even predominantly) be selectively present at the site of conversion.
  • the rate of conversion can be modifyed as the structure of the modified drug/biologically active molecule or the concentration/amount of the converting enzyme present at the site of conversion can influence the rate of conversion of the NCEs to the drug/biologically active compound.
  • Endogenous enzymes that are capable of converting these compounds belong to four International Union of Pure and Applied Chemistry classes. Enzymes from class 1 are the oxidoreductases, enzymes from class 2 are the transferases, enzymes from class 3 are hydrolases, and enzymes from class 4 are the lysases. Numerous modified compounds have been developed for the delivery of higher concentrations of a drug to the target than could otherwise be obtained by the administration of the unmodified compound itself. Four main modes of delivery have been identified which modified drugs or biologically active molecules as described in this patent may exploit: (1) passive drug enrichment in the target organ; (2) transporter mediated delivery; (3) selective metabolic activation through enzymes; and (4) antigen targeting.
  • This application of the present invention achieves more than simply modifying the pharmacokinetic and physicochemical properties of the drug/biologically active molecule. This results in the ability to use less, overall, of the drug/biologically active compound than would be required of the unmodified drug. This offers several benefits, including potential decrease or even elimination of unwanted side effects.
  • the methyl formyl reagents of the present invention are designed to be cleaved from the drug they are attached to by the endogenous systems, such as enzymes present, to a greater or lesser extent, in humans and most animals kept as pets or livestock. Accordingly, unlike making many other possible covalent modifications to an effective drug, derivatization according to the present invention permits modification of the modified compound's characteristics without sacrificing the safety, efficacy, or toxicology of the original, un-modified drug.
  • Table 2 shows an exemplary but a non-limiting list of currently-existing drugs/biologically active compounds that can be modified using the methods and modification agents described in this invention.
  • the first column provides the reference number for the drug and/or biologically active compound.
  • the second column gives the generic name for the drug and/ or biologically active compound.
  • the third column gives the trade name under which the drug is sold (where applicable).
  • the fourth column gives the lUPAC name of the drug and/ or biologically active compound.
  • the fifth column shows the chemical structure of the drug. For example, dimebon [4149] has two functional groups which can undergo derivation. One group is a tertiary amine and the other is an aromatic amine. Non-limiting examples of these derivations are illustrated in Schemes 31 and 32.
  • novel derivatized compounds of the present invention could be formed with any of a variety of drugs which have one or more of the functional groups referenced according to Schemes 1, 2 and/ or 3 by practicing the method of the present invention.
  • Table 2 A Non-limiting List of Drugs or Biologically Active Molecules which can be derivatized according to the embodiment of the invention.
  • the reagents of the present invention may be used to modify drugs which belong to the class of compounds may be selected from, but are not limited to: Central Nervous System Drugs, such as CNS/Respiratory Stimulants, Analgesics, Narcotic Agonists, Narcotic agonist/antagonists, Nonsteroidal Anti-inflammatory/Analgesic Agents, Behavior-Modifying Agents, Tranquilizers/Sedatives, Anesthetic Agents, Inhalants, Narcotics, Reversal Agents, Anticonvulsants, Muscle Relaxants, Skeletal, Muscle Relaxants, Smooth, Euthanasia Agent, Cardiovascular Agents, Inotropic Agents, Antiarrhythmic Drugs, Anticholinergics, Vasodilating Agents, Agents Used in Treatment of Shock, Alpha-Adrenergic Blocking Agents, Beta-Adrenergic Blocking Agents, Respiratory Drugs, Bronchodilators, Sympathomimetics, Antihistamines, Antituss
  • Endocrine/Reproductive Drugs Prostaglandins, Antiinfective Drugs, Antiparasitics, Anticoccidial Agents, Antibiotics, Anti-tuberculosis, Aminocyclitols,Cephalosporins, Macrolides, Penicillins, Tetracyclines, Lincosamides, Quinolones, Sulfonamides, Miscellaneous Antibacterials, Antifungal Agents, Antiviral Agents, Blood Modifying Agents, Clotting Agents, Anticoagulants, Erythropoietic Agents, Antineoplastics/ Immunosuppresives, Alkylating Agents, Antidotes, Bone/ Joint Agents, Dermatologic Agents (Systemic), Vitamins and Minerals/ Nutrients, Systemic Acidifiers, Systemic Alkalinizers, anti-cancer agents, anti-viral agents, etc.
  • the compounds of the present invention after being modified include but are not limited to: i. l-(((3,3-dimethylbutanoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l-ium
  • the present invention includes within its scope the salts and isomers.
  • Compounds of the present invention after being modified by the substituted methyl formyl reagent may in some cases form salts which are also within the scope of this invention.
  • the term "salt(s)", as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
  • Zwitterions are included within the term “salt(s)” as used herein (and may be formed, for example, where the substituents comprise an acid moiety such as a carboxyl group).
  • quaternary ammonium salts such as alkyl ammonium salts.
  • Salts of the compounds of may be formed, for example, by reacting a compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lypholization.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxy ethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, ox
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexyiamines, hydrabamines, N-methyl-D-glucamines, N- methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • the basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g.
  • dialkyl sulfates e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • Solvates of the compounds of the invention are also contemplated herein. Solvates of the compounds of formula I are preferably hydrates or any other pharmaceutically acceptable solvate.
  • All stereoisomers of the present compounds are contemplated within the scope of this invention.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration.
  • the present invention also envisages within its scope the effect of selection of suitable counter ions.
  • the counter ion of the compounds of the present invention may be chosen by selecting the dissociation constant for the drug capable of ionization within the said pH range.
  • the solubility and consequently the absorption of the drug may be modified.
  • the present invention includes in its scope, the modification of deuterated compounds.
  • Deuterated compounds are those wherein the compounds have selective incorporation of deuterium in place of hydrogen.
  • Deuterated compounds may be further modified by the substituted methyl formyl reagents of the present invention as per procedures as disclosed herein.
  • composition containing the modified entities of the invention The invention thus also provides the use of the modified entity as defined herein for use in human or veterinary medicine.
  • the compound for use as a pharmaceutical may be presented as a pharmaceutical formulation.
  • the invention therefore provides in a further aspect a pharmaceutical formulation comprising the modified compounds of the invention with a pharmaceutically acceptable carrier thereof and optionally other therapeutic and/or prophylactic ingredients.
  • the carriers must be "acceptable” in the sense of being compatible with the other ingredients of the formula and not deleterious to the recipient thereof.
  • the pharmaceutical formulation will be in an appropriate unit dosage form.
  • the pharmaceutical formulations may be any formulation and include those suitable for oral, intranasal, intraocular or parenteral (including intramuscular and intravenous) administration.
  • the formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.
  • the compounds of the present invention may be administered orally, topically, intranasall , intraocularly, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasteral injection or infusion techniques.
  • the compounds of the invention are effective in the treatment of humans.
  • the crude product was passed through column chromatography by using 100-200 mesh size silica and 1% MeOH-DCM as a solvent system to yield the product fert-butyl (iodomethyl) carbonate [275] as colorless liquid (136 mg, 30%).
  • methyl formyl reagents were synthesized using the synthetic procedures disclosed above and herein with various substituted or unsubstituted alcohols, phenols, amines and acids to get structures in Tables 3, 4 and 5 which were characterized using spectroscopic techniques such as MS and/or 1 H NMR.
  • the modifying reagents of the present invention can be synthesized in wide variety as taught and disclosed, including but not limited to the specific examples provided herein, including those in Tables 3, 4 and 5.
  • one aspect of the present invention is therefore the ability to tailor the substituents to the family of reagents disclosed in Figure 1 to suit a particular application or obtain the desired result.
  • mice Female Sprague Dawley (SD) rats 3 per group after overnight fasting were dosed orally (via gavage) with imatinib and its modified drugs in distilled water (5ml/kg) at a dose level of 3mg/kg .
  • Blood was collected by serial bleeding at 0.16 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h in heparinized tubes. Blood samples were centrifuged at 10,000rpm for 10 min. at 4°C to obtain the plasma, which were aspirated into separate labeled tubes and stored at -80°C. 400ng/ml of Verapmil in acetonitrile was used as the drug extraction solvent for extracting drug from plasma. Extraction solvent was added to plasma was vortexed and shaken on shaker for 10 minutes, centrifuged at 10000 rpm for 10 minutes at 4°C. Supernatant was kept for analysis.
  • Acetonitrile and plasma calibration curves were generated and percentage of drug recovery from plasma determined. Quantitative analysis was done by liquid chromatography tandem mass spectrometry using multiple reaction monitoring (API3000 LC-MS/MS). C max , T max , AUC and ti 2 were calculated using Graph Pad PRISM version 5.04.
  • Table 6 Some examples of chemical modifications of nicorandil and their Pharmacokinetic Parameters determined in Swiss mice at 3 mpk orally (T m-V . C m3 . AUC and Ti ⁇ )
  • the modifying reagents of the present invention can be synthesized in wide variety as taught and disclosed, including but not limited to the specific examples provided herein.
  • modification according to the teachings of the present invention provides a ready and flexible method of varying various pharmacokinetic parameters of a biologically active compound.
  • sildenafil may also be prepared in a similar manner. Some non-limiting examples of sildenafil are as below:
  • TEA 1.2 ml, 8.6 mmol, 5.0 eq
  • paracetamol [4147] (0.26 g, 1.7 mmol, 1.0 eq)
  • nicotinoyl chloride hydrochloride [296] (1.53 gm, 8.6 mmol, 5.0 eq) was added to the above reaction mixture.
  • the reaction mixture was stirred at room temperature for 24 h.
  • Step 2 Sodium iodide (0.083 g, 5.52 mmol, 3.0 eq.) was added to a solution of 4-acetamidophenyl 2- bromoacetate [299] (0.05 g, 1.84 mmol, 1.0 eq.) in acetonitrile (5ml) followed by the addition of dimethyl nicotinamide [300] (0.027g, 1.84 mmol, 1.0 eq). The resulting reaction mixture was stirred at 40°C for 48 h. Reaction progress was monitored by TLC. Solvent was removed under vacuum to get crude product.
  • CMCF chloromethyl chloroformate
  • Step 2 lodomethyl isopropylcarbamate [6318] (0.007 g, 0.028 mmol, 1.0 eq) was added to a solution of (S)- ((4,ll-diethyl-4-hydroxy-3,14-dioxo A12,14-tetrahydro-lH ⁇ yrano[3 4':6,7]indolizino[l ; 2-b]quinolin- 9-yl)oxy)methyl nicotinate [305] (0.015 g, 0.028 mmol, 1.0 eq) in DCM (5 ml). The reaction mixture was stirred at RT for 16 hours.
  • reaction mixture was stirred for 20 h at RT. Reaction was monitored by TLC.
  • the reactionjmixture was diluted with EtOAc (200 ml), washed by saturated NaHC0 3 solution (75 ml) and water (100 ml) successively.
  • the EtOAc layer was separated, dried with sodium sulphate and concentrated under reduced pressure to yield a crude product.
  • Step2 lodomethyl isopropylcarbamate [6318] (0.003 g, 10 mmol, 1.0 eq) was added to a solution of [310] (0.01 g, 10.0 mmol, 1.0 eq) in dry Acetonitrile under an argon atmosphere. The resulting reaction mixture was stirred for 6 hours at RT. Reaction progress was monitored by TLC. Solvent was evaporated under high vacuum pump to give crude product.
  • CMCF chloromethyl chloroformate
  • Sod ium iodide (0.022 g, 145.0 mmol, 5 eq) was added to a solution of [312] (0.03 g, 29.0 mmol, 1 eq) in acetone. The resulting reaction mixture was refluxed for 6 h at 60 °C. Reaction progress was monitored by TLC. The reaction mixture was cooled to room temperature and passed through a bed of silica (mesh 100 - 200).
  • Dimethyl nicotinate [300] (0.003 g, 20.0 mmol, x eq) was added to a solution of [313] (0.01 g, 10.0 mmol, x eq) in dry acetonitriie (y ml) under argon atmosphere. The resulting reaction mixture was stirred for 16 h at RT. Reaction progress was monitored by TLC. Solvent was removed under high vacuum pump to give a crude product.
  • paclitaxel may also be synthesized in a similar manner, for instance see compound number 9400 and 9405 as below:
  • Ibuprofen [327] (0.1 g, 0.48 mmol ,1.0 eq) DCM (2 ml), water(2 ml), sodium bicarbonate (0.131g , 1.8 mmol, 3.81 eq) and tetrabutylammonium hydrogen sulfate (0.016 g , 0.05 mmol, 0.1 eq) were stirred at 25°C for 2 min. to the above reaction mixture, a solution of chloromethyl chlorosulfate [323] (0.08 ml, 0.51 mmol, 1.1 eq) in DCM (1 ml) was added dropwise and the biphasic system was stirred at RT for 1 h.
  • Diclofenac sodium [331] (0.1 g, 0.33 mmol, 1.0 eq) DCM (2 ml), water (2 ml), sodium bicarbonate (0.105 g , 0.125 mmol, 3.81 eq) and tetrabutylammonium hydrogen sulfate (0.011 g , 0.033 mmol, 0.1 eq) were stirred at 25°C for 2 min.
  • a solution of chloromethyl chlorosulfate [323] (0.06 g, 0.363 mmol, 1.1 eq) in DCM (1 ml) was added dropwise. This biphasic system was stirred at RT for 1 h.
  • reaction progress was monitored by TLC and mass spectroscopy. Then, the reaction mass was filtered through cellite bed and washed with acetone (2 x 25ml). The acetone layer was then evaporated to dryness under vacuum to yield a brown gel.
  • the resultant crude product was purified on column chromatography (2% MeOH in DCM as eluent 100 - 200 mesh silica) to yield a white powder, (3-(4-amino-l-oxoisoindolin-2-yl)-2,6-dioxopiperidin-l-yl)methyl nicotinate [339] (0.032 g, 20%). m/z: 395
  • Step 2 lodomethyl isopropylcarbamate [6318] (0.018 g, 0.028 mmol, 1.0 eq) was added to a solution of (3-(4- amino-l-oxoisoindolin-2-yl)-2,6-dioxopiperidin-l-yl)methyl nicotinate [339] (0.03 g, 0.028 mmol, 1.0 eq) in DCM (5 ml). The reaction mixture was stirred at RT for 16 h.
  • Imatinib [148] (0.100 g, 0.2 mmol, 1 eq) was dissolved in DCM (10 ml) in a 25 ml two-necked round bottomed flask and iodomethyl pivalate [40] (0.185 g, 0.77 mmol, 3.8 eq) was added while stirring at RT.

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Abstract

The present invention relates to the synthesis and application of novel chiral/ achiral substituted methyl formyl reagents to modify pharmaceutical agents and/or biologically active substances to modify the physicochemical, biological and/or pharmacokinetic properties of the resulting compounds from the unmodified original agent.

Description

SUBSTITUTED METHYL FORMYL REAGENTS AND METHOD OF USING SAME TO MODIFY
PHYSICOCHEMICAL AND/OR PHARMACOKINETIC PROPERTIES OF COMPOUNDS
FIELD OF THE INVENTION
The present invention relates to the synthesis and application of novel chiral/ achiral substituted methyl formyl reagents to modify pharmaceutical agents and/or biologically active substances to modify the physicochemical, biological and/or pharmacokinetic properties of the resulting compounds from the unmodified original agent.
BACK GROUND OF THE INVENTION
A chemical entity, which is potent in activity against its target, is the first step in the drug discovery process. However, a potent compound is only effective when an appropriate quantity is transported to the site of action at an acceptable rate after it has been administered. Even potent compounds benefit from optimization of these aspects. Many potent chemical entities do not have optimal pharmacokinetic parameters and hence the pharmacodynamic properties of these drugs are also suboptimal. In addition, there are several chemical entities that are already available in the market which have restricted pharmacokinetic properties and hence cannot be formulated in a manner convenient for patient administration.
The rate and extent of transportation into the blood circulation can be controlled by addition of certain groups to the original molecule, thereby modifying the molecule and its properties. Molecular modification is the chemical modification of a known and previously characterized lead compound for the purpose of enhancing its usefulness as a drug. This could mean enhancing its specificity for a particular target site, increasing its potency, improving its rate and extent of absorption, modifying the time course over which the active components become bio-available in the body (e.g., time release formulation), reducing its toxicity, and/or changing its physical or chemical properties (e.g., solubility) to optimize those aspects for particular applications. However, the moiety used for molecular modification of the drug must be such that the therapeutic efficacy of the compound is retained and/or enhanced, while causing modification of the pharmacokinetic properties. Further, the modified compound, when administered, must not adversely affect the safety, toxicity and efficacy of the chemical entity beyond a tolerable degree.
The aforementioned strictures have resulted in limitations, some long standing, in the manner in which existing pharmaceuticals can be administered. For example, acetylsalicylic acid, the active ingredient in aspirin, is insufficiently soluble in saline to be administered intravenously. Hence, from the time it was discovered that chewing willow bark could reduce a fever, through the time aspirin was first compounded and till date, it is most frequently administered orally, and is not suitable for intravenous administration.
The strictures have also made it difficult to modify the pharmacodynamic properties of existing pharmaceuticals to optimize them for particular uses. Development of pharmaceuticals would be facilitated if it was possible to develop derivatization methods that could modify the pharmacokinetic and pharmacodynamic properties of a drug without detrimentally affecting a drug's efficacy, safety, and toxicity.
There is a need, as is illustrated by some of the examples shown herein, for a method of modifying chemical compounds that are useful as drugs such that one or more of their pharmacokinetic, physical, and/or pharmacodynamic properties are modified in the resultant compounds
Hence, to address this need, the present invention, aims to provide novel substituted methyl formyl based agents that may be used to modify existing compounds modify in terms of their pharmacokinetic, physical, and/or pharmacodynamic properties. The present invention discloses agents for modification and methods for using them to enhance particular properties while preserving the safety, toxicity, and efficacy of the original compound.
ADVANTAGES
This invention permits one to achieve one or more of the following: 1) Providing novel substituted methyl formyl based agents for molecular modification of chemical entities;
2) Modifying the pharmacokinetic profile of the modified entity;
3) Modifying the pharmacodynamic profile of the modified entity;
4) Maintaining a desirable safety and toxicity profile of the modified entity;
5) Improving the safety and toxicity profile;
6) Making pharmaceutical agents and other biologically active substances more soluble in saline and/or at biologically useful pH ranges;
7) Modifying the pharmacokinetic properties of pharmaceutical agents and other biologically active substances;
8) Modifying the rate of conversion of the modified pharmaceutical agents and other biologically active substances to the original pharmaceutical agents and biologically active substances by either modification of the structure of the substituted methyl formyl agents or by causing a change in the biological system favored to affect this conversion due to specificity and selectivity; and/or
9) Modifying the favored location(s) of conversion of the modified pharmaceutical agents and other biologically active substances to the original pharmaceutical agents and biologically active substances by either modification of the structure of the substituted methyl formyl agents or by causing a change in the biological system favored to affect this conversion due to specificity and selectivity.
SUMMARY OF THE INVENTION
The present invention provides a novel methyl formyl derivatizing reagent of the general formula shown below in Figure 1:
FIGURE 1:
Figure imgf000004_0001
1
Figure 1 represents the structure of a substituted methyl formyl reagent; Wherein:
X is selected from CI, Br, I, OTs, OMs; Y is selected from R2, OR2, or N(R2)2;
R and R1 can independently be H, Ci-Cs straight or branched chain alkyl - optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, IM, S, SO, or S02 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl;
R and R1 can also be joined to form 3-7 membered carbocyclic ring optionally containing 1- 2 heteroatoms selected from, 0, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI;
R2 can independently be H, Ci-C8 straight or branch chain alkyl - optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl; and
R2 can also be part of a 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from O, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI.
The methylformyl reagents of the present invention may be present in enantiomerically pure forms or as mixture of enantiomers or diastereomers.
Compounds that are derivatized with these substituted methyl formyl reagents have been found to possess notably enhanced aqueous solubility, and exhibit substantial and surprising improvements in pharmacokinetic and pharmacodynamic properties. These derivatizing agents are useful to favorably modify the physicochemical and pharmacodynamic properties of pharmaceutical compounds and other related uses. The present invention therefore also includes a method of using these novel derivatizing agents to modify one or more of the physicochemical and pharmacokinetic, and pharmacodynamic properties of pharmaceutical compounds. As the examples shown herein demonstrate, the method of the present invention can readily be applied to a wide variety of compounds to modify their properties in desirable ways and obtain resultant compounds with improved properties.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
This invention provides novel substituted methyl formyl compounds suitable as a reagent for molecular modification, in which the modified entities exhibit improved properties and are suitable for to pharmaceutical use. The resultant modified compounds obtained by using the novel reagents of this invention are suitable for use as drugs and/or pharmaceutical agents with improved pharmacokinetic and/or pharmacodynamic profile(s), while maintaining a desirable safety and toxicity profile. The invention also provides a method for preparation of pharmaceutical agents and other biologically active substances more soluble in saline and/or at biologically useful pHs, a method to affect the pharmacokinetic properties of pharmaceutical agents and other biologically active substances, a method to affect the rate of conversion of the modified pharmaceutical agents and other biologically active substances to the original pharmaceutical agents and biologically active substances by either modification of the structure of the substituted methyl formyl agents or by causing a change in the biological system favored to affect this conversion due to specificity and selectivity, and a method to affect the favored location(s) of conversion of the modified pharmaceutical agents and other biologically active substances to the original pharmaceutical agents and biologically active substances by either modification of the structure of the substituted methyl formyl agents or by causing an change in the biological system favored to affect this conversion due to specificity and selectivity. Process for preparation and isolation of modified compounds are also provided.
A. NOVEL SUBSTITUTED METHYL FORMYL REAGENTS B. A method of modifying a chemical compound by causing covalent attachment of a compound of formula 1, to a functional group or a heteroatom of a heterocyclic ring system to obtain a modified compound with improved chemical and biological properties;
Wherein in compound (1):
Figure imgf000007_0001
1
X is selected from CI, Br, I, OTs, OMs; Y is selected from R2, OR2, or N(R2)2 ; and
R and R1 are independently H, C C8 straight or branched chain alkyl — optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02; 3-7 membered cycloalkyi optionally containing 1-3 heteroatoms selected from O, N, S, SO, or S02 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl;
R and R1 can also be joined to substituted methyl formyl to form a 3-7 membered carbocyclic ring optionally containing 1-2 heteroatoms selected from, 0, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI;
R2 independently is H, Ci-C8 straight or branch chain alkyl - optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02; 3-7 membered cycloalkyi optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl; and
R2is independently part of a 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from, 0, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI. A.l NOVEL SUBSTITUTED METHYL FORMYL REAGENTS
Figure imgf000008_0001
1
Where:
Figure 1 represents the structure of a substituted methyl formyl reagent; X is selected from CI, Br, I, OTs, OMs; Y is selected from R2, OR2, or N(R2)2 ;
R and R1 can independently be H, C C8 straight or branched chain alkyl - optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl;
R and R1 can also be joined to substituted methyl formyl to form a 3-7 membered carbocyclic ring optionally containing 1-2 heteroatoms selected from, O, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI;
R2 can independently be H, C C8 straight or branch chain alkyl - optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl; and
R2 can also be part of a 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from, 0, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI. The terms "alk" or "alkyl" refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. The expression "lower alkyl" refers to alkyl groups of 1 to 4 carbon atoms.
The term "alkenyl" refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one double bond. Where an alkenyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a double bond.
The term "alkynyl" refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4 carbon atoms having at least one triple bond. Where an alkynyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a triple bond.
The term "alkylene" refers to a straight chain bridge of 1 to 5 carbon atoms connected by single bonds (e. g.,- (CH2) x- wherein x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.
The term "alkenylene" refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected by single bonds and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkenylene groups are -CH=CH-CH=CH-,-CH2-CH=CH-, -CH2-CH=CH-CH2-, - C(CH3)2CH=CH- and-CH(C2H5)-CH=CH-.
The term "alkynylene" refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkynylene groups are -C=C-, -CH2-C C-, -CH(CH3)-( C- and -f_ C-CH (C2H5)CH2-.
The terms "ar" or "aryl" refer to aromatic cyclic groups (for example 6 membered monocyclic, 10 membered bicyclic or 14 membered tricyclic ring systems) which contain 6 to 14 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, biphenyl and anthracene.
The terms "cycloalkyl" and "cycloalkenyl" refer to cyclic hydrocarbon groups of 3 to 12 carbon atoms.
The terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine. The term "unsaturated ring" includes partially unsaturated and aromatic rings.
The terms "heterocycle", "heterocyclic" or "heterocyclo" refer to fully saturated or unsaturated, including aromatic (i.e. "heteroaryl") cyclic groups, for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/ or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazoiidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-l,l-dioxothienyl, triazolyl, triazinyl, and the like.
Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo [2,3-c] pyridinyl, furo [3,2-b] pyridinyl] or furo [2,3-b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4- oxo-quinazolinyl), tetrahydroquinolinyl and the like.
Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
The term "heteroaryl" refers to aromatic heterocyclic groups. Exemplary heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, triazinyl, and the like.
The terms "alkylene" and "alkyl" in this text include both linear and branched, saturated and unsaturated (i.e. containing one double bond) divalent alkylene groups and monovalent alkyl groups, respectively. The term "alkanol" in this text likewise includes linear and branched, saturated and unsaturated alkyl components of the alkanol groups, in which the hydroxyl groups may be situated at any position on the alkyl moiety. The term "cycloalkanol" includes unsubstituted or substituted (e.g. methyl or ethyl) cyclic alcohols.
Pharmaceutical agents include any substance or agent considered to be a medicine, drug, or pharmaceutical agent.
Biologically active substances include any substance which exhibits a biological activity as understood by one skilled in the art.
Chemical and biological properties include pharmacokinetic and pharmacodynamic properties.
In a preferred embodiment, the novel substituted methyl formyl compounds Reagents of this invention have structures represented by Figure 1.
In another preferred embodiment, the present invention includes a method of using these novel derivatizing agents to modify one or more of the physicochemical and pharmacokinetic, and pharmacodynamic properties of pharmaceutical compounds. As the examples shown herein demonstrate, the method of the present invention can readily be applied to a wide variety of compounds to modify their properties in desirable ways.
Figure 1 reveals the general structure of the derivatizing agents of the present invention. The different structures related to Figure 1 may be divided in three classes i.e. Type I, where Y = R2; Type II, where Y = (NR2)2 and Type III, where Y = OR2.
A.2 General methods for the preparation of novel substituted methyl formyl Reagents The methyl formyl reagents (Type I, II, III) can be prepared from respective acids, amines and alcohols directly. An acid with or without activation can be reacted with a corresponding aldehyde in presence of a Lewis acid can provide Type I reagent. An alcohol can be reacted with a halomethylhaloacetate in presence of a base to provide Type III reagent. Similarly, an amine (primary or secondary) can be reacted with halomethyl haloacetate with or without the presence of base can provide Type II reagent.
A.2.2 General Method to Synthesize Type I Reagents
Scheme 1
Figure imgf000012_0001
General Procedure:
Aldehydes such as paraformaldehyde and acid chlorides, [3], can be reacted under anhydrous conditions and at appropriate temperatures with Lewis acids such as zinc chloride (dry), typically between -10°C and 60°C for a time ranging up to 24 hours. The reaction mixture can be diluted with solvents such as dichloromethane, washed with aqueous dilute base such as a solution of Na2HC03. Standard work up and purifications yield the desired substituted methyl formyl Reagents, [4].
Scheme 2
X O Br^^ l O ^
Y OH Y O Br
THF _
General Procedure: Metal salt of desired acid such as caesium salt of Acid [2], can be treated with bromoiodomethane in Dry THF at appropriate temperatures,typically between 0°C to RT for 16 hours and if required heating. The reaction mixture can be diluted with solvents such as ethyl acetate, washed with aqueous dilute base such as aqueous solution of Na2HC03. Standard work up and purifications yield the desired substituted methyl formyl Reagents [5].
Scheme 3
Figure imgf000013_0001
DCM:NaHC03[1 : 1 ]
tetrabutyl ammonium
sulfate
General Procedure:
To a vigorously stirred, solution of acid [2] in a solvent such as dichloromethane at room temperature, a base such as sodium bicarbonate and tetrabutyiammonium bisuifate in water was added, followed by the drop-wise addition of a solution of chloromethyl chlorosulfate in a solvent such as dichloromethane. After completion of reaction, organic layer was washed with 5% aqueous Na2C03. Standard work up and purifications yields desired substituted methyl formyl Reagents, [4].
As illustrated above and explained herein, Y = R2, R4 can be any of several moieties linking the compound to be modified to the methyl formyl reagent of the present invention. R2 can independently be H, Ci-Cg straight or branch chain alkyl - optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, N, 5, SO, or S02 and or lower al kyl, straight or bra nched a lkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl.
R2 can also be part of 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from, O, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI.
A.2.3: General Method to Synthesize Type II Reagents Scheme 2
Figure imgf000014_0001
General Procedure:
Corresponding primary or secondary amines can be reacted with substituted or unsubstituted chloro methylchloroformate, [6], in a solvent such as hexane or DCM at 0° C. The reaction mixture can be filtered and the filtrate can be washed with 1.0 N HCI. The organics can be evaporated to get the desired reagent, [7]. If required, further purification ca n be achieved using any general purification method practiced in organic chemistry laboratory such as precipitation or crystallization or preparative column purification.
As illustrated above and explained herei n, R and R1 ca n independently be H, Ci-C8 straight or branched alkyl chain - optionally containing 1-3 heteroatoms selected from O, N, S, SO, or S02; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl.
R and R1 can also be joined to substituted methyl formyl to form a 3-7 membered carbocyclic ring optionally containing 1-2 heteroatoms selected from, 0, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI.
R2 can independently be H, Ci-C8 straight or branch chain alkyl - optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl.
R2 can also be part of a 3-7 membered ring optionally containing an additional 1-2 heteroatoms selected from, 0, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI.
A.2.4: General Method to Synthesize Type III Reagents
Scheme 3:
Figure imgf000015_0001
8 9
General Procedure:
To the solution of chloromethylchloroformate, [8], in a solvent such as hexane, can be added solution of pyridine in hexane, drop wise under ice cooling. To this reaction mixture, the corresponding alcohol can be added at the same temperature. The reaction mixture can be stirred for a time ranging up to 24 hrs. Standard work up and purifications yield the desired corresponding carbonate reagent, [9].
As illustrated above and explained herein, R2 can be any of several moieties linking the compound to be modified to the methyl formyl reagent of the present invention. R2 can independently be H, C C8 straight or branch alkyl chain - optionally containing 1-3 heteroatoms selected from O, N, S, SO, or S02; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl.
R2 can also be part of a 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from, 0, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI.
Scheme 4: General Synthetic Scheme for halide exchange: Scheme 4.1:
Figure imgf000016_0001
Acetone/ ACN
General procedure:
Chloromethyl formyl Reagents [4] when treated with bromide suitable reagent such as lithium bromide or sodium bromide at appropriate temperatures, typically in the range of 40 -80°C for a time ranging up to 24 hours followed by standard work up and purification, yields desired bromo methyl formyl Reagents, [5].
Scheme 4.2:
Figure imgf000016_0002
4 10 General procedure:
Chloromethyl formyl Reagents [4] when treated with a reagent such as sodium iodide at appropriate temperatures, typically ranging from room temperature to 60°C for a time ranging up to 24 hours followed by a standard work up and purification, yields desired iodo methyl formyl Reagents, [10].
Scheme 4.3:
Figure imgf000017_0001
4 "
General procedure:
Chloromethyl formyl Reagents [4] when treated with silver salt of methane sulfonic acid at appropriate temperatures, typically ranging from room temperature to 60°C to 90°C for a time ranging up to 24 hours followed by standard work up and purification, yield desired ((methylsulfonyl)oxy) methyl formyl Reagents, [11].
Scheme 4.4:
Figure imgf000017_0002
4 12
General procedure: Chloromethyl formyl Reagents [4] when treated with silver salt of p-methyl benzene sulfonic acid at appropriate temperatures, typically ranging from room temperature to 60°C to 90°C for a time ranging up to 24 hours followed by standard work up and purification yield the desired ((methylsulfonyl)oxy) methyl formyl Reagents, [12].
A.3 Substituted methyl formyl reagents:
Based on the schemes as disclosed in A.2, a number of substituted methyl formyl reagents may be synthesized. Non limiting lists of substituted methyl formyl reagents of the present invention that may be synthesized as per schemes above are provided herein are as below and represented at Fig l:
Type I Reagents
i. chloromethyl isopropyl carbonate
ii. benzyl chloromethyl carbonate
iii. chloromethyl morpholinomethyl carbonate
iv. chloromethyl isobutyl carbonate
v. chloromethylmethyl carbonate
vi. (S)-sec-butyl chloromethyl carbonate
vii. (R)-sec-butyl chloromethyl carbonate
viii. chloromethyl ((3S,5R)-3,5-dimethylmorpholino)methyl carbonate
ix. chloromethyl 2-methylcyclopropyl carbonate
x. chloromethyl2-methoxyethyl carbonate
xi. chloromethyl propyl carbonate
xii. chloromethyl cyclobutyl carbonate
xiii. chloromethyl cyclopropyl carbonate
xiv. chloromethyl 2,2-dimethylcyclobutyl carbonate
xv. chloromethyl cyclopentyl carbonate
xvi. chloromethyl oxetan-3-yl carbonate
xvii. (S)-chloromethyl tetrahydrofuran-3-yl carbonate
xviii. chloromethyl cyclohexylmethyl carbonate χίχ. chloromethyl 3-methoxycyclohexyl carbonate
XX. (R)-chloromethyl tetrahydrofuran-3-yl carbonate
xxi. chloromethyl ethoxymethyl carbonate
xxii. chloromethyl oxepan-4-yl carbonate
xxiii. (lR,2S,4S)-bicyclo[2.2.1]heptan-2-yl chloromethyl carbonate xxiv. chloromethyl 2,3-dihydro-lH-inden-l-yl carbonate
XXV. benzyl chloromethyl carbonate
xxvi. (S)-chloromethyl 1-phenylethyl carbonate
xxvii. chloromethyl cyclohexyl carbonate
xxviii. chloromethyl isobutyl carbonate
xxix. chloromethyl 4-methylcyclohexyl carbonate
XXX. chloromethyl 2-(methylthio)ethyl carbonate
xxxi. chloromethyl 3-methylcyclohexyl carbonate
xxxii. chloromethylpentan-2-yl carbonate
xxxiii. chloromethyl neopentyl carbonate
xxxiv. methyl l-((chloromethoxy)carbonyloxy)cyclopropanecarboxylate xxxv. chloromethyl cyclopropylmethyl carbonate
xxxvi. chloromethyl 2,2-diethoxyethyl carbonate
xxxvii. chloromethyl cyclopentylmethyl carbonate
xxxviii. methyl 2-((chloromethoxy)carbonyloxy)propanoate
xxxix. (S)-ch!oromethyl 2,2,4-trimethylcyclopent-3-enyl carbonate xl. chloromethyl l,3-dioxolan-2-yl carbonate
xli. chloromethyl (2,6-dimethylcyclohexyl)methyl carbonate xlii. chloromethyl 2-(tetrahydro-2H-pyran-2-yl)ethyl carbonate xliii. chloromethyl(tetrahydro-2H-pyran-4-yl)methyl carbonate xliv. chloromethyl tetrahydro-2H-pyran-4-yl carbonate
xlv. chloromethyl 1-methylcyclopentyl carbonate
xlvi. chloromethyl 1-cyclopentylethyl carbonate
xlvii. chloromethyl 3-methylcyclopentyl carbonate xlviii. chloromethyl 3,3-dimethylcyclohexyl carbonate
xlix. chloromethyl 2,5-dimethylcyclohexyl carbonate
I. chloromethyl l-(4-methylcyclohexyl)ethyl carbonate
li. chloromethyl (3-methyloxetan-3-yl)methyl carbonate
lii. chloromethyl (3-methyloxetan-3-yl)methyl carbonate
liii. chloromethyl 2-isopropoxyethyl carbonate
liv. (chloromethyl carbonic) 5-((3aS,4S,6aR)-2-oxOhexahydro-lH-thieno[3,4 yl)pentanoic anhydride
Iv. 4-((chloromethoxy)carbonyloxy)-2-hydroxy-4-oxobutanoic acid
Ivi. chloromethyl 4-formyl-2-methoxyphenyl carbonate
Ivii. chloromethyl 3-oxobutan-2-yl carbonate
Iviii. methyl 4-((chloromethoxy)carbonyloxy)benzoate
lix. (R)-2-amino-3-((chloromethoxy)carbonyloxy)propanoic acid
Ix. 3-tert-butyl-4-methoxyphenyl chloromethyl carbonate
Ixi. (R)-2-amino-3-(4-((chloromethoxy)carbonyloxy)phenyl)propanoic acid
Ixii. (R)-2-amino-4-((chloromethoxy)carbonyloxy)-4-oxobutanoic acid
Ixiii. (E)-chloromethyl 3,7-dimethylocta-2,6-dienyl carbonate
Ixiv. methyl 4-((chloromethoxy)carbonyloxy)benzoate
Ixv. chloromethyl 2-(4-methylcyclohex-3-enyl)propan-2-yl carbonate
Ixvi. chloromethyl 3,7-dimethylocta-l,6-dien-3-yl carbonate
Ixvii. 4-allyl-2-methoxyphenyl chloromethyl carbonate
Ixviii. chloromethyl (lR,2S,5R)-2-isopropyl-5-methylcyclohexyl carbonate
Ixix. propyl 4-((chloromethoxy)carbonyloxy)benzoate
Ixx. (E)-chloromethyl 3,7-dimethylocta-2,6-dienyl carbonate
TYPE I Reagents i
nate
Figure imgf000021_0001
22 23 24 25
chloromethyl
2-methoxyethyl carbonate chloromethyl propyl chloromethyl chloromethyl
cyclopropyl carbonate
ethyl nate
Figure imgf000021_0002
30
31 32 33
chloromethyl
cyclohexylmethyl carbonate chloromethyl 3-methoxycyclohexyl (R)-chloromethyl chloromethyl carbonate tetrahydrofuran-3-yl carbonate ethoxymethyl carbonate
ate
Figure imgf000022_0001
39 40 41 42
chloromethyl cyclohexyl chloromethyl isobutyl chloromethyl 4-methylcyclohexyl chloromethyl 2- carbonate carbonate carbonate (methylthio)ethyl carbonate
Figure imgf000022_0002
44 45 46
43
chloromethyl 3-methylcyclohexyl chloromethyl chloromethyl
carbonate pentan-2-yl carbonate methyl 1 -((chloromethoxy)carbonyloxy) neopentyl carbonate cyclopropanecarboxylate
)
Figure imgf000022_0003
51 52 53 54
(S)-chloromethyl 2,2,4- chloromethyl trimethylcyclopent-3-enyl chloromethyl 1 ,3-dioxolan-2-yl chloromethyl (2,6-dimethylcyclohexyl) 2-(tetrahydro-2H-pyran-2-yl) carbonate carbonate methyl carbonate ethyl carbonate
Figure imgf000023_0001
Figure imgf000023_0002
62
59 60 chloromethyl 1-(4- chloromethyl 3- chloromethyl 3,3-dimethylcyclohexyl chloromethyl 2,5-dimethyl methylcyclohexyl)ethyl carbonate methylcyclopentyl
carbonate carbonate cyclohexyl carbonate
Figure imgf000023_0003
64
63 chloromethyl (3-methyloxetan-3-yl) chloromethyl 2-isopropoxyethyl carbonate chloromethyl (3-methyloxetan-3-yl) methyl carbonate
meth l carbonate
Figure imgf000023_0004
66
67 68
(chloromethyl carbonic) 5-((3aS,4S,6aR)-2- oxohexahydro-1 H-thieno[3,4-d]imidazol-4- 4-((chloromethoxy)carbonyloxy)- chloromethyl 4-formyl-2- yljpentanoic anhydride 2-hydroxy-4-oxobutanoic acid methoxyphenyl
carbonate
Figure imgf000023_0005
car ony oxy enzoate carbonyloxy)propanoic acid chloromethyl carbonate
Figure imgf000024_0001
(R)-2-amino-3-(4-((chlorometnoxy) (R)-2-amino-4-((chloromethoxy) (E)-chloromethyl 3,7- carbonyloxy)phenyl)propanoic acid carbonyloxy)-4-oxobutanoic acid dimethylocta-2,6-dienyl carbonate
Figure imgf000024_0002
Fig 1: Some non limiting examples of type I Reagents.
A non limiting examples of Type II reagents are listed herein below and represented at Figure 2.
Type II Reagents
'■ ch loromethyl cyclohexanecarboxylate
ii. ch loromethyl 2-cyclohexylacetate
iii. ch loromethyl 4-methylcyclohexanecarboxylate
iv. ch loromethyl 1-methylcyclohexanecarboxylate
v. ch loromethyl cyclopentanecarboxylate
vi. ch loromethyl l-(trifluoromethyl)cyclopenta necarboxylate
vii. ch loromethyl cyclobutanecarboxylate
viii. ch loromethyl 2-ethylhexanoate
ix. ch loromethyl 3-cyclopentylpropanoate
X. ch loromethyl cyclopropanecarboxylate
xi. ch loromethyl pentanoate
xii. ch loromethyl 2-methylpentanoate
xiii. ch loromethyl 3,5,5-trimethylhexanoate
xiv. ch loromethyl 2,2-dimethylbutanoate
XV. ch loromethyl 2-methylbutanoate
xvi. ch loromethyl hexanoate
xvii. ch loromethyl 2-ethylbutanoate
xviii. ch loromethyl butyrate
xix. ch loromethyl 3-phenylpropanoate
XX. ch loromethyl 2-phenylpropanoate
xxi. (R l-chloromethyl 2-phenylpropanoate
xxii. (S) -chloromethyl 2-phenylpropanoate
xxiii. (lr ",4r)-chloromethyl 4-methylcyclohexanecarboxylate
xxiv. ch loromethyl 4-methoxycyclohexa necarboxylate
XXV. ch loromethyl 4,4-difluorocyclohexanecarboxylate xxvi. chloromethyl 3-methoxycyclohexanecarboxylate xxvii. (2R)-chloromethyl 2-methylcyclopentanecarboxylate xxviii. (R)-chloromethyl 2-methylbutanoate
xxix. (S)-chloromethyl 2-methylbutanoate
xxx. (S)-chloromethyl 2-methoxy-2-phenylacetate xxxi. (S)-chloromethyl 2-phenylpropanoate xxxii. (S)-chloromethyl 2-phenylbutanoate
xxxiii. (S)-chloromethyl 3-phenylbutanoate
xxxiv. bis(chloromethyl) 2,2-dimethylmalonate
xxxv. bis(chloromethyl) oxalate
xxxvi. chloromethyl 2-cyclopropylacetate
xxxvii. chloromethyl 2-cyclobutylacetate
xxxviii. chloromethyl 2-cyclopentylacetate
xxxix. chloromethyl 2-(tetrahydrofuran-3-yl)acetate
xl. chloromethyl 2-(tetrahydro-2H-pyran-4-yl)acetate xli. chloromethyl 2-methylcyclopropanecarboxylate xlii. chloromethyl 2-(l-methylcyclobutyl)acetate xliii. chloromethyl 2-(l-methylcyclopropyl)'acetate xliv. chloromethyl propionate
xlv. chloromethyl acetate
xlvi. chloromethyl isobutyrate
xlvii. chloromethyl 2-isopropyl-3-methylbutanoate xlviii. chloromethyl 3,5-dimethylcyclohexanecarboxylate xlix. chloromethyl 2-propylpentanoate
I. chloromethyl 4-methoxybenzoate
li. chloromethyl 4-methylbenzoate
lii. chloromethyl 3-methylbenzoate
I'm. chloromethyl 2,2,2-trifluoroacetate
liv. chloromethyl 5,5-dimethyl-3-oxohexanoate Iv. bis(chloromethyl) cyclopropane-l,l-dicarboxylate
Ivi. chloromethyl 1,2-dihydrocyclobutabenzene-l-carboxylate
Ivii. chloromethyl 2-cyclopentenylacetate
Iviii. chloromethyl 2-phenylbutanoate
lix. chloromethyl 2,2-difluoroacetate
Ix. chloromethyl 4-fluorobenzoate
Ixi. chloromethyl 3-cyclohexylpropanoate
Ixii. chloromethyl 2-cyclohexylacetate
Ixiii. chloromethyl 3-(tetrahydro-2H-pyran-4-yl)propanoate
Ixiv. chloromethyl 2-(tetrahydro-2H-pyran-3-yl)acetate
Ixv. chloromethyl 3-(tetrahydro-2H-pyran-3-yl)propanoate
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000028_0001
-met ylbutanoate exanoate
Figure imgf000028_0002
phenylpropanoate chloromethyl 2- (R)-chloromethyl 2- phenylpropanoate -p enypropanoate phenylpropanoate
Figure imgf000028_0003
(2R)-chloromethyl
Figure imgf000028_0004
2-methylcyclo
pentanecarboxylate
Figure imgf000029_0001
2-phenylbutanoate
Figure imgf000029_0002
117 118 119 120 121
Figure imgf000029_0003
. . ,, .„ chloromethyl 2 cniorometnyi i- chloromethyl 2- chloromethyl 2-cyclo chloromethyl 2-(tetrahydro -(tetrahydro cyclopropyl cyclobutylacetate pentylacetate furan-3-yl)acetate -2H-pyran-4-yl) αθθΐαΐθ acetate
122 123 124 125 126
Figure imgf000030_0001
chloromethyl 2-methyl chloromethyl chloromethyl chlorom
130
cyclopropanecarboxylate 2-(1-methylcyclobutyl) 2-(1-methylcyclopropyl)' chloromethyl ethyl acetate acetate acetate isobutyr ate
127 128
128 129 131 132
Figure imgf000030_0002
carboxylate
133 134 135 136 137
hyl)
Figure imgf000030_0003
cyclopropane
-1 ,1-
139
140 dicarboxylate
138 141 difluoroacetate
Figure imgf000031_0001
4-fluor
145
chloromethyl 3- chloromethyl
Figure imgf000031_0002
chlorometh
cyclohexylpropanoate 2-cyclohexylacetate yl 2- chloromethyl 3-(tetra hydro chloromethyl 3-(tetr
(tetrahydro- -2H-pyran-4-yl)propanoate 2H-pyran-3- prop
148 yl)acetate
147 149 1i
150
Fig 2: A non limiting set of compounds of Type II reagents.
A non limiting set of compounds belonging to type III is listed hereblpw and represnted at Fig 3. Type III Reagents chloromethyl isopropylcarbamate
I chloromethyl diisopropylcarbamate
ii chloromethyl dimethylcarbamate
iv chloromethyl isobutylcarbamate
v chloromethyl methylcarbamate
vi chloromethyl ethyl(isopropyl)carbamate
vii chloromethylisobutyl(methyl)carbamate
viii (S)-chloromethyl sec-butylcarbamate
i chloromethyl methylcarbamate
x chloromethyl isopropyl(methyl)carbamate
xi chloromethyl propylcarbamate xii. chloromethyl 2-methoxyethylcarbamate
xiii. chloromethyl methyl(propyl)carbamate
xiv. chloromethyl diisobutylcarbamate
XV. chloromethyl tert-butyl(isopropyl)carbamate
xvi. chloromethyl di-sec-butylcarbamate
xvii. chloromethyl aziridine-l-carboxylate
xviii. chloromethyl 2-methylcyclopropylcarbamate
xix. chloromethyl cyclopropylcarbamate
XX. chloromethyl cyclopropylmethyl(propyl)carbamate xxi. chloromethyl cyclopropyl(methyl)carbamate
xxii. chloromethyl azetidine-l-carboxylate
xxiii. chloromethyl cyclobutylcarbamate
xxiv. chloromethyl 2,2-dimethylcyclobutylcarbamate
XXV. chloromethyl 3-methoxyazetidine-l-carboxylate
xxvi. chloromethyl cyclobutyl(methyl)carbamate
xxvii. chloromethyl oxetan-3-ylcarbamate
xxviii. (S)-chloromethyl 2-methylpyrrolidine-l-carboxylate xxix. chloromethyl cyclopentylcarbamate
XXX. chloromethl cyclopentyl(methyl)carbamate
xxxi. chloromethyl tetrahydrofuran-3-ylcarbamate
xxxii. chloromethyl piperidine-l-carboxylate
xxxiii. (2R,6S)-chloromethyl 2,6-dimethylpiperidine-l-carboxylate xxxiv. (R)-chloromethyl 2-methylpiperidine-l-carboxylate
XXXV. chloromethyl piperidine-l-carboxylate
xxxvi. chloromethyl 3-methoxycyclohexylcarbamate
xxxvii. chloromethyl cyclohexylmethylcarbamate
xxxviii. chloromethyl cyclohexylmethyl(methyl)carbamate xxxix. chloromethyl morpholine-4-carboxylate
xl. (3S,5R)-chloromethyl 3,5-dimethylmorpholine-4-carboxylate xli. (3R,5S)-chloromethyl 3,5-dimethylmorpholine-4-carboxylate
xlii. (2S,6R)-chloromethyl 2,6-dimethylmorpholine-4-carboxylate
xliii. chloromethyl 4-methylpiperazine-l-carboxylate
xliv. chloromethylazepane-l-earboxylate
xlv. chloromethylcycloheptylcarbamate
xlvi. chloromethyl oxepan-4-ylcarbamate
xlvii. chloromethyl (lR,2S,4S)-bicyclo[2.2.1]heptan-2-ylcarbamate
xlviii. chloromethyl 2,3-dihydro-lH-inden-l-ylcarbamate
xlix. chloromethyl benzylcarbamate
I. (S)-chloromethyl 1-phenylethylcarbamate
li. ethyl 2-((chloromethoxy)carbonylamino)-3-methylbutanoate
lii. ethyl 2-((chloromethoxy)carbonylamino)-3-phenylpropanoate
liii. (S)-diethyl 2-((chloromethoxy)carbonylamino)pentanedioate
liv. ethyl((chloromethoxy)carbonylamino)propanoate
Iv. ethyl 2-amino-6-((chloromethoxy)carbonylamino)hexanoate
Ivi. ethyl 2-((chloromethoxy)carbonylamino)-4-methylpentanoate
Ivii. ethyl 2-((chloromethoxy)carbonylamino)-3-methylpentanoate
Iviii. (S)-dimethyl 2-((chloromethoxy)carbonylamino)succinate
lix. (S)-ethyl 2-((chloromethoxy)carbonylamino)-5-guanidinopentanoate
Ix. (S)-ethyl 4-amino-2-((chloromethoxy)carbonylamino)-4-oxobutanoate
Ixi. (S)-ethyl 2-amino-5-((chloromethoxy)carbonylamino)pentanoate
Ixii. (S)-ethyl 5-amino-2-((chloromethoxy)carbonylamino)-5-oxopentanoate
Ixiii. ethyl 2-((chloromethoxy)carbonylamino)-4-(methylthio)butanoate
Ixiv. 1-chloromethyl 3-methyl 2-methyl-5,6-dihydropyridine-l,3(2H)-dicarboxylate
Ixv. (S)-chloromethyl (l-methylpyrrolidin-2-yl)methyl carbonate
Ixvi. (R)-chloromethyl (l-methylpyrrolidin-2-yl)methyl carbonate
Ixvii. (S)-(l-benzylpyrrolidin-2-yl)methyl chloromethyl carbonate
Ixviii. chloromethyl lH-pyrrole-l-carboxylate
Ixix. chloromethyl 2-nicotinoylhydrazinecarboxylate Ixx. (6S)-3-chloro-7-((chloromethoxy)carbonylamino)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2- ene-2-carboxylic acid
Ixxi. (6S)-7-((chloromethoxy)carbonylamino)-8-oxo-3-vinyl-5-thia-l-azabicyclo[4.2.0]oct-2-ene- 2-carboxylic acid
Ixxii. (6S)-7-((chloromethoxy)carbonylamino)-3-(methoxymethyl)-8-oxo-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Ixxiii. (6R,7R)-7-((chloromethoxy)carbonylamino)-3-methoxy-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-
2-ene-2-carboxylic acid
Ixxiv. chloromethyl 3-(4-chlorophenyl)-lH-pyrazole-l-carboxylate
Ixxv. chloromethyl 3-(4-fluorophenyl)-lH-pyrazole-l-carboxylate
Ixxvi. chloromethyl 3-phenyl-lH-pyrazole-l-carboxylate
Ixxvii. chloromethyl 3-(4bromophenyl)-lH-pyrazole-l-carboxylate
Ixxviii. chloromethyl 2-cyano-lH-pyrrole-l-carboxylate
Ixxix. chloromethyl 4-oxopiperidine-l-carboxylate
Ixxx. 1-chloromethyl 3-ethyl 2-oxopiperidine-l,3-dicarboxylate
Ixxxi. chloromethyl 2,2,6,6-tetramethyl-4-oxopiperidine-l-carboxylate
Ixxxii. chloromethyl 2-oxopiperidine-l-carboxylate
Figure imgf000034_0001
diisopropylcarbamate ime y car ama e
152 153 154 155 156
mat
Figure imgf000034_0002
157 158 159 160 161
Figure imgf000035_0001
162 163 164 165 166
chloromethyl cyclopropylmethyl
Figure imgf000035_0002
(propyl)carbamate
167 168 169 170 171
Figure imgf000035_0003
75
172 173 1
174 176
Figure imgf000035_0004
chloromethyl ch ΟloromeΛthyl°'
late
Figure imgf000036_0001
tetrahydrofuran- piperidine- 3-ylcarbamate 1 -carboxylate -1-carboxylate - -car oxy ate
182 183 184 185 186
l
Figure imgf000036_0002
187 188 189 190 191
Figure imgf000036_0003
(3R.5S)- chloromethyl 4- chloromethyl
chloromethyl 3,5- (2S,6f?)-chloro methyl chloromethyl
azepane-1- dimethylmorpholine methyl 2,6-dimethyl piperazine- cycloheptylcarbamate
carboxylate
-4-carboxylate morpholine- 1 -carboxylate
4-carboxylate
192 193 194 195 196
Figure imgf000036_0004
chloromethyl chloromethyl
oxepan-4- (1R,2S,4S)- chloromethyl 2,3- benzylcarbamate
ylcarbamate bicyclo[2.2.1] dihydro-1H-inden- heptan-2-ylcarbamate 1-ylcarbamate 1 -phenylethylcarbamate
197 198 199 200 201
Figure imgf000037_0001
ethyl 2- ethyl((chloromethoxy) ethyl 2-((chloromethoxy)
((chloromethoxy)c (S)-diethyl 2-((chloromethoxy) carbonylamino) carbonylamino)-3- arbonylamino)-3- carbonylamino)pentanedioate propanoate phenylpropanoate
methylbutanoate
202 203 204 205
Figure imgf000037_0002
te
206 207 208 209
Figure imgf000037_0003
guanidinopentanoate
210 211 212 ne
Figure imgf000038_0001
-1,3(2/-/)-dicarboxylate mno- -oxopenanoae (methylthio)butanoate
213 214 215
Figure imgf000038_0002
216 217 218
Figure imgf000038_0003
219 220 221 222
Figure imgf000039_0001
-car oxy a e
223 224 225 226 227
carboxylate
Figure imgf000039_0002
-carboxylate chloromethyl 2-oxopiperidine-1 -carboxylate
228 229 230 231 232 233
Fig 3: List of Type III compounds.
C. Modifications of chemical compounds by substituted methyl formyl reagents
The novel substituted methyl formyl Reagents of the present invention are used to modify the properties of any chemical molecule that may be used for pharmaceutical, nutraceutical or other purposes. Such modification may be carried out on a wide variety of substrates to modify several parameters. This modification may be carried out by reacting a functional group of the chemical molecule, with the substituted methyl formyl reagents of the present invention. The modification may also be carried out by effecting a chemical reaction of the substituted methyl formyl reagents of the present invention with a heteroatom of a heterocyclic ring system.
The modification may be carried out by converting any functional group present in the chemical molecule of interest of type I, II or III and then reacting with an suitable external quaternization agent, or by reaction of the reagent on a heteroatom present on molecule of interest to make a quart.
The term 'Chemical compound' includes within its scope, all molecules that are currently present in the market as drugs, including antibiotics and orphan drugs, molecules currently undergoing clinical trials, molecules awaiting approval, molecules meant for use as nutraceuticals or as nutrients, molecules meant for agricultural purposes as pesticide, herbicide, insecticide, fungicide and other similar applications.
The term 'functional group' includes the specific groups of atoms and/or bonds within molecules that are responsible for the characteristic chemical reactions of those molecules and include hydrocarbons, groups containing halogens, groups containing oxygen, groups containing nitrogen, groups containing sulfur, groups containing phosphorus, groups containing boron. The functional groups may be aliphatic or aromatic in nature.
Preferred groups for modification by the substituted methyl formyl reagents, which may be termed as sites of translation are the carboxylic group, amino group, the heteroatom of the ring, alcoholic group, amide, etc.
The heteroatom of the'heterocyclic ring system may be any heteroatom, but is preferably 0, N, S or P.
B.l. General synthetic schemes for the modification of Chemical compounds
The general schemes of modification various functional groups using the methyl formyl Reagents are provided below as a means of illustration.
B. 1.1: Nitrogen Containing Aromatic Rings Scheme 5: Modification of drugs/biologically active molecules with nitrogen-containing aromatic rings such as pyridine, imidazole, triazole, etc.
Figure imgf000041_0001
236
R3 and R4 can independently be H, Ci-C8 straight or branched alkyl chain - optionally containing 1- 3 heteroatoms selected from 0, N, S, SO, or S02; 3-7 membered cycloalkyl optionally containing 1- 3 heteroatoms selected from 0, N, S, SO, or S02 and/ or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl.
R3 and/ or R4 can also be part of 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from, 0, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI. Appropriately, R3 and R4 may be connected to form 3-8 membered aliphatic or aromatic ring fused to the hetero-aromatic ring. One skilled in the art would know which rings would be appropriately aliphatic and which would be aromatic.
General Procedure:
Drugs or biological active molecules with nitrogen containing aromatic rings such as [234] can be reacted with a Type I reagent such as [235] using a solvent such as DCM or ACN under anhydrous conditions at room temperature for a time ranging up to 24 hours. The reaction mixture can be evaporated to dryness and triturated with ether. The standard work up yields desired product
[236]. Any drug or molecule of biological importance having an aromatic nitrogen such as pyridine can be reacted with a desired methyl formyl reagent (Type I (Y= R2) or Type II (Y = NR2)2) or Type III (Y=OR2) in a solvent such as ACN at temperatures typically ranging from RT to 60 °C. After completion, the reaction was concentrated by evaporating excess of organic solvent to get the desired product, which can be purified if required by any general purification method practiced in organic chemistry laboratory such as precipitation or crystallization or preparative column purification.
B.1.2 Amines
Scheme 6: Modification of drugs/biologically active molecules containing aliphatic tertiary amines such as piperidine, piperazine and trialkyl amines.
Figure imgf000042_0001
238
R3 and R4 can independently be H, Ci-C8 straight or branched chain alkyl - optionally containing 1-
3 heteroatoms selected from 0, N, S, SO, or S02; 3-7 membered cycloalkyl optionally containing 1- 3 heteroatoms selected from O, N, S, SO, or S02 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl.
R3 and/ or R4 can also be part of 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from, O, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI. Appropriately, R3 and R4 may be connected to form 3-8 membered aliphatic or aromatic ring fused to the hetero-alicyclic ring. One skilled in the art would know which rings would be appropriately aliphatic and which would be aromatic. General Procedure:
Drugs or biologically active molecules with aliphatic tertiary amines such as [234] can be reacted with a Type I reagent such as [237] using acetonitrile/ tetrahydrofuran/ dichloromethane as solvents under anhydrous conditions at room temperature for a time ranging up to 24 hours. The reaction mixture can be evaporated to dryness and triturated with ether. The standard work up yields the desired product such as [238].
Any drug or molecule of biological importance having an aliphatic tertiary nitrogen such as piperidine can be reacted with a desired methyl formyl reagent (Type I (Y = 2) or Type II (Y = N(R2)2) or Type III (Y = OR2)) in a solvent such as ACN at temperatures typically ranging from RT to 60 °C. After completion of the reaction, evaporation of the excess of the organic solvent will yield the desired product which can be purified if required by any general purification method practiced in organic chemistry such as precipitation or crystallization or preparative column purification.
Drugs or biologically active molecules with alcohols and/ or phenols and/ or amines can also be modifyed by conversion to a respective methyl formyl reagent followed by making a quaternary ammonium cation using amines such as pyridine, for example nicotinamide is a preferred embodiment. Non-limiting examples of such conversions with drugs or biologically active molecules with alcohols and/ or phenols are shown in Schemes below . Non-limiting examples of such conversions of drugs or biologically active molecules with primary or secondary amines are shown in Schemes 7 and8.
Modification of drugs/biologically active molecules with primary or secondary aliphatic amines
Scheme 7:
Figure imgf000044_0001
Rx/Ry = H or alkyl;
In a similar fashion, Drugs or biological active molecules containing amine such as [239] were reacted first with chloromethyl chloroformate such as [8] using pyridine as a base and DCM as solvent. Standard workup of the reaction mixture yields intermediate [240]. This intermediate when further reacted with iodide suitable metal salt such as Nal in acetone or acetonitrile at room temperature or under heating followed by standard workup of the reaction mixture yielded intermediate [241]. This intermediate on reaction with a quaternizing reagent such as nicotinamide [243] using solvent such as DCM or ACN at room temperature Followed by evaporation of organic solvent under vacuum to yield the desired modified drug or biological active molecule [242].
Scheme 8:
Figure imgf000045_0001
Wherein Rx/Ry = H or alkyl;
Similarly, drugs or biological active molecules with a primary or secondary amino group [239] can be reacted first with a suitable halo actetyl chloride such as bromo acetylchloride [244] using DCM as solvent. Standard workup of the reaction mixture yields the intermediate [245]. This intermediate [245] can be further reacted with a quaternization reagent such as nicotinamide [243] using a solvent such as DCM at room temperature. The reaction mixture can be evaporated to yield the desired final modified drug or biological active molecule [246].
Figure imgf000045_0002
In a similar fashion, a corresponding drug or biologically active molecule with a primary or secondary amino group, such as [239], can be reacted with chloromethyl nicotinic acid [247] using DCM as solvent at room temperature. Standard work up of the reaction yields the intermediate
[248], which can be further treated with suitable methyl formyl reagents [235] (Y = R2, N(R2)2/ or OR2) using DCM as solvent at room temperature. A similar work up yields the desired modified biologically active molecule [249].
B.1.3 Alcohols
Scheme for Modification of drugs/biologically active molecules with alcohols/ phenols
Scheme 10 :
Figure imgf000046_0001
Drugs or biological active molecules containing alcohol such as [250] can be reacted with chloromethyl chloroformate [8] in presence of a base such as pyridine and a solvent such as DCM. Standard workup of the reaction mixture yields an intermediate [251]. This intermediate on reaction with a suitable metal salt such as sodium iodide in a solvent such as acetone at a desired temperature starting from ambient to heating followed by a standard workup yields compound
[252]. Compound [252] on reaction with a suitable quaternization reagent such as nicotinamide
[243] using solvent such as DCM at room temperature followed by evaporation of organic solvent provides the desired modified drug or biological active molecule [253]. Scheme 11-
Figure imgf000047_0001
In a similar fashion, the corresponding drug or biological active molecule [250] were reacted with a suitable acid chloride such as nicotinoyi chloride [254] in a solvent such as DCM in presence of a base such as pyridine at a desire temperature ranging from ambient to refluxing followed by a standard work up to yield intermediate [255]. which on further treatment with suitable methyl formyl reagents [235] (Y = R2, N(R2)2, or OR2) using a solvent such as acetonitrile at a desired temperature ranging from ambient to refluxing yield the desired modified biological active molecule [256].
Scheme 12:
Figure imgf000047_0002
Drugs or biological active molecules containing alcohol such as [250] can be reacted first with a suitable haloacetylhalides such as bromoacetylchloride [244] in a solvent such as DCM at a desired temperature followed by a standard workup yield compound [257]. Compound [257] can be further reacted with a suitable quaternizing agent such as nicotinamide [243] using solvent such as ACN at desired temperature. Upon evaporation the reaction mixture yields the desired final modified drug or biological active molecule [258].
Scheme 13:
Figure imgf000048_0001
In a similar fashion, the corresponding drug or biological active molecule [250] can be reacted with suitable halomethyl reagents such as chloromethyl nicotinate [259] in a solvent such as DCM at a desired temperature ranging from ambient to refluxing. The standard work up of the reaction yields intermediate [260], which can be further treated with suitable methyl formyl reagents such as [10] (Y = R2, N(R2)2, or OR2) using DCM as solvent at room temperature. A similar work up yields the desired modified biological active molecule [261].
B.1.4 Carboxylic acids - Modification of drugs/ biologically active molecules with a carboxylic acid moiety Scheme 14:
Figure imgf000049_0001
263 264
Drugs or biological active molecules with a carboxylic group [262] can be reacted with a suitable halomethyl reagent such as chloromethyl nicotinate [259] in a solvent such as DCM at desired temperature. Standard work up of the reaction yields the intermediate [263], which can be further treated with suitable methyl formyl reagents [235] (Y = 2, N(R2)2, or OR2) using DCM as solvent at room temperature to yield the desired modified biological active molecule [264].
Scheme 15:
Figure imgf000049_0002
265 266
In a similar fashion, the corresponding drug or biological active molecule with a carboxylic acid group [262] can be reacted with Lewis acids such as Zinc chloride (dry) and aldehydes such as paraformaldehyde at temperatures ranging from -10 °C to 60 °C for a time ranging up to 20-24 hours. Standard work up of the reaction mixture yields the intermediate [265], which can be further reacted with nicotinamide [322] using DCM or ACN as a solvent at room temperature. The reaction mixture can be evaporated to yield the desired final modified drug or biological active molecule [266]. Scheme 16:
Figure imgf000050_0001
tetrabutyl ammonium
262 sulfate 265
In a similar fashion, the corresponding drug or biological active molecule with a carboxylic acid group [262] in dichloromethane can be treated with a base such as sodium bicarbonate and tetrabutylammonium bisulfate followed by dropwise addition of chloromethyl chlorosulfate in solvent such as dichloromethane. On completion of the reaction, the organic layer was washed with aqueous Na2C03 Followed by standard work up and purifications, yielded substituted methyl formyl Reagents, [265]. 29 can be further reacted with a quaternization reagent such as nicotinamide [243] in solvent such as ACN. The reaction mixture on evaporation provides modified drug or biological active molecule [267].
Scheme 17:
Figure imgf000050_0002
262 268 269
In a similar fashion, the corresponding drug or biological active molecule with a carboxylic acid group [262] can be reacted with a base such as cesium carbonate followed by the addition of a reagent such as bromo iodomethane in a solvent such as THF. On completion of the reaction followed by standard work up and purifications, yield substituted methyl formyl Reagents, [268], which can be further reacted with a quaternization reagent such as nicotinamide [243] in a solvent such as ACN. The reaction mixture on evaporation yields desired products [269].
Scheme 18: Anion Exchnage on quaternary salts:
Figure imgf000051_0001
A quaternary salt such as [273] can be prepared by the method describe above with a suitable halomethyl formyl reagent such as iodo methyl formyl (Type I or Type II or Type III). The quat [272] can be treated with a suitable metal salt such as silver mesylate in a solvent such as acetonitrile at a desired temperature ranging from ambient to refluxing which results in the precipitation of silver iodide and formation of desired product. The insoluble silver halide can be filtered out to get reasonably pure desired product [273].
The above method is applicable to do anion exchange on all type of quat salts having any halide such as chloride, bromide or iodide as the counter ion. The various types of silver salts can be used such as silver acetate, silver mesylate or silver tosylate etc.
B.2. Examples of Chemical compounds modified by the substituted methyl formyl groups
The substituted methyl formyl reagents as referred herein may be utilized in modifying the chemical compounds by schemes as explained above. A non-limiting set of compounds modified using the method and reagents of the present invention are illustrated at Table 1. The list is meant only for illustration and may not be construed as limiting the scope of the invention. 51
Figure imgf000052_0001
Figure imgf000053_0001
53
Figure imgf000054_0001
54
Figure imgf000055_0001
55
Figure imgf000056_0001

Figure imgf000057_0001

Figure imgf000058_0001

Figure imgf000059_0001
Figure imgf000060_0001
60
Figure imgf000061_0001
Figure imgf000062_0001
62
Figure imgf000063_0001
63
Figure imgf000064_0001
64
Figure imgf000065_0001
65
Figure imgf000066_0001
Figure imgf000067_0001

Figure imgf000068_0001
Figure imgf000069_0001

Figure imgf000070_0001
70
Figure imgf000071_0001
71
Figure imgf000072_0001
C. Use of substituted methyl formyl reagents to modify Chemical compounds to modify the rate and site specificity of conversion in the body.
Substituted methyl formyl reagents of the present invention are used to generate New Chemical Entities (NCEs) so that the rate and site of conversion of these NCEs to the parent drugs/biologically active compounds can be controlled. This can be achieved, due to the presence of the converting enzyme(s) or other converting parameters and reagents that are involved in the transformation of the NCEs to the parent drugs/biologically active substances which may only (or even predominantly) be selectively present at the site of conversion. The rate of conversion can be modifyed as the structure of the modified drug/biologically active molecule or the concentration/amount of the converting enzyme present at the site of conversion can influence the rate of conversion of the NCEs to the drug/biologically active compound. Endogenous enzymes that are capable of converting these compounds belong to four International Union of Pure and Applied Chemistry classes. Enzymes from class 1 are the oxidoreductases, enzymes from class 2 are the transferases, enzymes from class 3 are hydrolases, and enzymes from class 4 are the lysases. Numerous modified compounds have been developed for the delivery of higher concentrations of a drug to the target than could otherwise be obtained by the administration of the unmodified compound itself. Four main modes of delivery have been identified which modified drugs or biologically active molecules as described in this patent may exploit: (1) passive drug enrichment in the target organ; (2) transporter mediated delivery; (3) selective metabolic activation through enzymes; and (4) antigen targeting.
This application of the present invention achieves more than simply modifying the pharmacokinetic and physicochemical properties of the drug/biologically active molecule. This results in the ability to use less, overall, of the drug/biologically active compound than would be required of the unmodified drug. This offers several benefits, including potential decrease or even elimination of unwanted side effects.
Accordingly, as one of ordinary skill in the art will appreciate, the methyl formyl reagents of the present invention are designed to be cleaved from the drug they are attached to by the endogenous systems, such as enzymes present, to a greater or lesser extent, in humans and most animals kept as pets or livestock. Accordingly, unlike making many other possible covalent modifications to an effective drug, derivatization according to the present invention permits modification of the modified compound's characteristics without sacrificing the safety, efficacy, or toxicology of the original, un-modified drug. Based upon this principle, one of ordinary skill in the art will readily comprehend that the method of the present invention can be used, along with the agents disclosed and taught herein, to make a variety of derivatized compounds with modified pharmacokinetic, pharmacodynamic, and physiochemical properties without decreasing the potency of the original drug. As such, one of ordinary skill in the art will understand that the examples shown herein are simply illustrations of the present invention and its application and do not in any manner limit the scope and breadth of the invention disclosed or the teachings of the present invention.
Table 2, shows an exemplary but a non-limiting list of currently-existing drugs/biologically active compounds that can be modified using the methods and modification agents described in this invention. The first column provides the reference number for the drug and/or biologically active compound. The second column gives the generic name for the drug and/ or biologically active compound. The third column gives the trade name under which the drug is sold (where applicable). The fourth column gives the lUPAC name of the drug and/ or biologically active compound. The fifth column shows the chemical structure of the drug. For example, dimebon [4149] has two functional groups which can undergo derivation. One group is a tertiary amine and the other is an aromatic amine. Non-limiting examples of these derivations are illustrated in Schemes 31 and 32. As one of ordinary skill in the art would readily apprehend, the present invention teaches that novel derivatized compounds of the present invention could be formed with any of a variety of drugs which have one or more of the functional groups referenced according to Schemes 1, 2 and/ or 3 by practicing the method of the present invention.
Table 2: A Non-limiting List of Drugs or Biologically Active Molecules which can be derivatized according to the embodiment of the invention.
Drug or
Chemical
No. Biologically Trade Name lUPAC Name
Active Structure
Molecule
(6/?-rrans)-6-(l,3- benzodioxol-5-yl)-
4101 2,3,6,7,12,12a-hexahydro- i T
Tadalafil Cialis
2-methyl-pyrazino [ , Π
2': 1,6] pyrido[3,4- 6]indole-l,4-dione
l-[4-ethoxy-3-(6,7- dihydro-l-methyl-7-oxo-3-
4102 propyl-lH-pyrazolo[4,3-
Sildenafil Viagra
d]pyrimidin-5- yl)phenylsulfonyl]-4-
Figure imgf000074_0001
methylpiperazine
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
4152 Hydroxy 5-((l,4-diazepan-l- Fasudil yl)sulfonyl)isoquinolin-l-ol
4153 5-((l,4-diazepan-l-
Fasudil
yl)sulfonyl)isoquinoline
4154 Aspirin Aspirin 2-acetoxybenzoic acid
Figure imgf000082_0001
Ikorel,
Dancor,
Nikoran,
4155 2-(nicotinamido)ethyl
Nicorandil
Aprior, nitrate
N
Nitrorubin,
Sigma rt
The reagents of the present invention may be used to modify drugs which belong to the class of compounds may be selected from, but are not limited to: Central Nervous System Drugs, such as CNS/Respiratory Stimulants, Analgesics, Narcotic Agonists, Narcotic agonist/antagonists, Nonsteroidal Anti-inflammatory/Analgesic Agents, Behavior-Modifying Agents, Tranquilizers/Sedatives, Anesthetic Agents, Inhalants, Narcotics, Reversal Agents, Anticonvulsants, Muscle Relaxants, Skeletal, Muscle Relaxants, Smooth, Euthanasia Agent, Cardiovascular Agents, Inotropic Agents, Antiarrhythmic Drugs, Anticholinergics, Vasodilating Agents, Agents Used in Treatment of Shock, Alpha-Adrenergic Blocking Agents, Beta-Adrenergic Blocking Agents, Respiratory Drugs, Bronchodilators, Sympathomimetics, Antihistamines, Antitussives, Renal and Urinary Tract, Agents for Urinary Incontinence/Retention, Urinary Alkalinizers, Urinary Acidifiers, Cholinergic Stimulants, Agents for Urolithiasis, Gastrointestinal Agents, Antiemetic Agents, Antacids, H2 Antagonists, Gastromucosal Protectants, Proton Pump Inhibitors, Appetite Stimulants, Gl Antispasmodics-Anticholinergics, Gl Stimulants, Laxatives, Saline, Bulk producing, Lubricant, Surfactant, Antidiarrheals, Hormones/Endocrine/Reproductive Agents, Sex Hormones, Anabolic steroids, Posterior Pituitary Hormones, Adrenal Cortical Steroids, Glucocorticoids, Antidiabetic Agents, Thyroid Drugs, Thyroid Hormones, Misc. Endocrine/Reproductive Drugs, Prostaglandins, Antiinfective Drugs, Antiparasitics, Anticoccidial Agents, Antibiotics, Anti-tuberculosis, Aminocyclitols,Cephalosporins, Macrolides, Penicillins, Tetracyclines, Lincosamides, Quinolones, Sulfonamides, Miscellaneous Antibacterials, Antifungal Agents, Antiviral Agents, Blood Modifying Agents, Clotting Agents, Anticoagulants, Erythropoietic Agents, Antineoplastics/ Immunosuppresives, Alkylating Agents, Antidotes, Bone/ Joint Agents, Dermatologic Agents (Systemic), Vitamins and Minerals/ Nutrients, Systemic Acidifiers, Systemic Alkalinizers, anti-cancer agents, anti-viral agents, etc.
The compounds of the present invention after being modified include but are not limited to: i. l-(((3,3-dimethylbutanoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l-ium
iodide;
ii. 3-((2-(nitrooxy)ethyl)carbamoyl)-l-((pivaloyloxy)methyl)pyridin-l-ium iodide;
iii. l-((isobutyryloxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l-ium iodide;
iv. l-(((diisopropylcarbamoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l-ium
iodide;
v. l-(((ethoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l-ium iodide; vi. 3-((2-(nitrooxy)ethyl)carbamoyl)-l-(((piperidine-l-carbonyl)oxy)methyl)pyridin-l-ium
iodide;
vii. l-(((isopropoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l-ium iodide; viii. l-(((isopropylcarbamoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l-ium iodide; ix. l-(((tert-butoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l-ium iodide; x. 2-(((diisopropylcarbamoyl)oxy)methyl)-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)- 2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-2-ium iodide;
xi. 2-(((diisopropylcarbamoyl)oxy)methyl)-5-(2-(l-(((diisopropylcarbamoyl)oxy)methyl)-6- methylpyridin-l-ium-3-yl)ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-2- ium diiodide;
xii. (S)-((4,ll-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-lH- pyrano[3',4':6,7]indolizino[l,2-b]quinolin-9-yl)oxy)methyl nicotinate; xiii. (S)-3-((((4,ll-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-lH- pyrano[3'(4':6,7]indolizino[l,2-b]quinolin-9-yl)oxy)methoxy)carbonyl)-l- (((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium iodide;
xiv. 4-((lE,4Z,6E)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-3-oxohepta-l,4,6-trien-l-yl)-2- methoxyphenyl nicotinate;
xv. ((lE,3Z/6E)-3-hydroxy-5-oxohepta-l,3,6-triene-l;7-diyl)bis(2-methoxy-4,l-phenylene) dinicotinate;
xvi. 3,3'-(((((lEJ3Z;6E)-3-hydroxy-5-oxohepta-l;3;6-triene-l,7-diyl)bis(2-methoxy-4,l- phenylene))bis(oxy))bis(carbonyl))bis(l-(((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium) diiodide;
xvii. (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2-(nicotinoyloxy)-3- phenylpropanoyl)oxy)-12-(benzoyloxy)-4,ll-dihydroxy-4a,8,13,13-tetramethyl-5-oxo- 2a,3,4,4ai5,6,9,10,ll;12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2- b]oxete-6,12b-diyl diacetate;
xviii. 3-((((lS,2R)-l-benzamido-3-(((2aR;4S,4aS 6R,9S,llS,12S,12aR,12bS)-6,12b-diacetoxy-12- (benzoyloxy)-4,ll-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-
2a,3i4,4a,5(6,9,10,ll;12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l;2- b]oxet-9-yl)oxy)-3-oxo-l-phenylpropan-2-yl)oxy)carbonyl)-l- (((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium iodide;
xix. (2aR;4S,4aS,6R,9S,llS,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2- (((chloromethoxy)carbonyl)oxy)-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-4- (((chloromethoxy)carbonyl)oxy)-ll-hydroxy-4a,8,13,13-tetramethyl-5-oxo- 2a,3/4,4a,5,6,9,10,ll;12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2- b]oxete-6,12b-diyl diacetate;
xx. (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2- (((iodomethoxy)carbonyl)oxy)-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-ll-hydroxy-4- (((iodomethoxyJcarbonylJoxyJ^a^ SAS-tetramethyl-S-oxo-
2a,3A4a;5,6,9,10,ll,12;12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l/2- b]oxete-6,12b-diyl diacetate;
xxi. mono(l-((((((lSJ2R)-l-benzamido-3-(((2aR,4S;4aS,6R 9S/llS,12S,12aR,12bS)-6J12b- diacetoxy-12-(benzoyloxy)-4-((((3-(dimethylcarbamoyl)pyridin-l-ium-l- yl)methoxy)carbonyl)oxy)-ll-hydroxy-4a,8,13,13-tetramethyl-5-oxo- 2a,3,4,4a,5,6,9,10;ll,12,12a,12b-clodecariydro-lH-7;ll-methanocyclodeca[3,4]benzo[l,2- b]oxet-9-yl)oxy)-3-oxo-l-phenylpropan-2-yl)oxy)carbonyl)oxy)methyl)-3- (dimethylcarbamoyl)pyridin-l-ium) diiodide;
xxii. ((2-acetoxybenzoyl)oxy)methyl nicotinate;
xxiii. 3-((((2-acetoxybenzoyl)oxy)methoxy)carbonyl)-l-(((dimethylcarbamoyl)oxy)methyl)pyridin- 1-ium iodide.
D. Salts and Isomers and counter ions
The present invention includes within its scope the salts and isomers. Compounds of the present invention after being modified by the substituted methyl formyl reagent may in some cases form salts which are also within the scope of this invention. The term "salt(s)", as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. Zwitterions (internal or inner salts) are included within the term "salt(s)" as used herein (and may be formed, for example, where the substituents comprise an acid moiety such as a carboxyl group). Also included herein are quaternary ammonium salts such as alkyl ammonium salts.
Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are useful, for example, in isolation or purification steps which may be employed during preparation. Salts of the compounds of may be formed, for example, by reacting a compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lypholization.
Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxy ethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates, undecanoates, and the like. Exemplary basic salts (formed, for example, wherein the substituent comprise an acidic moiety such as a carboxyl group) include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexyiamines, hydrabamines, N-methyl-D-glucamines, N- methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. The basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
Solvates of the compounds of the invention are also contemplated herein. Solvates of the compounds of formula I are preferably hydrates or any other pharmaceutically acceptable solvate.
All stereoisomers of the present compounds, such as those which may exist due to asymmetric carbons on the R substituents of the compound, including enantiomeric and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration.
The present invention also envisages within its scope the effect of selection of suitable counter ions. The counter ion of the compounds of the present invention may be chosen by selecting the dissociation constant for the drug capable of ionization within the said pH range. By estimating the ionized and unionized drug concentration of any compound (using well established equations such a Henderson- Hasselbach equation), the solubility and consequently the absorption of the drug may be modified.
The present invention includes in its scope, the modification of deuterated compounds. Deuterated compounds are those wherein the compounds have selective incorporation of deuterium in place of hydrogen. Deuterated compounds may be further modified by the substituted methyl formyl reagents of the present invention as per procedures as disclosed herein.
E. Composition containing the modified entities of the invention The invention thus also provides the use of the modified entity as defined herein for use in human or veterinary medicine. The compound for use as a pharmaceutical may be presented as a pharmaceutical formulation.
The invention therefore provides in a further aspect a pharmaceutical formulation comprising the modified compounds of the invention with a pharmaceutically acceptable carrier thereof and optionally other therapeutic and/or prophylactic ingredients. The carriers must be "acceptable" in the sense of being compatible with the other ingredients of the formula and not deleterious to the recipient thereof. Suitably the pharmaceutical formulation will be in an appropriate unit dosage form.
The pharmaceutical formulations may be any formulation and include those suitable for oral, intranasal, intraocular or parenteral (including intramuscular and intravenous) administration. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.
For these purposes the compounds of the present invention may be administered orally, topically, intranasall , intraocularly, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasteral injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats; horses, dogs, cats, etc., the compounds of the invention are effective in the treatment of humans.
EXAMPLES Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced other than as specifically exemplified herein.
EXPERIMENTAL
Scheme 19: Example of a typical Synthetic Procedure for the synthesis of Type III reagents
Figure imgf000088_0001
8 274 275
Procedures:
Step (A):
To a solution of chloromethylchlorofornnate [8] (7.75 mmol, 1 eq) in hexane was added a solution of pyridine (19.3 mmol, 2.5 eq) in hexane drop wise under ice cooling. After the complete addition, a white solid precipitate formed. f-Butanol (11.62 mmol, 1.5 eq) was added in hexane at the same temperature. After the addition of f-butanol the reaction mixture became a clear solution. The resulting mixture was stirred for 2 hours under ice cooling and then 1 hour at room temperature (RT). Reaction completion was monitored by TLC, which showed one non-polar spot compared to starting material. The reaction was worked up by diluting the reaction mixture with hexane and washing with saturated NaHC03 solution, followed by 2N HCI solution, followed by a second washing with saturated NaHC03 solution, and lastly by water. The organic layer was separated, dried over Na2S04 and evaporated under reduced pressure to give the reagent ferf-butyl (chloromethyl) carbonate [274] as a colorless sticky liquid (0.900 g, 70%). H NMR: [CDCI3, 300 MHz] :- δ 5.774 (s, 2 H), 1.518 (s, 9 H).
Step (B):
To a solution of rert-butyl (chloromethyl) carbonate [274] (9.87 mmol, 1 eq) dissolved in acetone was added sodium iodide (29.61 mmol, 3 eq). The resulting reaction mixture was stirred overnight at RT. The TLC showed consumption of starting material and one new non polar spot compared to starting material. The reaction was worked up by filtering out any precipitated solid and evaporating the acetone layer. The solid obtained was dissolved in DCM. The solution was filtered once again to eliminate any solid not dissolved in the DCM. The DCM layer obtained was evaporated. The crude product was passed through column chromatography by using 100-200 mesh size silica and 1% MeOH-DCM as a solvent system to yield the product fert-butyl (iodomethyl) carbonate [275] as colorless liquid (136 mg, 30%).
XH NMR [CDCI3, 300 MHz]: δ 5.90 (s, 2 H), 1.518 (s, 9 H).
Scheme 20: Example of a typical Synthetic Procedure for the synthesis of Type I reagents
Figure imgf000089_0001
276 277 278
Step (A):
An appropriate Lewis acid such as zinc chloride (catalytic amount- 0.50 g) was fused in a dried 2-neck round bottomed flask under inert atmosphere, /so-butyryl chloride [276] (46.72 mmol, 1 eq) and paraformaldehyde (47.0 mmol, 10 eq) are added to the prepared Lewis Acid at RT. The reaction mixture was heated to 60° C overnight. The reaction was monitored by TLC. The reaction was stopped by addition of DCM and washed with saturated NaHC03 then brine. The organic layer was separated, dried over Na2S04 and evaporated under reduced pressure to yield the product, chloromethyl isobutyrate [277], as colorless oil (2.0 g, 31 %). H NMR [CDCI3, 300 MHz]: δ 5.71 - 5.76 (d, 2 H), 2.54-2.64 (m, 1 H), 1.17 - 1.21 (d, 6 H)
Step (B): Sodium iodide (43.9 mmol, 3 eq) was added to a solution of chloromethyl isobutyrate [277] (14.6 mmol, 1 eq) in acetone. The resulting reaction mixture was stirred at RT overnight. Reaction completion was monitored by TLC. The reaction was worked up by filtering out precipitated solid and evaporation of excess of acetone under reduced pressure. A solid was obtained and washed with DCM while filtering under suction using a Buchner funnel. The DCM layer obtained was evaporated to provide crude product which was further purified using silica gel column chromatography (100 - 200 mesh) and DCM as an eluent. The product, iodomethyl isobutyrate [278], (1.6 g, 50% yield) was obtained as a brownish liquid.
XH NMR [CDCI3, 300 MHz]: δ 6.21 (s, 2 H), 2.54-2.64 (m, 1 H), 1.17 - 1.21 (d, 6 H). Scheme 21: Synthesis of ((methylsulfonyl)oxy)methyl 3-methylbutanoate:
Figure imgf000090_0001
Procedure:
Silver salt of methane sulfonic acid [0.34 g, 1.6 mmol, 0.5 eq] was taken in acetonitrile (8 ml) and chloromethyl 3-methylbutanoate [279] (0.5 g, 3.3 mmol, 1.0 eq) was added to it. The resulting solution was heated to 60°C for 5 h. Reaction progress was monitored by TLC. After completion, the reaction was filtered and solvent was evaporated under vacuum to yield colorless oil. The crude compound was purified by silica gel column chromatography (10% EtOAc: Cyclohexane, 100-200 mesh) which afforded [280] ((methylsulfonyl)oxy)methyl 3-methylbutanoate [0.25 g, 40%] as a colorless oil.
Scheme 22: Type I reagent (chloro methyl nicotinate)
Figure imgf000091_0001
254 281
To a three necked oven dried R.B.F equipped with dry condenser, take- off and stopper, was added zinc chloride (0.3 g, 10%) and fused using hot gun under dry conditions. After cooling to RT dry DCM (60 ml) was added, followed by addition of paraformaldehyde (5.2 g, 170 mmol, 10.0 eq) and compound [254] (3.0 g, 17 mmol, 1.0 eq). The reaction was refluxed for two days under dry conditions. After cooling the reaction was treated with saturated solution of NaHC03 and extracted with DCM. Combined organic layer were dried over Na2S04 and evaporated under vacuum to get [281] as colorless oil (0.6 g, 16.6%). ^NMR (300 MHz; CDCI3) δ: 9.28-9.27 (s, 1H); 8.89-8.83 (dd, 1H); 8.34-8.33 (d, 1H); 7.47-7.42 (dd, 1H); 5.97 (s, 2H).
M+l= 172
Scheme 23: odifynative Procedure to Synthesis of Type I reagent (chloro methyl nicotinate):
Figure imgf000091_0002
281
To a vigorously stirred, solution of nicotinic acid [282] (1.0 g, 10.0 mmol, 1.0 eq) at room temperature, sodium bicarbonate (3.2 g, 40.0 mmol, 4.0 eq), and tetrabutylammonium bisuifate (0.175 g, 0.1 mmol, 0.1 eq) in water (10ml) was added dichloromethane (10ml) followed by the dropwise addition of a solution of chloromethyl chlorosulfate (0.1 g, 12.5 mmol, 1.1 eq) in dichloromethane (5ml). After stirring the reaction at room temperature for 1 h, the dichloromethane layer was separated, washed with 5% aqueous Na2C03 solution (1 x 25 ml), organic layer separated and dried over Na2S04, followed filtering and concentrating under vacuum to yield chloro methyl nicotinate [281] as a colorless oil (0.70 g, 50%).
Scheme 24: Synthesis of reagent ((methylsulfonyl)oxy)methyl nicotinate:
Figure imgf000092_0001
Procedure:
Silver salt of methane sulfonic acid [0.096 g, 0.47 mmol, 0.8 eq] was taken in acetonitrile (8 ml) and chloromethyl nicotinate [281] (0.1 g, 0.59 mmol, 1.0 eq) was added to it. The resulting solution was heated to 60°C for 5 h. Reaction progress was monitored by TLC. After completion the reaction was filtered and solvent evaporated under vacuum to yield colorless oil. The crude compound was purified by silica gel column chromatography (35% EtOAc: Cyclohexane, 100-200 mesh) to afforded [282]
((methylsulfonyl)oxy)methyl nicotinate [0.035 g, 25%] as a colorless oil. m/z: 232
Scheme 25: Example of a typical Synthetic Procedure for the synthesis of Type II reagents
Isopropyl amine,
Figure imgf000092_0002
283 284
Step (A):
To the solution of chloromethylchloroformate [8] (1.00 g, 7.75 mmol, 1.0 eq) in DCM (y ml) was added a solution of isopropyl amine (1.14 g, 19.30 mmol, 2.5 eq) in DCM drop wise at 0°C. White solid precipitated out in the reaction mixture on addition. The resulting mixture was stirred for 2 hours at 0°C and then at RT for 1 hour. Reaction was monitored by TLC,. The reaction was worked up by diluting the reaction mixture with DCM, washing with saturated NaHC03 solution, followed by a wash with 2N HCI solution, again washing with saturated NaHC03 solution, and lastly with water. The organic layer was separated, dried over Na2S04 and evaporated under reduced pressure to give chloromethyl isopropylcarbamate [283] as colorless oil (0.50 g, 44 %). H NMR [CDCI3, 300 MHz]: δ 5.73 (s, 2 H), 4.73 (s, -NH), 3.78 - 3.91 (m, 1 H), 1.17 - 1.19 (d, 6 H) Step (B):
Sodium iodide (0.89 g, 5.94 mmol, 3.0 eq) was added to a solution of chloromethyl isopropylcarbamate
[283] (0.30 g, 1.98 mmol, 1.0 eq) in acetone. The resulting reaction mixture was stirred at RT overnight. Reaction was monitored by TLC. The reaction was worked up by filtering out precipitated solid and evaporating the acetone layer under vacuum. The solid obtained was dissolved in DCM and filtered to get rid of residual solid. The DCM layer thus obtained was evaporated under reduced pressure to get a crude product, which was purified using silica gel column chromatography (2% MeOH: DCM, 100 - 200 mesh yield pure iodomethyl isopropylcarbamate [284] as colorless sticky material (0.12 g, 37 %). H NMR [CDCI3, 300 MHz]: δ 5.96 (s, 2 H), 4.65 (s, -NH), 3.80 - 3.91 (m, 1 H), 1.17 - 1.19 (d, 6 H).
Scheme 26: Synthesis of bromomethyl morpholine-4-carboxylate
Figure imgf000093_0001
Procedure:
Chloromethyl morpholine-4-carboxylate [285] (0.3 g, 1.67 mmol, 1.0 eq) and sodium bromide (0.86 g, 8.3 mmol, 5.0 eq) was taken in acetone (10ml). The reaction was refluxed at 60°C for 24 h. Reaction progress was monitored by TLC^H NMR. The reaction was filtered off and filtrate was evaporated to dryness under reduced pressure to yield light brown gel, bromomethyl morpholine-4-carboxylate[286] (0.30 g, 80%) H NMR (CDCI3): δ ppm 5.92 (s, 2H), 3.72 (t, 4H), 3.54 6(t, 4H)s
Scheme 27:
Figure imgf000093_0002
Procedure:
Chloromethyl morpholine-4-carboxylate [6316] (0.3 g, 1.67 mmol, 1.0 eq) and lithium bromide (0.72 g, 8.3 mmol, 5.0 eq) was taken in acetonitrile (10ml). The reaction was refluxed at 90°C for 30 h. Reaction progress was monitored by TLQ^H NMR. The reaction was filtered off and filtrate was evaporated to dryness under reduced pressure to yield light brown gel, bromomethyl morpholine-4-carboxylate [6327] (0.30 g, 80%)
JH NMR (CDCI3): δ ppm 5.92 (s, 2H), 3.72 (t, 4H), 3.54 (t, 4H)
Other methyl formyl reagents were synthesized using the synthetic procedures disclosed above and herein with various substituted or unsubstituted alcohols, phenols, amines and acids to get structures in Tables 3, 4 and 5 which were characterized using spectroscopic techniques such as MS and/or 1H NMR.
Table 3: Examples of Type I Reagents
No. STRUCTURE NMR, 'HNMR (300 MHz; CDCI3) δ lUPAC Name
277 O 5.75(s, 2H), 2.50-2.70 (m, 1H), 1.15- chloromethyl
1.25 (m, 6H). isobutyrate
^^O^CI
5.70 (2H, s); 1.80-1.90 (2H, q); 1.50
5202 chloromethyl 2,2- (6H, s); 1.6-1.82 (6H, m); 0.90-1.00
dimethylbutanoate (3H, m).
0
5203 chloromethyl 3,3-
5.37 (s, 2H), 2.21(s, 2H), 1.05(s, 9H).
dimethylbutanoate
Figure imgf000094_0001
279 5.65 (s, 2H), 2.21-2.30 (m, 2H), 2.10- chloromethyl 3-
^^O^CI 2.20 (m, 1H), 0.90-1.00 (m, 6H). methylbutanoate
0
5205 5.50 (s, 2H), 4.15(s, 2H), 3.42(s, 3H). chloromethyl 2- methoxyacetate
/°^O^CI
1.16-1.21 (m, 6H), 2.54-2.64 (m, 6H),
5206 iodomethyl
6.21-6.25(s, 2H)
isobutyrate 7.20-7.40 (m, 5H), 5.30 (s, 2H), 3.85
5207 chloromethyl 2- (s, 2H).
phenylacetate
0
281 8.89-8.83 (1H, dd); 8.34-8.33 (1H, d); chloromethyl
7.47-7.42 (1H, dd); 5.97 (2H, s) nicotinate
5209 5.92(s,2H), 1.28(s,9H). iodomethyl pivalate
1.9(d,3H) ; 1.15- 1-chloroethyl
5210
1.25(d,6H);6.1(q,lH);2.6(m,lH) isobutyrate
1.25(m,6H);5.94(t,lH);2.6(m,lH);1.8 1-chloropropyl
5211
5(m,2H);0.9(t,3H) isobutyrate
5212 5.74(s,2H);2.1(s,3H) chloromethyl acetate
((methylsulfonyl)oxy)
5.81 (2H, s); 3.1 (3H,s); 2.3 (2H, d);
280 methyl 3- 2.10 (2H, m); 0.99 (6H, d)
methylbutanoate
7.8 (2H, d); 7.35 (2H, d); 5.74 (2H, s); (tosyloxy)methyj 3-
5214
2.45 (3H, s); 1.96 (2H, d): 1.85 (1H, methylbutanoate m): 0.85 (6H, d)
9.28-9.27 (1H, d); 8.89-8.83 (1H, dd);
((methylsulfonyl)oxy) 8.34-8.33 (1H, d); 7.47-7.42 (1H, dd);
282
methyl nicotinate 6.08 (2H, s):3.14 (3H,s)
Table 4: Examples of Type II Reagents
No. STRUCTURE NMR, ^NMR (300 MHz; CDCI3) 6 lUPAC Name 0 Ί.21-132, (m, 5H), 5.78-5.81 (d,
6301 2H), 5.192 (s, IH), 4.39-4.43 (m, chloromethyl
2H), benzylcarbamate
6302 1.17 - 1.19 (d, 6 H), 3.78 - 3.91 (m, chloromethyl
1 H), 4.73 (s, -NH), 5.73 (s, 2 H) isopropylcarbamate
Figure imgf000096_0001
O
6303 1.09-1.25 (m, 12H), 3.20-3.40 (m, chloromethyl
2H), 5.75-5.85 (d, 2H) diisopropylcarbamate
1 0
6304 1.09-1.25 (m, 12H), 3.20-3.40 (m, iodomethyl
2H), 6.01 (d, 2H) diisopropylcarbamate
7.20-7.40 (m, 5H), 6.83(s, 2H),
6305 chloromethyl
Figure imgf000096_0002
4.42-4, 55 (m, 2H), 2.82-2.95(m,
benzyl(methyl)carbamate 2H).
O
1.10-2.05 (m, 3H), 1.30-1.45 (m,
2H), 1.55-1.65 (m, IH), 1.65-1.80
6306 chloromethyl piperidine- (m, 2H), 1.90-2.00 (m, 2H), 3.45- 1-carboxylate 3.60 (m; IH), 4.75-4.95 (s, IH),
5.75 (s, 2H)
0
A ^ : 5.71-5.80 (2H, s); 5.85-5.95 (IH,
H ^O CI (S)-chloromethyl (1-
6307 bs); 3.58-3.70 (IH, q); 1.6-1.82 (6H,
cyclohexylethyl)carbamat m); 0.8-1.45 (7H, m).
e
0
A ^ 5.71-5.80 (2H, s); 5.85-5.95 (IH,
HN O CI (R)-chloromethyl (1-
6308 bs); 3.58-3.60 (IH, q); 1.6-1.8 (4H,
cr cyclohexylethyl)carbamat m); 0.8-1.45 (7H, m).
e
Figure imgf000097_0001
Figure imgf000098_0001
0
1.10 (d, 3H), 1.30-1.45 (q, 4H), chloromethyl 4-
6326 1.55-1.65 (m, 1H), 1.65-1.80 (t, methylpiperidine-1- 4H), 6.1 (s, 2H) carboxylate
0
6327 5.92 δ (2H,S),3.72 6(4H,t),3.54 bromomethyl
6(4H,t) morpholine-4-carboxylate
Table 5: Examples of Type III Reagents
No. STRUCTURE MR, 1HNM (300 MHz; CDCI3) δ lUPAC Name tert-butyl
7401 1.50 (s, 9H), 5.65 (s, 2H) (chloromethyl) carbonate
Figure imgf000099_0001
1.25-1.40 (t, 3H), 4.25-4.35 (q, 2H),
chloromethyl 5.75 (s, 2H)
7402 T
0
ethyl carbonate chloromethyl
1.20-1.40 (m, 3H), 1.45-1.6 (m, 3H),
7403 1.70-1.80 (m, 2H), 1.90-2.0 (m, 2H), cyclohexyl
4.75- 4.75 (m, 1H), 5.75 (s, 2H) carbonate chloromethyl (1-
1.40-1.60 (m, 10H), 2.10-2.20 (m, 3H),
7404 methylcyclohex
1.70-1.80 (m, 2H), 5.65 (s, 2H)
yl) carbonate
Figure imgf000099_0002
chloromethyl
1.55-1.65 (m, 3H), 1.65-1.95 (m, 7H),
7405 cyclopentyl
5.10-5.20 (m, 1H), 5.7 (s, 2H)
carbonate
Figure imgf000100_0001
Figure imgf000101_0001
Accordingly, as a person of ordinary skill in the art will readily apprehend from the teachings herein, the modifying reagents of the present invention can be synthesized in wide variety as taught and disclosed, including but not limited to the specific examples provided herein, including those in Tables 3, 4 and 5. As such, one aspect of the present invention is therefore the ability to tailor the substituents to the family of reagents disclosed in Figure 1 to suit a particular application or obtain the desired result.
Example of chemical modifications of drugs/biologically active compounds with aromatic nitrogen as a heteroatom.
Scheme 28: Synthesis of modified form of Nicorandil
Figure imgf000102_0001
To a solution of nicorandil, (2-(nicotinamido)-ethyl nitrate) [287], (0.28 mmol, 1 eq) in acetonitrile (3 ml) was added iodomethyl isopropyl carbamate [6318] (0.28 mmol, 1.2 eq) drop wise. The resulting reaction mixture was stirred overnight at RT. Reaction completion was monitored by TLC. The excess of acetonitrile was removed under vacuum with a Buchi rotavapor. The resulting crude was dissolved in a minimum amount of MeOH and washed with an excess of ether. This process was repeated twice to get nearly pure solid product, l-(((isopropylcarbamoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l-ium iodide
[288], which was dried under high vacuum to obtain the product as a yellow sticky solid (0.085 g, 88 %). m/z: 327 (M+) H NMR [DMSO, 300 MHz]: δ ppm 9.54 (s, 1H), 9.43 - 9.46 (m, 1H), 9.27 - 9.29 (d, 1H), 9.01 - 9.04 (d, 1H), 8.33 - 8.38 (m, 1H), 7.86 - 7.88 (m, 1H), 6.41 (s, 2H), 4.67 - 4.70 (t, 2H), 3.69 - 3.74 (m, 2H), 3.52 - 3.63 (m, 1H), 1.04 - 1.11 (m, 6H) Other chemical modifications of nicorandil were accomplished using similar synthetic procedure with various substituted methyl formyl reagents to get structures in Table 6 which were characterized using spectroscopic techniques such as MS and/or 1H NMR.
These compounds were tested for their Pharmacokinetic parameters and were found to be more active than nicorandril. The Pk data corresponding to the compounds are presented at Table 6.
The PK data of the compounds were tested by following the protocol as below:
Female Sprague Dawley (SD) rats 3 per group after overnight fasting were dosed orally (via gavage) with imatinib and its modified drugs in distilled water (5ml/kg) at a dose level of 3mg/kg . Blood was collected by serial bleeding at 0.16 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h in heparinized tubes. Blood samples were centrifuged at 10,000rpm for 10 min. at 4°C to obtain the plasma, which were aspirated into separate labeled tubes and stored at -80°C. 400ng/ml of Verapmil in acetonitrile was used as the drug extraction solvent for extracting drug from plasma. Extraction solvent was added to plasma was vortexed and shaken on shaker for 10 minutes, centrifuged at 10000 rpm for 10 minutes at 4°C. Supernatant was kept for analysis.
Acetonitrile and plasma calibration curves were generated and percentage of drug recovery from plasma determined. Quantitative analysis was done by liquid chromatography tandem mass spectrometry using multiple reaction monitoring (API3000 LC-MS/MS). Cmax, Tmax, AUC and ti 2 were calculated using Graph Pad PRISM version 5.04.
Table 6: Some examples of chemical modifications of nicorandil and their Pharmacokinetic Parameters determined in Swiss mice at 3 mpk orally (Tm-V. Cm3 . AUC and Ti^)
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Accordingly, as a person of ordinary skill in the art will readily apprehend from the teachings herein, the modifying reagents of the present invention can be synthesized in wide variety as taught and disclosed, including but not limited to the specific examples provided herein. As taught herein, and exemplified in herein, modification according to the teachings of the present invention provides a ready and flexible method of varying various pharmacokinetic parameters of a biologically active compound.
Example of chemical modifications of drugs/biologically active compounds with aliphatic tertiary nitrogen as a heteroatom
Scheme 31: Synthesis of modified form of Dimebon, Derivative I
Figure imgf000108_0001
Procedure:
To a stirred solution of dimebon, 2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-lH- pyr'ido[4,3-b]indole [4149], (0.070 g, 0.22 mmol, 1.0 eq) in ethyl acetate was added iodomethyl di- isopropyl carbonate [6304] (0.057 g, 0.20 mmol, 0.9 eq) at RT. The reaction mixture was stirred at RT for 4 to 6 hours. The resulting precipitate was collected by filtration under suction and washed four times with ethyl acetate followed by an additional wash by diethyl ether.to get a pale yellow, solid which was dried under vacuum at RT to yield the desired product, 2- (((diisopropylcarbamoyl)oxy)methyl)-2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro- lH-pyrido[4,3-b]indol-2-ium iodide [292] (0.020 g, 15%). m/z: 477.3 Scheme 32: Synthesis of modified form of Dimebon, Derivative II
Figure imgf000109_0001
Procedure: lodomethyl diisopropyl carbamate [6304] (0.134 g, 0.47 mmol, 5.0 eq) was added to a stirred solution of dimebon [4149] (0.030 g, 0.094 mmol, 1.0 eq) in ethyl acetate at RT. The reaction mixture was stirred at RT for 4 to 6 hours. The resulting precipitate was filtered under suction and washed four times with ethyl acetate followed by an additional wash with diethyl ether to get a pale yellow solid, which was dried under vacuum at RT to yield the desired product, 2-(((diisopropylcarbamoyl)oxy)methyl)-5-(2-(l- (((diisopropylcarbamoyl)oxy)methyl)-6-methylpyridin-l-ium-3-yl)ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-b]indol-2-ium diiodide [293] (0.033 g, 39%) m/z: 317.8
Scheme 33: Synthesis of modified forms of Olanzapine
Figure imgf000109_0002
294 Procedure:
To a stirred solution of Olanzapine, (2-methyl-4-(4-methylpiperazin-l-yl)-10H-benzo[b]thieno[2;3- e][l,4]diazepine )[4134] (0.025 g, 0.086 mmol, 1.0 eq) in ACN was added iodomethyl isopropylcarbamate [6318] (0.20 g, 0.086 mmol, 1.0 eq) at RT. The reaction mixture was stirred at RT for four to 16 h. Reaction progress was monitored by TLC. Solvent was removed under vacuum to get a crude product. The crude product obtained was triturated with diethyl ether (5ml x 2) to give the desired product [294], l-(((isopropylcarbamoyl)oxy)methyl)-l-methyl-4-(2-methyl-10H- benzo[b]thieno[2,3-e][l,4]diazepin-4-yl)piperazin-l-ium iodide (0.013 g, 41%) as yellow solid.
Scheme 34: Synthesis of modified forms of Sildenafil
Figure imgf000110_0001
4102 295
Procedure:
Chloromethyl acetate [5212] (0.007 g, 0.063 mmol, 1.0 eq) & sodium iodide (0.018 g, 0.063 mmol, 3.0 eq) was added to a stirred solution of sildenafil [4102] (0.03 g, 0.063 mmol, 1.0 eq) in ACN (3ml) at RT. The reaction mixture was stirred at RT for 4 to 48 h. Reaction progress was monitored by TLC. Solvent was removed under vacuum to get a crude product. DCM was added to the crude product to precipitate out sodium iodide, which was separated by filtration, and the filtrate was evaporated to get a white solid. The product was dried under vacuum at room temperature to yield [295] l-(acetoxymethyl)-4-((4- ethoxy-3-(l-methyl-7-oxo-3-propyl-4,7-dihydro-lH-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)-l- methylpiperazin-l-ium iodide (0.14 g, 42%) Other derivatives of sildenafil may also be prepared in a similar manner. Some non-limiting examples of sildenafil are as below:
Figure imgf000111_0001
Examples of chemical modifications of drugs/biologically active compounds with alcohol/phenol as a functional group Scheme 35: Synthesis of modified forms of Paracetamol, Derivative I
Figure imgf000112_0001
4147 297 298
Step 1:
TEA (1.2 ml, 8.6 mmol, 5.0 eq) was added to a solution of paracetamol [4147] (0.26 g, 1.7 mmol, 1.0 eq) in dry THF under argon atmosphere. At 0 °C, nicotinoyl chloride hydrochloride [296] (1.53 gm, 8.6 mmol, 5.0 eq) was added to the above reaction mixture. The reaction mixture was stirred at room temperature for 24 h. After 24 h, organic solvent was evaporated under vacuum and residue was dissolved in dichloromethane (50 ml) and washed with a 10% solution of NaHC03 (15 ml) and then with brine (10 ml) followed by drying of organic layer over anhydrous sodium sulfate. Evaporation of the solvents provided white solid which was purified by silica gel column chromatography (4% MeOH: DCM, 100-200 mesh silica) to give the product 4-acetamidophenyl nicotinate [297] (0.34 g,78%). m/z: 257
Step 2:
To a solution of 4-acetamidophenyl nicotinate [297], (0.05 g, 1.95 mmol, 1.0 eq) in acetonitrile (4 ml) was added iodomethyl diisopropylcarbamate [6304] (0.055 g, 1.95 mmol, 1.0 eq). The resulting reaction mixture was stirred overnight at RT. The reaction was monitored by TLC. Acetonitrile was removed under vacuum and the resulting crude mixture was washed with diethyl ether (10 ml) to give pale yellow solid product 3-((4-acetamidophenoxy)carbonyl)-l-(((diisopropylcarbamoyl)oxy)methyl)pyridin-l- ium iodide [298] (0.086 g, 81 %). m/z: 414
Scheme 36: Synthesis of modified forms of Paracetamol, Derivative II
Figure imgf000113_0001
Step 1:
TEA (0.28 ml, 1.98 mmol, 3.0 eq) was added to a solution of paracetamol [4147] (0.10 g, 0.66 mmol, 1.0 eq) of in dry THF under argon atmosphere. At 0 °C, bromoacetyl chloride [244] (0.123 g, 0.79 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 24 h. After 24 h, solvent was evaporated under vacuum and residue was taken in dichloromethane (50 ml) and washed with a 10% solution of NaHC03 (15 ml) and then with brine (10 ml), followed by drying of the organic layer over anhydrous sodium sulfate. Evaporation of the solvent provided white solid which was purified by silica gel column chromatography (0.5% MeOH: DCM, 100-200 mesh silica) to give the product 4- acetamidophenyl 2-bromoacetate [299] (0.05 g, 28%). m/z: 272
Step 2: Sodium iodide (0.083 g, 5.52 mmol, 3.0 eq.) was added to a solution of 4-acetamidophenyl 2- bromoacetate [299] (0.05 g, 1.84 mmol, 1.0 eq.) in acetonitrile (5ml) followed by the addition of dimethyl nicotinamide [300] (0.027g, 1.84 mmol, 1.0 eq). The resulting reaction mixture was stirred at 40°C for 48 h. Reaction progress was monitored by TLC. Solvent was removed under vacuum to get crude product. The crude product obtained was taken in DCM to precipitate excess of sodium iodide and sodium bromide, which was removed by filtration and filtrate was evaporated to get a yellow solid, which was washed with diethyl ether (10ml) and then dried under vacuum to yield light yellow solid, 1- (2-(4-acetamidophenoxy)-2-oxoethyl)-3-(dimethylcarbamoyl)pyridin-l-ium iodide[301], (0.038 g, 44%) m/z: 342
Scheme 37: Synthesis of modified forms of Paracetamol, Derivative III
Figure imgf000114_0001
7 302 303 304
Step 1:
Pyridine (0.375 g, 47.5 mmol, 2.5 eq) was added to a solution of chloromethyl chloroformate (CMCF) [8] (0.294 g, 22.8 mmol, 1.2 eq) in dry THF (10 ml) under an argon atmosphere at 0°C. At 0 °C, a solution of Paracetamol [4147] (0.30 g, 19.0 mmol, 1.0 eq) in dry THF was added to the above reaction mixture. The reaction mixture was stirred at RT for 20 h. Reaction progress was monitored by TLC. After 20 h, the reaction mixture was diluted with dichloromethane (50 ml), washed with water (15ml), 10% solution of NaHC03 (15 ml), dilute HCI (10 ml), followed with brine (10 ml). The organic layer dried over anhydrous sodium sulfate. Evaporation of the solvents under vacuum gave crude product. The crude product was purified by silica gel column chromatography (2% MeOH: DCM, 100-200 mesh) to yield a off white product, 4-acetamidophenyl (chloromethyl) carbonate [302] (0.33 g, 68 %). m/z: 244
Step 2:
Sodium iodide (0.454 g, 107 mmol 3.7 eq) was added to a solution of 4-acetamidophenyl (chloromethyl) carbonate [302] (0.20 g, 29 mmol, 1.0 eq) in acetone. The resulting reaction mixture was heated for 6 h at 50 °C. Reaction progress was monitored by TLC. The reaction mixture was cooled to room temperature and passed through a bed of silica (mesh 100 - 200). The silica bed was washed several times with acetone and fractions collected and evaporated under vacuum to yield the desired product, 4-acetamidophenyl (iodomethyl) carbonate [303] (0.27gm, 98%). m/z: 336
Step 2:
Dimethyl nicotinamide [300] (0.022 g, 15 mmol, 1.0 eq) was added to a solution of 4-acetamidophenyl (iodomethyl) carbonate [303] (0.05 g, 15.0 mmol, 1.0 eq) in dry acetonitrile (2ml) under argon atmosphere. The resulting reaction mixture was stirred for 2 days at RT. Reaction progress was monitored by TLC. Solvent was removed under vacuum to get a crude product. The crude product obtained was triturated with diethyl ether (2 x 10 ml) to give the desired product, l-((((4- acetamidophenoxy)carbonyl)oxy)methyl)-3-(dimethylcarbamoyl)pyridin-l-ium iodide [304] (0.021 g, 29 %). m/z: 358
Scheme 38: Synthesis of modified forms of SN-38 procedure
Figure imgf000116_0001
Step 1:
NaH (0.012 g, 0.51 mmol, 1.0 eq) was added portion wise to a solution of SN-38, (S)-4,ll-diethyl-4,9- dihydroxy-lH-pyrano[3',4,:6/7]indolizino[l,2-b]quinoline-3,14(4H,12H)-dione [4150] (0.20 g , 0.51 mmol, 1.0 eq) in DMF (2 ml) under N2 atmosphere at 0°C. The resulting reaction mixture was stirred at 0°C for an additional 30 min. To the reaction mixture, chloromethyl nicotinate [259] (0.087g, 0.51 mmol, 1.0 eq) dissolved in DMF was added dropwise while maintaining the temperature at 0°C. The reaction was then allowed to come to RT and stirred overnight. The reaction mass was quenched with addition of water. The reaction mixture was extracted with DCM (2 x 100 ml). The organic layers were combined and washed with brine, dried over Na2S04 and evaporated. The resultant crude product was purified on column chromatography (2% MEOH: DCM, silica gel 100 - 200 mesh) to yield a pale yellow solid, (S)- ((4Al-diethyl-4-hydroxy-3,14-dioxo
9-yl)oxy)methyl nicotinate [305] (0.036g, 13%). m/z = 528 H NMR (DMSO, 300 MHz): δ ppm 9.36 (s, 1 H); 8.95 (d; 1 H); 8.58 (d, 1 H); 8.23 - 8.25 (dd, 2 H); 7.84 (d, 1 H); 7.69 - 7.72 (m, 1 H), 7.29 (d, 1 H); 6.50 - 6.53 (m, 1 H); 6.01 - 6.04 (d, 1 H); 5.75 (s, 1 H); 5.29 (s, 2 H); 4.80 - 4.84 (bs, 1 H); 4.67 (br, 1 H); 4.03-4.09(bs, 1 H); 3.31 - 3.33 (m, 2 H); 1.82 - 1.92 (m, 2 H); 1.29 - 1.34 (t, 3 H); 0.85 - 0.93 (t, 3 H)
Step 2: lodomethyl isopropylcarbamate [6318] (0.007 g, 0.028 mmol, 1.0 eq) was added to a solution of (S)- ((4,ll-diethyl-4-hydroxy-3,14-dioxo A12,14-tetrahydro-lH^yrano[3 4':6,7]indolizino[l;2-b]quinolin- 9-yl)oxy)methyl nicotinate [305] (0.015 g, 0.028 mmol, 1.0 eq) in DCM (5 ml). The reaction mixture was stirred at RT for 16 hours. The DCM was evaporated under reduced pressure and washed thoroughly with diethyl ether to yield [306], as a yellow solid (S)-3-((((4,ll-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14- tetrahydro-lH-pyrano[3',4':6,7]indolizino[l,2-b]quinolin-9-yl)oxy)methoxy)carbonyl)-l- (((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium iodide (0.018 g, 85 %). m/z: 643 H NMR (300 MHz; DMSO): δ 9.98 (s, 1 H); 9.39-9.46 (d, 1 H); 9.36 (d, 1 H); 8.45 - 8.49(t, 1 H); 8.28 - 8.29 (dd, 2 H); 7.25 (s, 1 H); 6.50 - 6.53 (m, 3 H); 6.04 - 6.07 (d, 1 H); 5.39 - 5.42 (s, 2 H); 4.80 - 4.87 (br, 1 H); 4.72 (br, 1H); 4.03 - 4.09 (br, 1 H); 3.36 (m, 1 H); 3.07 - 3.11 (m, 2 H); 1.84 - 1.90 (m, 2 H); 1.29 - 1.34 (t, 3 H); 1.06 - l.ll(m, 6 H); 0.85 - 0.93 (t, 3 H)
Scheme 39: Synthesis of modified forms of Curcumin
Figure imgf000118_0001
Stepl:
To a solution of nicotinoyi chloride hydrochloride [296] (0.725 g, 4.0 mmol, 1.5 eq) in THF (30 ml) was added TEA (1 ml, x mmol, y eq) drop-wise at 0°C. A solution of curcumin, (lE,4Z,6E)-5-hydroxy-l,7-bis(4- hydroxy-3-methoxyphenyl)hepta-l,4,6-trien-3-one [4151] (l.Og, 2.7 moles, 1.0 eq) and pyridine (1 ml) in THF (10 ml) was then added at the same temperature. The reaction temperature was gradually increased to RT. The reaction mixture was stirred for 20 h at RT. Reaction was monitored by TLC. The reactionjmixture was diluted with EtOAc (200 ml), washed by saturated NaHC03 solution (75 ml) and water (100 ml) successively. The EtOAc layer was separated, dried with sodium sulphate and concentrated under reduced pressure to yield a crude product. The crude product was purified by column chromatography using (2% MeOH: DCM, 100 - 200 mesh) get the desired product, 4- ((lE,4Z,6E)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-3-oxohepta-l,4,6-trien-l-yl)-2-methoxyphenyl nicotinate [307] as yellow solid (0.30 g, 23 %). m/z: 579
A yellow solid was also generated corresponding to ((lE,3Z,6E)-3-hydroxy-5-oxohepta-l,3,6-triene-l,7- diyl)bis(2-methoxy-4,l-phenylene) dinicotinate [308] (0.03 g, 2.3%). m/z: 474. Step 2:
Compound [308] [((lE,3Z,6E)-3-hydroxy-5-oxohepta-l,3,6-triene-l,7-diyl)bis(2-methoxy-4,l-phenylene) dinicotinate] (0.02 g, 0.035 mmol, 1.0 eq) was dissolved in solvent ACN (1ml) followed by the addition of
[6318] (0.018 g, 0.076 mmol, 2.2 eq) at room temperature under stirring. Resulting reaction mixture was further stirred for overnight at RT. Reaction was monitored by TLC. Excess of acetonitrile was evaporated under vacuum to get a crude product which on trituration by ethyl acetate (5 ml) followed by diethyl ether (10ml) gave a yellow solid 3,3'-(((((lE,3Z,6E)-3-hydroxy-5-oxohepta-l,3,6-triene-l,7- diyl)bis(2-methoxy-4,l-phenylene))bis(oxy))bis(carbonyl))bis(l- (((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium) diiodide, [309] (0.017 g, 46 %). m/z: 405 .
Scheme 40: Synthesis of modified forms of Paclitaxel, Derivative I
Figure imgf000119_0001
Step 1:
4 drops of pyridine were added to a solution of paclitaxel [4114] (0.10 g, 0.117 mmol 1.0 eq) of in dry dichloromethane under argon atmosphere. At 0 °C, nicotinoyl chloride hydrochloride [296] (0.17 g, 1.17 mmol 10.0 eq) was added. The reaction mixture was stirred at room temperature for 24 hours. After 24 hours, the mixture was diluted with dichloromethane (25 ml) and washed with a 10% solution of NaHC03 (15 ml) and brine (10 ml) followed by drying over anhydrous sodium sulfate. Evaporation of the solvents provided residual yellow solid which was purified by silica gel column chromatography (30% ethyl acetate: cyclohexane, 100-200 mesh silica) to get a white solid [310], (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2-(nicotinoyloxy)-3- phenylpropanoyl)oxy)-12-(benzoyloxy)-4,ll-dihydroxy-4a,8,13,13-tetramethyl-5-oxo- 23,3,4,43;5,6,9,10,11,12,123,12^άθ€ΐθε3ήγάΓθ-1Η-7,11-ηηθΐΓ)3ηοενεΙοάθε3[3;4]6εηζο[1,2-6]οχθίε- 6,12b-diyl diacetate, (0.05 g, 45 %) m/z: 959.2
Step2: lodomethyl isopropylcarbamate [6318] (0.003 g, 10 mmol, 1.0 eq) was added to a solution of [310] (0.01 g, 10.0 mmol, 1.0 eq) in dry Acetonitrile under an argon atmosphere. The resulting reaction mixture was stirred for 6 hours at RT. Reaction progress was monitored by TLC. Solvent was evaporated under high vacuum pump to give crude product. Crude product obtained was triturated with diethyl ether (2 xlOml) to get a yellow solid [311], 3-((((lS,2R)-l-benzamido-3-(((2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-6,12b- diacetoxy-12-(benzoyloxy)-4,ll-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-
2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-9- yl)oxy)-3-oxo-l-phenylpropan-2-yl)oxy)carbonyl)-l-(((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium iodide, (0.01 g, 90%). m/z: 1075.2
Scheme 41: Synthesis of modified forms of Paclitaxel, Derivative II
Figure imgf000120_0001
Step 1:
Pyridine (0.026 g, 23.0 mmol, 2.0 eq) was added to a solution of chloromethyl chloroformate (CMCF) [8] (0.02 g, 23.0 mmol, 2.0 eq) in dry dichloromethane under an argon atmosphere at 0°C. At 0 °C, a solution of paclitaxel [4114] (0.10 g, 11.7 mmol, 1.0 eq) in dry dichloromethane was added to the above reaction mixture. The reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After 2 h the reaction mixture was diluted with dichloromethane (25 ml), washed with a 10% solution of NaHC03 (15 ml), brine (10 ml), and then dried over anhydrous sodium sulfate. Evaporation of the solvent under vacuum gave a white solid, [312], (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2-(((chloromethoxy)carbonyl)oxy)-3- phenylpropanoyl)oxy)-12-(benzoyloxy)-4-(((chloromethoxy)carbonyl)oxy)-ll-hydroxy-4a,8,13,13- tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll- methanocyclodeca[3,4]benzo[l,2-b]oxete-6,12b-diyl diacetate, (0.11 g, 90%) m/z: 1038.3
Step 2:
Sod ium iodide (0.022 g, 145.0 mmol, 5 eq) was added to a solution of [312] (0.03 g, 29.0 mmol, 1 eq) in acetone. The resulting reaction mixture was refluxed for 6 h at 60 °C. Reaction progress was monitored by TLC. The reaction mixture was cooled to room temperature and passed through a bed of silica (mesh 100 - 200). The silica bed was washed with acetone which was collected and evaporated under vacuum to yield a white solid [313], (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2- (((iodomethoxy)carbonyl)oxy)-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-ll-hydroxy-4- (((iodomethoxy)carbonyl)oxy)-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b- dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxete-6,12b-diyl diacetate, (0.02 g, 70 %) m/z: 1221.7
Step 3:
Dimethyl nicotinate [300] (0.003 g, 20.0 mmol, x eq) was added to a solution of [313] (0.01 g, 10.0 mmol, x eq) in dry acetonitriie (y ml) under argon atmosphere. The resulting reaction mixture was stirred for 16 h at RT. Reaction progress was monitored by TLC. Solvent was removed under high vacuum pump to give a crude product. The crude product obtained was triturated with diethyl ether (10 ml x 2) to give a yellow solid [314], mono(l-((((((lS,2R)-l-benzamido-3- (((2aR;4S,4aS,6R,9S,llS,12S,12~aR,i2bS)-6,12b-diacetoxy-12-(benzoyloxy)-4-((((3- (dimethylcarbamoyl)pyridin-l-ium-l-yl)m
oxo-2a;3,4,4a,5,6,9;10,ll,12i12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-9- yl)oxy)-3-oxo-l-phenylpropan-2-yl)oxy)carbonyl)oxy)methyl)-3-(dimethylcarbamoyl)pyridin-l-ium) doiodide (0.014 g, 60%). m/z: 1268
Scheme 42: Synthesis of modified forms of Paclitaxel, Derivative III
Figure imgf000122_0001
Step 1:
DIPEA (0.026 g, 46.0 mmol, 4.0 eq) was added to a solution of chloromethyl chloroformate (CMCF) [8] (0.04 g, 23.0 mmol, 4.0 eq) in dry dichloromethane under an argon atmosphere at 0°C. To the above reaction mixture at 0 °C, a solution of paclitaxel [4114] (0.10 g, 11.7 mmol, 1.0 eq) in dry dichloromethane (y ml) was added. The reaction mixture was stirred at room temperature for 16 h. reaction progress was monitored by TLC. After 16 h the reaction mixture was diluted with dichloromethane (25 ml), washed with a 10% solution of NaHC03 (15 ml), brine (10 ml), and then dried over anhydrous Na2S04. Evaporation of the solvents under vacuum gave a white solid, (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2-(((chloromethoxy)carbonyl)oxy)-3- phenylpropanoyl)oxy)-12-(benzoyloxy)-4,ll-dihydroxy-4a,8,13,13-tetramethyl-5-oxo- 2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxete- 6,12b-diyl diacetate [315], (0.08 g, 70 %) m/z = 946 Step 2:
Sodium iodide (0.14 g, 0.42 mmol, 4.0 eq) was added to a solution of [315] (0.10 g, 0.116 mmol, 1.0 eq) in Acetonitrile (5 ml) followed by the addition of dimethyl nicotinamide [300] (0.034 g, 0.233 mmol, 2.0 eq). The resulting reaction mixture was stirred at 50°C for 24 h. Reaction progress was monitored by TLC. Solvent was removed under vacuum to get a crude product. DCM was added to the crude product to precipitate out sodium iodide, which was separated by filtration, and the filtrate was evaporated under vacuum to get a yellow oil l-((((((lS,2R)-l-benzamido-3-(((2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)- 6,12b-diacetoxy-12-(benzoyloxy)-4,ll-dihydroxy-4a,8,13,13-tetramethyl-5-oxo- 2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxet-9- yl)oxy)-3-oxo-l-phenylpropan-2-yl)oxy)carbonyl)oxy)methyl)-3-(dimethylcarbamoyl)pyridin-l-ium iodide iodomethyl 2-(4-isobutylphenyl) propanoate [316] (0.012 g, 10%). m/z: 1060.
Other derivatives of paclitaxel may also be synthesized in a similar manner, for instance see compound number 9400 and 9405 as below:
Figure imgf000123_0001
Examples of chemical modifications of drugs/biologically active compounds with a carboxylic acid as a functional group
Scheme 43: Synthesis of modified forms of Aspirin, Derivative I:
Derivative I:
Figure imgf000124_0001
TEA (0.08 ml, 0.68 mmol, 1.2 eq) and methyl formyl reagent [259] (0.1 g, 0.56 mmol, 1.0 eq) was added to a solution of aspirin [4154] and 2-acetoxybenzoic acid, (0.1 g, 0.56 mmol, 1.0 eq ) in DMF (2 ml). The reaction mixture was heated at 45°C for 16 h, followed by cooling to room temperature and dilution with water. The organic material was extracted with ethyl acetate, was washed with water dried over Na2S04 and evaporated under vacuum to get crude product. The crude product was purified by silica gel column chromatography (ethyl acetate in cyclohexane 100-200 mesh) to yield a dark colored sticky product [318], ((2-acetoxybenzoyl)oxy)methyl nicotinate, (0.09 g, 50 %). m/z :316
[318] (0.09 g, 0.28 mmol, 1.0 eq) was dissolved in ACN (2 ml) followed by addition of iodomethyl dimethylcarbamate reagent [6320] (0.078g, 0.34 mmol, 1.2 eq) and stirred at RT for 12 h. Excess solvent was evaporated under vacuum to obtain crude product. Compound was purified by precipitation of crude product using DCM: diethyl ether, which provided solid [319], 3-((((2- acetoxybenzoyl)oxy)methoxy)carbonyl)-l-(((dimethylcarbamoyl)oxy)methyl)pyridin-l-ium iodide (0.085 g, 71%). m/z: 417 H NMR [CDCI3, 300 MHz]: δ 9.82-9.80, (d, 1H); 9.588, (s, 1H); 9.07-9.03, (d, H); 8.39-8.34, (t, 1H); 8.11- 8.06, (d, 1H); 7.66-7.63, (t, 1H), 7.38-7.33, (t, 1H); 7.15-7.12, (d, 1H), 6.26, (s, 2H), 3.014, (s, 3H); 2.89, (s, 3H); 2.34, (s, 3H)
Scheme 44: Synthesis of modified forms of Aspirin, Derivative II:
Figure imgf000125_0001
4154 320 321
Step 1:
To a vigorously stirred solution of Aspirin [4154] (0.2 g, 1.11 mmol, 1.0 eq) at room temperature, sodium bicarbonate (0.3 g, 4.1 mmol, 3.81 eq), and tetrabutylammonium bisulfate (0.035 g , 0.11 mmol, 0.1 eq) in water (5 ml) was added dichloromethane (5 ml) followed by the dropwise addition of a solution of chloromethyl chlorosulfate [323] (0.02 ml, 1.2 mmol, 1.1 eq) in dichloromethane (5 ml). After stirring at room temperature for 1 h, dichloromethane layer was separated, washed with 5% aqueous sodium bicarbonate solution (1 x 25 ml), separated and dried over Na2S04, filtered and concentrated under vacuum to get a colorless oil [320] (Chloromethyl 2-acetoxybenzoate) , (0.18 mg, 71 %) m/z: 229.
Step 2:
Chloromethyl 2-acetoxybenzoate [320] (0.050 g, 0.21 mmol, 1.0 eq) sodium iodide (0.098 g, 0.6 mmol, 3.0 eq) and nicotinamide [322] (0.026 g, 0.2 mmol, 1.0 eq) were added in ACN (3 ml). The reaction mixture was stirred at RT for 16 h Reaction progress was monitored by TLC. After completion of the reaction solvent was removed vacuum to get a crude product. The crude product obtained was triturated with diethyl ether (2 x 10 ml) to give the desired product [321], l-(((2-acetoxybenzoyl)oxy)-3- carboylpyridin-l-ium iodide (0.01 g, 14%) m/z: 315
Scheme 45: Synthesis of modified forms of Indomethacin
Figure imgf000126_0001
Step 1:
A mixture of Indomethacin [324] (0.2 g, 0.56 mmol, 1.0 eq), DCM (1 ml), water (1 ml), sodium bicarbonate (0.126 g, 1.78 mmol, 3.81 eq) and tetrabutylammonium hydrogen sulfate (0.018 g , 0.056 mmol, 0.1 eq) were stirred room temperature for 2 min. A solution of chloromethyl chlorosulfate [323] (0.1 ml, 0.61 mmol, 1.1 eq) in DCM (1 ml) was added dropwise. This biphasic system was stirred at RT for 1 h. The organic layer was separated and dried over Na2S04. Evaporation of the solvent under vacuum gave a yellow oil [325] (Chloromethyl 2-(-l-(4-chlorobenzoyl)-5methoxy-2-methyl-lH-indol-3yl) acetate), (0.16 ml, 70%)
Step 2:
Chloromethyl 2-(-l-(4-chlorobenzoyl)-5methoxy-2-methyl-lH-indol-3yl)acetate [325] (0.05 g, 0.12 mmol, 1.0 eq) sodium iodide (0.055 g, 0.36 mmol, 3.0 eq) and nicotinamide (0.015 g, 0.12 mmol , 1.0 eq) were added in ACN (3 ml). The reaction mixture was stirred at RT for 16 h Reaction progress was monitored by TLC. After completion solvent was removed under vacuum to get a crude product. The crude product obtained was triturated with diethyl ether (2 x 10 ml) to get the desired product [326], 3- carbamoyl-l-((2-(-l-(4-chlorobenzoyl)-5methoxy-2-methyl-lH-indol-3yl)acetoxy)methyl)pyridine-l-ium iodide (0.015 g, 25%).
Scheme 46: Synthesis of modified forms of Ibuprofen:
Figure imgf000127_0001
Step 1:
Ibuprofen [327] (0.1 g, 0.48 mmol ,1.0 eq) DCM (2 ml), water(2 ml), sodium bicarbonate (0.131g , 1.8 mmol, 3.81 eq) and tetrabutylammonium hydrogen sulfate (0.016 g , 0.05 mmol, 0.1 eq) were stirred at 25°C for 2 min. to the above reaction mixture, a solution of chloromethyl chlorosulfate [323] (0.08 ml, 0.51 mmol, 1.1 eq) in DCM (1 ml) was added dropwise and the biphasic system was stirred at RT for 1 h. The organic layer was separated and dried over anhydrous Na2S04. Evaporation of the solvent under vacuum gave the desired product as a colorless oil [328] (chloromethyl 2-(4-isobutylphenyl)propanoate), (0.06 ml, 50%) Step 2:
Sodium iodide (0.14 g, 0.925 mmol, 4.0 eq) was added to a solution of [328] (0.06 g, 0.22 mmol, 1.0 eq) in acetone (5 ml). The resulting reaction mixture was stirred at RT for 14 h. Reaction progress was monitored by TLC. Solvent was removed under vacuum to get a crude product. Then DCM was added to the crude product to precipitate out sodium iodide which was separated by filtration, and filtrate was evaporated under vacuum to get a yellow oil [329] iodomethyl 2-(4-isobutylphenyl) propanoate (0.07 g, 86%).
Step 3:
Iodomethyl 2-(4-isobutylphenyl) propanoate [329] (0.07 g, 0.23 mmol, 1.0 eq) and nicotinamide [322] (0.03 g, 0.22 mmol, 1.0 eq) were added in ACN (3 ml). The reaction mixture was stirred at RT for 16 h. Reaction progress was monitored by TLC. Solvent was removed under vacuum to get a crude product. The crude product obtained was triturated with diethyl ether (2 x 5 ml) to give the desired product
[330], 3-(dimethylcarbamoyl)-l-(((2-(4-isobutylphenyl)propanoyl)oxy)methyl)pyridin-l-ium iodide (0.045 g, 60%).
Scheme 47: Synthesis of modified forms of Diclofenac
Figure imgf000128_0001
Step 1:
Diclofenac sodium [331] (0.1 g, 0.33 mmol, 1.0 eq) DCM (2 ml), water (2 ml), sodium bicarbonate (0.105 g , 0.125 mmol, 3.81 eq) and tetrabutylammonium hydrogen sulfate (0.011 g , 0.033 mmol, 0.1 eq) were stirred at 25°C for 2 min. A solution of chloromethyl chlorosulfate [323] (0.06 g, 0.363 mmol, 1.1 eq) in DCM (1 ml) was added dropwise. This biphasic system was stirred at RT for 1 h. The organic layer was separated and dried over anhydrous Na2S04. Evaporation of the solvent under vacuum gave the product as a white solid, chloromethyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate [332] (0.11 g, 95%) m/z: 343
Step 2:
Sodium iodide (0.192 g, 1.28 mmol, 4.0 eq) was added to a solution of [332] (0.11 g, 0.32 mmol, 1.0 eq) in acetone (5 ml). The resulting reaction mixture was stirred at RT for 16 h. Reaction progress was monitored by TLC. Solvent was removed under vacuum to get a crude product. DCM was added to the crude product to precipitate out sodium iodide, which was separated by filtration, and the filtrate was evaporated to get a yellow oil [333] iodomethyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate (0.1 g, 71%) m/z: 436
Step 3:
Iodomethyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate [333] (0.1 g, 0.23 mmol, 1.0 eq) & dimethyl Nicotinamide (0.034 g , 0.23 mmol, 1.0 eq) were added in ACN (3 ml) .The reaction mixture was stirred at RT for 16 h. Reaction progress was monitored by TLC. Solvent was removed under vacuum to get a crude product. The crude product obtained was triturated with diethyl ether (2 x 5 ml) to get the desired product l-((2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)methyl)-3-(dimethylcarbamoyl)pyridin-l- ium iodide [334] (0.082 g, 61%) . m/z: 585 Scheme 48: Synthesis of modified forms of HPPH:
Figure imgf000130_0001
335 336 337
Step 1:
HPPH [335] (0.4 g, 0.62 mmol, 1.0 eq) DCM (5 ml), water (5 ml), sodium bicarbonate (0.17 g, 2.3 mmol, 3.81 eq) and tetrabutylammonium hydrogen sulfate (0.02 g, 0.05 mmol, 0.1 eq) were stirred at 25°C for 2min in dark. A solution of chloromethyl chlorosulfate [323] (0.11 ml, 0.69 mmol, 1.1 eq) in DCM (1 ml) was added dropwise. This biphasic system was stirred at RT in dark for 1 h. The organic phase was separated and dried over anhydrous Na2S04. Evaporation of the solvent under vacuum gave the desired product [336] as black solid (0.42 g, 80%)
Step 2:
[336] (0.05 g, 0.072 mmol, 1.0 eq) sodium iodide (0.038 g, 0.21 mmol, 3.0 eq) and nicotinamide [322] (0.011 g, 0.072 mmol, 1.0 eq) were added in ACN (3 ml). The reaction mixture was stirred at RT for 16 h in dark. Reaction progress was monitored by TLC. Solvent was removed under vacuum to get a crude product. The crude product obtained was triturated with diethyl ether (2 x 10 ml) to get the desired product [337], as black solid (0.044 g, 75%). Examples of chemical modifications of drugs/biologically active compounds with an amide as a functional group
Scheme 49: Synthesis of modified forms of linalidomide
Figure imgf000131_0001
Step 1:
K2C03 (0.105 g, 0.76 mmol, 2.0 eq) was added to a solution of 3-(4-amino-l-oxoisoindolin-2- yl)piperidine-2,6-dione [338] (0.2 g, 0.38 mmol, 1.0 eq) in Acetone (17 ml) under N2 atmosphere at room temperature and heated at 60°C for 30 min followed by the addition of methyl formyl reagent [259] (0.164 g, 0.48 mmol, 1.25 eq) and sodium lodide(0.29 g, 0.95 mmol, 2.5 eq). The resulting reaction mixture was refluxed at 60°C for 24 h. Reaction progress was monitored by TLC and mass spectroscopy. Then, the reaction mass was filtered through cellite bed and washed with acetone (2 x 25ml). The acetone layer was then evaporated to dryness under vacuum to yield a brown gel. The resultant crude product was purified on column chromatography (2% MeOH in DCM as eluent 100 - 200 mesh silica) to yield a white powder, (3-(4-amino-l-oxoisoindolin-2-yl)-2,6-dioxopiperidin-l-yl)methyl nicotinate [339] (0.032 g, 20%). m/z: 395
Step 2: lodomethyl isopropylcarbamate [6318] (0.018 g, 0.028 mmol, 1.0 eq) was added to a solution of (3-(4- amino-l-oxoisoindolin-2-yl)-2,6-dioxopiperidin-l-yl)methyl nicotinate [339] (0.03 g, 0.028 mmol, 1.0 eq) in DCM (5 ml). The reaction mixture was stirred at RT for 16 h. The DCM was evaporated under reduced pressure and washed thoroughly with diethyl ether to yield a yellow powder [340], 3-(((3-(4-amino-l- oxoisoindolin- -yO- ^G-dioxopiperidin-l-ylJmethoxyJcarbonyl)-!- (((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium iodide , (0.015 g, 40%). m/z: 510
Example of chemical modifications of drugs/biologically active compounds with aliphatic tertiary nitrogen as a heteroatom
Synthesis of modified forms of Imatinib
Scheme 50: Derivatization at an aliphatic tertiary amine with a Type I agent
Figure imgf000132_0001
Imatinib, N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-4-((4-methylpiperazin-l- yl)methyl)benzamide, [148] (0.100 g, 0.2 mmol,l eq) was dissolved in dichloromethane (10 ml) in a 25 ml two-necked round bottom flask, and iodomethyl pivalate [40] (0.049g, 0.2mmol, 1 eq) was added at RT. After stirring for 3 - 4 hours, the precipitate formed was filtered and washed with DCM to give the product, l-methyl-4-(4-((4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2- yl)amino)phenyl)carbamoyl)benzyl)-l-((pivaloyloxy)methyl)piperazin-l-ium iodide, [41] as a yellow solid. (0.040 g, 27%yield). m/z 608. H NMR (DMSO): δ 1.24 (s, 9 H), 2.20 (s, 3 H), 2.7 (m, 4 H), 3.10 (s, 3 H), 3.07 (s, 3 H), 3.48 (br s, 4 H), 3.71 (s, 2 H), 5.39 (s, 2 H), 7.19 (d, 1 H), 7.42 - 7.54 (m, 5 H), 7.9 (d, 2 H), 8.06 (d, 1 H), 8.45 - 8.52 (m, 2 H), 8.60 (dd, 1 H), 9.0 (s, 1 H), 9.27 (d, 1 H), 10.18 (s, 1 H). Scheme 51: Derivatization at both an aromatic nitrogen and an aliphatic tertiary amine, with a Type I derivatizing agent
Figure imgf000133_0001
Imatinib [148] (0.100 g, 0.2 mmol, 1 eq) was dissolved in DCM (10 ml) in a 25 ml two-necked round bottomed flask and iodomethyl pivalate [40] (0.185 g, 0.77 mmol, 3.8 eq) was added while stirring at RT. After 48h stirring, the precipitate formed was filtered under vacuum and washed with DCM to give the product, l-methyl-4-(4-((4-methyl-3-((4-(l- ((pivaloyloxy)methyl)pyridin-l-ium-3-yl)pyrimidin-2-yl)amino)phenyl)carbamoyl)benzyl)-l- ((pivaloyloxy)methy piperazin-l-ium diiodide [42], as a yellow solid. (0.050 g, 25% yield). m/z =361 H NMR (DMSO, 300 MHz): 6 1.10 (s, 9 H), 1.24 (s, 9 H), 2.24 (s, 3 H), 2.78 (m, 4 H), 3.11 (s, 3 H), 3.48 (br s, 4 H), 3.72 (s, 2 H), 5.40 (s, 2 H), 6.50 (s, 2 H), 7.21 - 7.24 (d, 1 H), 7.32 (d, 1 H), 7.44 (dd, 1 H), 7.58 (d, 1 H), 7.98 (d, 2 H), 8.20 (s, 1 H), 8.36 (dd, 1 H), 8.72 (d, 1 H), 9.23 (s, 1 H), 9.28 (d, 1 H), 9.36 (d, 1 H), 9.9 (s, 1 H), 10.25 (s, 1 H) Scheme 52: Modification of Docetaxol.
Figure imgf000134_0001
To a solution of docetaxel [500](0.06 g, 0.074 mmol, 1.0 eq) in DCM (5 ml) was added pyridine (0.1 ml) at RT. The reaction mixture was cooled to -23°C, followed by the addition of chloromethyl chloroformate (0.054 g, 0.42 mmol, 6.0 eq) and stirred for 30 min at -23°C. The reaction mixture was washed with dil. HQ, followed by brine, dried over anhydrous Na2S04 and solvent removed under vacuum to get the desired product [501].
The product was confirmed by H NMR.
To a solution of docetaxel [501](0.075 g, 0.093 mmol, 1.0 eq) in ACN (5 ml) was added Nal (0.055 g, 0.372 mmol, 4.0 eq) and Ν,Ν-dimethyl nicotinamide (0.023 g, 0.186 mmol, 2.0 eq) at RT. The reaction mixture was 60°C over night. Solvent was removed under vacuum, solid residue taken in DCM, inorganic impurities filtered off, DCM removed under vacuum and the product triturated with ether, filtered and vacuum dried to get the product [502].
Example demonstrating the effect of modification of the compounds:
The compounds as synthesized above are tested for their pK by the procedure as described above and their PK is provided at Table 7. TABLE 7: PK of Modified Drugs
Compound PK Value
Number Compound Name (AUC)* nm/h Dosage (mpk) Vehicle
4154 Aspirin 3839 30.00 PEG400
318 Aspirin Mod Drug 1112 30.00 PEG400
4114 Paclitaxel 186 10.00 PEG400
5% Tween 80, Ethanol:
311 Paclitaxel Mod Drug 1491 10.00 Normal Saline:: 1:30
9400 Paclitaxel Mod Drug 135 14.50 PEG400
40% PEG400, 10%
316 Paclitaxol Mod Drug 87 10.00 Ethanol, Distilled Water
40% PEG400, 10%
9405 Paclitaxol Mod Drug 519 10.00 Ethanol, Distilled Water
4102 Sildenafil 1451 10.00 Normal saline
295 Sildenafil Mod Drug 146 10.00 Normal saline
9500 Sildenafil Mod Drug 382 10.00 Normal saline
9505 Sildenafil Mod Drug 261 10.00 Normal saline
9510 Sildenafil Mod Drug 519 10.00 Normal saline
4150 SN-38 BDL 10.00 PEG400
306 SN-38 Mod Drug BDL 3.00 PEG400
305 SN-38 Mod Drug BDL 10.00 PEG400
148 Imatinib 9199 3.00 PEG400
41 Imatinib mod drug 5233 3.00 PEG400

Claims

We claim:
1. A method of modifying a chemical compound by causing covalent attachment of a modifying agent of the structure provided for compound 1, to a functional group or a heteroatom of a heterocyclic ring system in chemical compound to obtain a modified compound with improved chemical and biological properties;
Wherein in compound 1:
Figure imgf000136_0001
1
X is selected from CI, Br, I, OTs, OMs; Y is selected from R2, OR2, or N(R2)2 ; and
R and R1 are independently H, Ci-C8 straight or branched chain alkyl - optionally containing 1-3 heteroatoms selected from 0, N, S, SO, or S02; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from O, N, S, SO, or S02 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl;
R and R1 can also be joined to substituted methyl formyl to form a 3-7 membered carbocyclic ring optionally containing 1-2 heteroatoms selected from, O, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI;
R2 independently is H, Ci-C8 straight or branch chain alkyl - optionally containing 1-3 heteroatoms selected from O, N, S, SO, or S02; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from O, N, S, SO, or S02 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl; and
R2 is independently part of a 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from, O, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI.
2. A method according to claim 1, wherein Y=R2.
3. A method according to claim 2, wherein compound 1, is selected from the group comprising:
i. chloromethyl isopropyl carbonate;
ii. benzyl chloromethyl carbonate;
iii. chloromethyl morpholinomethyl carbonate;
iv. chloromethyl isobutyl carbonate;
v. chloromethylmethyl carbonate;
vi. (S)-sec-butyl chloromethyl carbonate;
vii. (R)-sec-butyl chloromethyl carbonate;
viii. chloromethyl ((3S,5R)-3,5-dimethylmorpholino)methyl carbonate;
ix. chloromethyl 2-methylcyclopropyl carbonate;
x. chloromethyl2-methoxyethyl carbonate;
xi. chloromethyl propyl carbonate;
xii. chloromethyl cyclobutyl carbonate;
xiii. chloromethyl cyclopropyl carbonate;
x'lv. chloromethyl 2,2-dimethylcyclobutyl carbonate;
xv. chloromethyl cyclopentyl carbonate;
xvi. chloromethyl oxetan-3-yl carbonate;
xvii. (S)-chloromethyl tetrahydrofuran-3-yl carbonate;
xviii. chloromethyl cyclohexylmethyl carbonate;
xix. chloromethyl 3-methoxycyclohexyl carbonate;
xx. (R)-chloromethyl tetrahydrofuran-3-yl carbonate;
xxi. chloromethyl ethoxymethyl carbonate;
xxii. chloromethyl oxepan-4-yl carbonate;
xxiii. (lR,2S,4S)-bicyclo[2.2.1]heptan-2-yl chloromethyl carbonate;
xxiv. chloromethyl 2,3-dihydro-lH-inden-l-yl carbonate;
XXV. benzyl chloromethyl carbonate;
xxvi. (S)-chloromethyl 1-phenylethyl carbonate; xxvii. chloromethyl cyclohexyl carbonate;
xxviii. chloromethyl isobutyl carbonate;
xxix. chloromethyl 4-methylcyclohexyl carbonate;
xxx. chloromethyl 2-(methylthio)ethyl carbonate;
xxxi. chloromethyl 3-methylcyclohexyl carbonate;
xxxii. chloromethylpentan-2-yl carbonate;
xxxiii. chloromethyl neopentyl carbonate;
xxxiv. methyl l-((chloromethoxy)carbonyloxy)cyclopropanecarboxylate;
xxxv. chloromethyl cyclopropylmethyl carbonate;
xxxvi. chloromethyl 2,2-diethoxyethyl carbonate;
xxxvii. chloromethyl cyclopentylmethyl carbonate;
xxxviii. methyl 2-((chloromethoxy)carbonyloxy)propanoate;
xxxix. (S)-chloromethyl 2,2,4-trimethylcyclopent-3-enyl carbonate;
xl. chloromethyl l,3-dioxolan-2-yl carbonate;
xli. chloromethyl (2,6-dimethylcyclohexyl)methyl carbonate;
xlii. chloromethyl 2-(tetrahydro-2H-pyran-2-yl)ethyl carbonate;
xliii. chloromethyl(tetrahydro-2H-pyran-4-yl)methyl carbonate;
xliv. chloromethyl tetrahydro-2H-pyran-4-yl carbonate;
xlv. chloromethyl 1-methylcyclopentyl carbonate;
xlvi. chloromethyl 1-cyclopentylethyl carbonate;
xlvii. chloromethyl 3-methylcyclopentyl carbonate;
xlviii. chloromethyl 3,3-dimethylcyclohexyl carbonate;
xlix. chloromethyl 2,5-dimethylcyclohexyl carbonate;
I. chloromethyl l-(4-methylcyclohexyl)ethyl carbonate;
li. chloromethyl (3-methyloxetan-3-yl)methyl carbonate;
lii. chloromethyl (3-methyloxetan-3-yl)methyl carbonate;
liii. chloromethyl 2-isopropoxyethyl carbonate;
liv. (chloromethyl carbonic) 5-((3aS,4S,6aR)-2-oxohexahydro-lH-thieno[3,4- d]imidazol-4-yl)pentanoic anhydride;
Iv. 4-((chloromethoxy)carbonyloxy)-2-hydroxy-4-oxobutanoic acid;
Ivi. chloromethyl 4-formyl-2-methoxyphenyl carbonate; I ii. chloromethyl 3-oxobutan-2-yl carbonate;
Iviii. methyl 4-((chloromethoxy)carbonyloxy)benzoate;
lix. (R)-2-amino-3-((chloromethoxy)carbonyloxy)propanoic acid;
Ix. 3-tert-butyl-4-methoxyphenyl chloromethyl carbonate;
Ixi. (R)-2-amino-3-(4-((chloromethoxy)carbonyloxy)phenyl)propanoic acid;
Ixii. (R)-2-amino-4-((chloromethoxy)carbonyloxy)-4-oxobutanoic acid;
Ixiii. . (E)-chloromethyl 3,7-dimethylocta-2,6-dienyl carbonate;
Ixiv. methyl 4-((chloromethoxy)carbonyloxy)benzoate;
Ixv. chloromethyl 2-(4-methylcyclohex-3-enyl)propan-2-yl carbonate;
Ixvi. chloromethyl 3,7-dimethylocta-l,6-dien-3-yl carbonate;
Ixvii. 4-allyl-2-methoxyphenyl chloromethyl carbonate;
Ixviii. chloromethyl (lR,2S,5R)-2-isopropyl-5-methylcyclohexyl carbonate;
Ixix. propyl 4-((chloromethoxy)carbonyloxy)benzoate; and
Ixx. (E)-chloromethyl 3,7-dimethylocta-2,6-dienyl carbonate.
4. A method according to claim 2, wherein compound 1, is is selected from the group comprising:
i. chloromethyl isobutyrate;
ii. chloromethyl 2,2-dimethylbutanoate;
iii. chloromethyl 3,3-dimethylbutanoate;
iv. chloromethyl 3-methylbutanoate;
v. chloromethyl 2-methoxyacetate;
vi. iodomethyl isobutyrate;
vii. chloromethyl 2-phenylacetate;
viii. chloromethyl nicotinate;
ix. iodomethyl pivalate;
x. 1-chloroethyl isobutyrate;
xi. 1-chloropropyl isobutyrate;
xii. chloromethyl acetate;
xiii. ((methylsulfonyl)oxy)methyl 3-methylbutanoate;
xiv. (tosyloxy)methyl 3-methylbutanoate; and xv. ((methylsulfonyl)oxy)methyl nicotinate.
5. A method according to claim 1, wherein Y=NR2. i.
6. A method according to claim 5, wherein compound 1 is selected from the group comprising:
chloromethyl cyclohexanecarboxylate;
ii. chloromethyl 2-cyclohexylacetate;
iii. chloromethyl 4-methylcyclohexanecarboxylate;
iv. chloromethyl 1-methylcyclohexanecarboxylate;
v. chloromethyl cyclopentanecarboxylate;
vi. chloromethyl l-(trifluoromethyl)cyclopentanecarboxylate;
vii. chloromethyl cyclobutanecarboxylate;
viii. chloromethyl 2-ethylhexanoate;
ix. chloromethyl 3-cyclopentylpropanoate;
x. chloromethyl cyclopropanecarboxylate;
xi. chloromethyl pentanoate;
xii. chloromethyl 2-methylpentanoate;
xiii. chloromethyl 3,5,5-trimethylhexanoate;
xiv. chloromethyl 2,2-dimethylbutanoate;
xv. chloromethyl 2-methylbutanoate;
xvi. chloromethyl hexanoate;
xvii. chloromethyl 2-ethylbutanoate;
xviii. chloromethyl butyrate;
xix. chloromethyl 3-phenylpropanoate;
xx. chloromethyl 2-phenylpropanoate;
xxi. (R)-chloromethyl 2-phenylpropanoate;
xxii. (S)-chloromethyl 2-phenylpropanoate;
xx iii. (lr,4r)-chloromethyl 4-methylcyclohexanecarboxylate;
xxiv. chloromethyl 4-methoxycyclohexanecarboxylate;
. XXV. chloromethyl 4,4-difluorocyclohexanecarboxylate; xxvi. chloromethyl 3-methoxycyclohexanecarboxylate; xxvii. (2R)-chloromethyl 2-methylcyclopentanecarboxylate; xxviii. (R)-chloromethyl 2-methylbutanoate;
xxix. (S)-chloromethyl 2-methylbutanoate;
XXX. (S)-chloromethyl 2-methoxy-2-phenylacetate;
xxxi. (S)-chloromethyl 2-phenylpropanoate;
xxxii. (S)-chloromethyl 2-phenylbutanoate;
xxxiii. (S)-chloromethyl 3-phenylbutanoate;
xxxiv. bis(chloromethyl) 2,2-dimethylmalonate;
XXXV. bis(chloromethyl) oxalate;
xxxvi. chloromethyl 2-cyclopropylacetate;
xxxvii. chloromethyl 2-cyclobutylacetate;
xxxviii. chloromethyl 2-cyclopentylacetate;
xxxix. chloromethyl 2-(tetrahydrofuran-3-yl)acetate;
xl. chloromethyl 2-(tetrahydro-2H-pyran-4-yl)acetate; xli. chloromethyl 2-methylcyclopropanecarboxylate; xlii. chloromethyl 2-(l-methylcyclobutyl)acetate;
xliii. chloromethyl 2-(l-methylcyclopropyl)'acetate;
xliv. chloromethyl propionate;
xlv. chloromethyl acetate;
xlvi. chloromethyl isobutyrate;
xlvii. chloromethyl 2-isopropyl-3-methylbutanoate;
xlviii. chloromethyl 3,5-dimethylcyclohexanecarboxylate; xlix. chloromethyl 2-propylpentanoate;
1. chloromethyl 4-methoxybenzoate;
li. chloromethyl 4-methylbenzoate;
lii. chloromethyl 3-methylbenzoate;
liii. chloromethyl 2,2,2-trifluoroacetate;
liv. chloromethyl 5,5-dimethyl-3-oxohexanoate;
Iv. bis(chloromethyl) cyclopropane-l,l-dicarboxylate; Ivi. chloromethyl 1,2-dihydrocyclobutabenzene-l-carboxylate;
Ivii. chloromethyl 2-cyclopentenylacetate;
Iviii. chloromethyl 2-phenylbutanoate;
lix. chloromethyl 2,2-difluoroacetate;
Ix. chloromethyl 4-fluorobenzoate;
Ixi. chloromethyl 3-cyclohexylpropanoate;
Ixii. chloromethyl 2-cyclohexylacetate;
Ixiii. chloromethyl 3-(tetrahydro-2H-pyran-4-yl)propanoate;
Ixiv. chloromethyl 2-(tetrahydro-2H-pyran-3-yl)acetate; and
Ixv. chloromethyl 3-(tetrahydro-2H-pyran-3-yl)propanoate.
7. A method according to claim 5, wherein compound 1 is selected from the group comprising:
i. chloromethyl benzylcarbamate;
i'i. chloromethyl isopropylcarbamate;
iii. chloromethyl diisopropylcarbamate;
iv. iodomethyl diisopropylcarbamate;
v. chloromethyl benzyl(methyl)carbamate;
vi. chloromethyl piperidine-l-carboxylate;
vii. (S)-chloromethyl (l-cyclohexylethyl)carbamate;
viii. (R)-chloromethyl (l-cyclohexylethyl)carbamate;
ix. chloromethyl (l-phenylethyl)carbamate;
x. (S)-chloromethyl (l-phenylethyl)carbamate;
xi. chloromethyl cyclohexylcarbamate;
xii. (S)-chloromethyl (3-methylbutan-2-yl)carbamate;
xiii. (S)-chloromethyl sec-butylcarbamate;
xiv. chloromethyl 2-methylpiperidine-l-carboxylate;
xv. . chloromethyl sec-butylcarbamate;
xvi. chloromethyl morpholine-4-carboxylate;
xvii. chloromethyl pyrrolidine- 1-carboxylate;
xviii. iodomethyl isopropylcarbamate; xix. chloromethyl dimethylcarbamate;
XX. iodomethyl dimethylcarbamate;
xxi. chloromethyl 4-methylpiperazine-l-carboxylate;
xxii. 1-chloroethyl diisopropylcarbamate;
xxiii. 1-chloroethyl isopropylcarbamate;
xxiv. 1-chloroethyl morpholine-4-carboxylate;
XXV. 1-chloroethyl piperidine-l-carboxylate;
xxvi. chloromethyl 4-methylpiperidine-l-carboxylate; and
xxvii. bromomethyl morpholine-4-carboxylate.
8. A method according to claim 1, wherein Y=OR2.
9. A method according to claim 8, wherein compound 1 is selected from the group comprising:
i. chloromethyl isopropylcarbamate;
ii. chloromethyl diisopropylcarbamate;
iii. chloromethyl dimethylcarbamate;
iv. chloromethyl isobutylcarbamate;
v. chloromethyl methylcarbamate;
vi. chloromethyl ethyl(isopropyl)carbamate;
vii. chloromethylisobutyl(methyl)carbamate;
viii. (S)-chloromethyl sec-butylcarbamate;
ix. chloromethyl methylcarbamate;
x. chloromethyl isopropyl(methyl)carbamate;
xi. chloromethyl propylcarbamate;
xii. chloromethyl 2-methoxyethylcarbamate;
xiii. chloromethyl methyl(propyl)carbamate;
xiv. chloromethyl diisobutylcarbamate;
xv. chloromethyl tert-butyl(isopropyl)carbamate;
xvi. chloromethyl di-sec-butylcarbamate;
xvii. chloromethyl aziridine-l-carboxylate; xviii. chloromethyl 2-methylcyclopropylcarbamate;
xix. chloromethyl cyclopropylcarbamate;
XX. chloromethyl cyclopropylmethyl(propyl)carbamate;
xxi. chloromethyl cyclopropyl(methyl)carbamate;
xxii. chloromethyl azetidine-l-carboxylate;
xxiii. chloromethyl cyclobutylcarbamate;
xxiv. chloromethyl 2,2-dimethylcyclobutylcarbamate;
XXV. chloromethyl 3-methoxyazetidine-l-carboxylate;
xxvi. chloromethyl cyclobutyl(methyl)carbamate;
xxvii. chloromethyl oxetan-3-ylcarbamate;
xxviii. (S)-chloromethyl 2-methylpyrrolidine-l-carboxylate;
xxix. chloromethyl cyclopentylcarbamate;
XXX. chloromethl cyclopentyl(methyl)carbamate;
xxxi. chloromethyl tetrahydrofuran-3-ylcarbamate;
xxxii. chloromethyl piperidine-l-carboxylate;
xxxiii. (2R,6S)-chloromethyl 2,6-dimethylpiperidine-l-carboxylate; xxxiv. (R)-chloromethyl 2-methylpiperidine-l-carboxylate;
xxxv. chloromethyl piperidine-l-carboxylate;
xxxvi. chloromethyl 3-methoxycyclohexylcarbamate;
xxxvii. chloromethyl cyclohexylmethylcarbamate;
xxxviii. chloromethyl cyclohexylmethyl(methyl)carbamate;
xxxix. chloromethyl morpholine-4-carboxylate;
xl. (3S,5R)-chloromethyl 3,5-dimethylmorpholine-4-carboxylate; xli. (3R,5S)-chloromethyl 3,5-dimethylmorpholine-4-carboxylate; xlii. (2S,6R)-chloromethyl 2,6-dimethylmorpholine-4-carboxylate; xliii. chloromethyl 4-methylpiperazine-l-carboxylate;
xliv. chloromethylazepane-l-carboxylate;
xlv. chloromethylcycloheptylcarbamate;
xlvi. chloromethyl oxepan-4-ylcarbamate;
xlvii. chloromethyl (lR,2S,4S)-bicyclo[2.2.1]heptan-2-ylcarbamate; xlviii. chloromethyl 2,3-dihydro-lH-inden-l-ylcarbamate; xlix. chloromethyl benzylcarbamate;
I. (S)-chloromethyl 1-phenylethylcarbamate;
li. ethyl 2-((chloromethoxyjcarbonylamino)-3-methylbutanoate;
lii. ethyl 2-((chloromethoxy)carbonylamino)-3-phenylpropanoate;
liii. (S)-diethyl 2-((chloromethoxy)carbonylamino)pentanedioate;
liv. ethyl((chloromethoxy)carbonylamino)propanoate;
Iv. ethyl 2-amino-6-((chloromethoxy)carbonylamino)hexanoate;
Ivi. ethyl 2-((chloromethoxy)carbonylamino)-4-methylpentanoate;
Ivii. ethyl 2-((chloromethoxy)carbonylamino)-3-methylpentanoate;
Iviii. (S)-dimethyl 2-((chloromethoxy)carbonylamino)succinate;
lix. (S)-ethyl 2-((chloromethoxy)carbonylamino)-5-guanidinopentanoate;
Ix. (S)-ethyl 4-amino-2-((chloromethoxy)carbonylamino)-4-oxobutanoate;
Ixi. (S)-ethyl 2-amino-5-((chloromethoxy)carbonylamino)pentanoate;
Ixii. (S)-ethyl 5-amino-2-((chloromethoxy)carbonylamino)-5-oxopentanoate;
Ixiii. ethyl 2-((chloromethoxy)carbonylamino)-4-(methylthio)butanoate;
Ixiv. 1-chloromethyl 3-methyl 2-methyl-5,6-dihydropyridine-l,3(2H)-dicarboxylate; Ixv. (S)-chloromethyl (l-methylpyrrolidin-2-yl)methyl carbonate;
Ixvi. (R)-chloromethyl (l-methyipyrrolidin-2-yl)methyl carbonate;
Ixvii. (S)-(l-benzylpyrrolidin-2-yl)methyl chloromethyl carbonate;
Ixviii. chloromethyl lH-pyrrole-l-carboxylate;
Ixix. chloromethyl 2-nicotinoylhydrazinecarboxylate;
Ixx. (6S)-3-chloro-7-((chloromethoxy)carbonylamino)-8-oxo-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
Ixxi. (6S)-7-((chloromethoxy)carbonylamino)-8-oxo-3-vinyl-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
Ixxii. (6S)-7-((chloromethoxy)carbonylamino)-3-(methoxymethyl)-8-oxo-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
Ixxiii. (6R,7R)-7-((chloromethoxy)carbonylamino)-3-methoxy-8-oxo-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;
Ixxiv. chloromethyl 3-(4-chlorophenyl)-lH-pyrazole-l-carboxylate;
Ixxy. chloromethyl 3-(4-fluorophenyl)-lH-pyrazole-l-carboxylate; Ixxvi. chloromethyl 3-phenyl-lH-pyrazole-l-carboxylate;
Ixxvii. chloromethyl 3-(4bromophenyl)-lH-pyrazole-l-carboxylate;
Ixxviii. chloromethyl 2-cyano-lH-pyrrole-l-carboxylate;
Ixxix. chloromethyl 4-oxopiperidine-l-carboxylate;
Ixxx. 1-chloromethyl 3-ethyl 2-oxopiperidine-l,3-dicarboxylate;
Ixxxi. chloromethyl 2,2,6,6-tetramethyl-4-oxopiperidine-l-carboxylate; and
Ixxxii. chloromethyl 2-oxopiperidine-l-carboxylate.
10. A method according to claim 8, wherein compound 1 is selected from the group comprising:
tert-butyl (chloromethyl) carbonate;
ii. chloromethyl ethyl carbonate;
iii. chloromethyl cyclohexyl carbonate;
iv. chloromethyl (1-methylcyclohexyl) carbonate;
v. chloromethyl cyclopentyl carbonate;
VI. chloromethyl tert-pentyl carbonate;
vii. chloromethyl (2,4-dimethylpentan-3-yl) carbonate;
viii. chloromethyl (cyclopropylmethyl) carbonate;
ix. chloromethyl (3-methylbutan-2-yl) carbonate;
X. (S)-sec-butyl (chloromethyl) carbonate;
xi. (R)-sec-butyl (chloromethyl) carbonate;
xii. chloromethyl cyclobutyl carbonate;
xiii. chloromethyl (l-methoxypropan-2-yl) carbonate;
xiv. sec-butyl (chloromethyl) carbonate;
XV. chloromethyl (l-methylcyclopentyl) carbonate;
xvi. chloromethyl isopropyl carbonate;
xvii. 1-chloroethyl isopropyl carbonate;
xviii. benzyl (iodomethyl) carbonate;
xix. (S)-iodomethyl (1-phenylethyl) carbonate; and
XX. (R)-iodomethyl (1-phenylethyl) carbonate.
11. A method according to claim 1, wherein the functional group is a primary, secondary or tertiary amine.
12. A method according to claim 1, wherein the functional group is a primary, secondary or tertiary alcohol.
13. A method according to claim 1, wherein the functional group is a carboxylic acid.
14. A method according to claim 1, wherein the heteroatom is nitrogen.
15. A method according to claim 1, wherein the chemical compound is any of Tadalafil, Sildenafil, Amprenavir, Fosamprenavir,Buproprion,Duloxetine,Finasteride,Latanoprost, Lopinavir, Raloxifene, Tropicamide, Geldanamycin, Metformin, Paclitaxel, Doxorubicin, Nelfinavir, Rapamycin, Piroxicam, Amlexanox, Rosoxacin, Etoricoxib, Sumatriptan, Vardenafil, Quinacrine, Atorvastatin, Valciclovir Hydrochloride, Atovaquone, Dihydroergotamine, Donepezil, Levofloxacin, Topotecan, Estradiol, Quetiapine, Olanzapine, Venlafaxine, Azelastine, Pioglitazone, Nevirapine, Rizatriptan, Escitalopram, Losartan, Saquinavir, Fluticasone/ salmeterol, Rosuvastatin,Budesonide/ Formoterol, Montelukast, Acetaminophen, Imatinib, Dimebon, SN-38, Curcumin, Hydroxy Fasudil, Fasudil, Aspirin, and/or Nicorandil.
16. A method according to claim 1, wherein the chemical compound is selected from Central Nervous System Drugs, such as CNS/Respiratory Stimulants, Analgesics, Narcotic Agonists, Narcotic agonist/antagonists, Nonsteroidal Anti- inflammatory/Analgesic Agents, Behavior-Modifying Agents, Tranquilizers/Sedatives, Anesthetic Agents, Inhalants, Narcotics, Reversal Agents, Anticonvulsants, Muscle Relaxants, Skeletal, Muscle Relaxants, Smooth, Euthanasia Agent, Cardiovascular Agents, Inotropic Agents, Antiarrhythmic Drugs, Anticholinergics, Vasodilating Agents, Agents Used in Treatment of Shock, Alpha-Adrenergic Blocking Agents, Beta-Adrenergic Blocking Agents, Respiratory Drugs, Bronchodilators, Sympathomimetics, Antihistamines, Antitussives, Renal and Urinary Tract, Agents for Urinary Incontinence/Retention, Urinary Alkalinizers, Urinary Acidifiers, Cholinergic Stimulants, Agents for Urolithiasis, Gastrointestinal Agents, Antiemetic Agents, Antacids, H2 Antagonists, Gastromucosal Protectants, Proton Pump Inhibitors, Appetite Stimulants, Gl Antispasmodics-Anticholinergics, Gl Stimulants,
Laxatives, Saline, Bulk producing, Lubricant, Surfactant, Antidiarrheals, Hormones/Endocrine/Reproductive Agents, Sex Hormones, Anabolic steroids, Posterior Pituitary Hormones, Adrenal Cortical Steroids, Glucocorticoids, Antidiabetic Agents, Thyroid Drugs, Thyroid Hormones, Misc. Endocrine/Reproductive Drugs, Prostaglandins, Antiinfective Drugs, Antiparasitics, Anticoccidial Agents, Antibiotics, - Anti-tuberculosis, Aminocyclitols,Cephalosporins, Macrolides, Penicillins, Tetracyclines, Lincosamides, Quinolones, Sulfonamides, Miscellaneous Antibacterials, Antifungal Agents, Antiviral Agents, Blood Modifying Agents, Clotting Agents, Anticoagulants, Erythropoietic Agents,Antineoplastics/lmmunosuppresives, Alkylating Agents, Antidotes, Bone/Joint Agents, Dermatologic Agents (Systemic), Vitamins and Minerals/Nutrients, Systemic Acidifiers, Systemic Alkalinizers, anticancer agents, and anti-viral agents.
17. A method according to claim 1, wherein the chemical compound after modification may be altered and converted to a salt, solvate, a stereoisomer.
18. A method according to claim 1, wherein the chemical compound after modification is present as its counter ion.
19. A method according to claim 1, wherein the chemical compound to be modified is a deuterated compound.
20. A method as claimed in claim 1, wherein one or more of the chemical and biological properties altered includes the pharmacokinetic and/or pharmacodynamic properties of the modified chemical compound in comparison to those of the original chemical compound.
21. The modified chemical compound prepared by the method of claim 1.
22. The reagent for modification of chemical compound by using compound 1
23. The compound of claim 21, wherein the compound is:
i. 3-(dimethylcarbamoyl)-l-((((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)carbamoyl)oxy)methyl)pyridin-l-ium;
ii. 3-(((3-(4-amino-l-oxoisoindolin-2-yl)-2,6-dioxopiperidin-l-yl)methoxy)carbonyl)- l-(((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium;
iii. l-(acetoxymethyl)-4-((4-ethoxy-3-(l-methyl-7-oxo-3-propyl-4,7-dihydro-lH- pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)-l-methylpiperazin-l-ium;
iv. (2Ri3S)-l-(((2aR/4S/4aS;6R,9S,llS,12S,12aR,12bS)-12b-acetoxy-12-(benzOyloxy)- 4,6,ll-trihydroxy-4a,8,13,13-tetramethyl-5-oxo-
2a/3A4a,5,6,9,10,ll,12,12ay12b-dodecahydro-lH-7/ll- methanocyclodeca[3,4]benzo[l,2-b]oxet-9-yl)oxy)-3-((tert- butoxycarbonyl)amino)-l-oxo-3-phenylpropan-2-yl nicotinate;
v. (3-(4-amino-l-oxoisoindoNn-2-yl)-2,6-dioxopiperidin-l-yl)methyl nicotinate vi. 4-((4-ethoxy-3-(l-methyl-7-oxo-3-propyl-4,7-dihydro-lH-pyrazolo[4,3- d]pyrimidin-5-yl)phenyl)sulfonyl)-l-(((isopropylcarbamoyl)oxy)methyl)-l- methylpiperazin-l-ium;
vii. 3-((((lS/2R)-l-benzamido-3-(((2aR,4S,4aS 6R;9S,llS,12S,12aR,12bS)-6i12b- diacetoxy-12-(benzoyloxy)-4,ll-dihydroxy-4a,8,13,13-tetramethyl-5-oxo- 2a/3,4/4a,5,6,9,10,H,12,12a,12b-dodecahydro-lH-7,ll- methanocyclodeca[3,4]benzo[l,2-b]oxet-9-yl)oxy)-3-oxo-l-phenylpropan-2- yl)oxy)carbonyl)-l-(((isopropoxycarbonyl)oxy)methyl)pyridin-l-ium; viii. 4-((4-ethoxy-3-(l-methyl-7-oxo-3-propyl-4,7-dihydro-lH-pyrazolo[4,3- d]pyrimidin-5-yl)phenyl)sulfonyl)-l-(((isopropoxycarbonyl)oxy)methyl)-l- methylpiperazin-l-ium;
ix. 4-((4-ethoxy-3-(l-methyl-7-oxo-3-propyl-4(7-dihydro-lH-pyrazolo[4,3- d]pyrimidin-5-yl)phenyl)sulfonyl)-l-((isobutyryloxy)methyl)-l-methylpiperazin-l- ium;
x. 3-(2-((5-benzamido-2-methylphenyl)amino)pyrimidin-4-yl)-l- ((isobutyryloxy)methyl)pyridin-l-ium;
xi. l-((((((lS,2R)-l-benzamido-3-(((2aR/4S,4aS/6R;9S llS,12S,12aR,12bS)-6,12b- diacetoxy-12-(benzoyloxy)-4,ll-dihydroxy-4a,8/13,13-tetramethyl-5-oxo- 2a,3/4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,H- methanocyclodeca[3,4]benzo[l,2-b]oxet-9-yl)oxy)-3-oxo-l-phenylpropan-2- yl)oxy)carbonyl)oxy)methyl)-3-(dimethylcarbamoyl)pyridin-l-ium;
xii. 3-(2-((5-benzamido-2-methylphenyl)amino)pyrimidin-4-yl)-l-(((piperidine-l- carbonyl)oxy)methyl)pyridin-l-ium;
xiii. 2-amino-l-(((diisopropylcarbamoyl)oxy)methyl)-5-(4-(4- (dimethylcarbamoyl)phenoxy)-6-morpholino-1 ,5-triazin-2-yl)pyridin-l-ium; xiv. 3-(2-((5-benzamido-2-methylphenyl)amino)pyrimidin-4-yl)-l-(((pyrrolidine-l- carbonyl)oxy)methyl)pyridin-l-ium;
xv. 3-carbamoyl-l-((2-{l-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3- yl)acetoxy)methyl)pyridin-l-ium;
xvi. 3-(2-((5-benzamido-2-methylphenyl)amino)pyrimidin-4-yl)-l- (((diisopropylcarbamoyl)oxy)methyl)pyridin-l-ium;
xvii. (2-(l-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH-indolr3-yl)acetoxy)methyl nicotinate;
xviii. 3-(((2-acetoxybenzoyl)oxy)methyl)-lH-imidazol-3-ium;
xix. l-(((2-acetoxybenzoyl)oxy)methyl)-l-methyl-lH-imidazol-l-ium;
xx. l-(((2-acetoxybenzoyl)oxy)methyl)-3-(methylcarbamoyl)pyridin-l-ium;
xxi. ((2-acetoxybenzoyl)oxy)methyl nicotinate;
xxii. l-(((2-acetoxybenzoyl)oxy)methyl)-3-carbamoylpyridin-l-ium;
xxiii. Compound No. 337;
Figure imgf000151_0001
xxiv. l-((((((lS,2R)-l-benzamido-3-(((2aR,4S,4aS76R,9S,llS,12S;12aR,12bS)-6,12b- diacetoxy-12-(benzoyloxy)-4-((((3-(dimethylcarbamoyl)pyridin-l-ium-l- yl)methoxy)carbonyl)oxy)-ll-hydroxy-4a,8,13/13-tetramethyl-5-oxo-
2a,3(4,4a,5,6y9,10,ll,12,12a(12b-dodecahydro-lH-7,ll- methanocyclodeca[3,4]benzo[l,2-b]oxet-9-yl)oxy)-3-oxo-l-phenylpropan-2- yl)oxy)carbonyl)oxy)methyl)-3-(dimethylcarbamoyl)pyridin-l-ium;
xxv. (R)-l-(((sec-butoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin- 1-ium;
xxvi. (S)-l-(((sec-butoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin- 1-ium;
xxvii. (R)-l-((((l-cyclohexylethyl)carbamoyl)oxy)methyl)-3-((2- (nitrooxy)ethyl)carbamoyl)pyridin-l-ium;
xxviii. (S)-l-((((l-cyclohexylethyl)carbamoyl)oxy)methyl)-3-((2- (nitrooxy)ethyl)carbamoyl)pyridin-l-ium;
xxix. l-(((isopropylcarbamoyl)oxy)methyl)-l-methyl-4-(2-methyl-10H- benzo[b]thieno[2,3-e][l,4]diazepin-4-yl)piperazin-l-ium;
xxx. l-(((2-acetoxybenzoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l- ium;
xxxi. 3-(2-hydroxy-2,2-diphenylacetoxy)-l-(((isopropylcarbamoyl)oxy)methyl)-l- methylpiperidin-l-ium;
xxxii. l-((2-(l-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3-yl)acetoxy)methyl)-3- (dimethylcarbamoyl)pyridin-l-ium;
xxxiii. 3-(dimethylcarbamoyl)-l-(((2-(4-isobutylphenyl)propanoyl)oxy)methyl)pyridin-l- ium; xxxiv. l-(((2-(4-isobutylphenyl)propanoyl)oxy)methyl)-2-(methoxycarbonyl)-l- methylpyrrolidin-l-ium;
xxxv. 2-(((diisopropylcarbamoyl)oxy)methyl)-2,8-dimethyl-5-(2-(6-methylpyridin-3- yl)ethyl)-2;3,4,4a,5,9b-hexahydro-lH-pyrido[4,3-b]indol-2-ium;
xxxvi. 5-chloro-l'-(((isopropylcarbamoyl)oxy)methyl)-6'-methyl-3-(4- (methylsulfonyl)phenyl)-[2,3'-bipyridin]-l'-ium;
xxxvii. (S)-4-(9-fluoro-6r(methoxycarbonyl)-3-methyl-7-oxo-3,7-dihydro-2H- [l,4]oxazino[2,3,4-ij]quinolin-10-yl)-l-(((isopropylcarbamoyl)oxy)methyl)-l- methylpiperazin-l-ium;
xxxviii. 3-((((lS,2S)-l-benzamido-3-(((2aR,4S,4aS,6 ,9S/llS,12S,12aR,12bS)-6,12b- diacetoxy-l2-(benzoyloxy)-4,ll-dihydroxy-4a/8,13,13-tetramethyl-5-oxo-
2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7;ll- methanocyclodeca[3,4]benzo[l,2-b]oxet-9-yl)oxy)-3-oxo-l-phenylpropan-2- yl)oxy)carbonyl)-l-(((diisopropylcarbamoyl)oxy)methyl)pyridin-l-ium; xxxix. 5-chloro-6'-methyl-3-(4-(methylsulfonyl)phenyl)-l,-((pivaloyloxy)methyl)-[2,3'- bipyridin]- -ium;
xl. l-((2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)methyl)-3-
(dimethylcarbamoyl)pyridin-l-ium;
xli. 3-((((2-acetoxybenzoyl)oxy)methoxy)carbonyl)-l-((pivaloyloxy)methyl)pyridin-l- ium;
xlii. l-(((2-acetoxybenzoyl)oxy)methyl)-3-(dimethylcarbamoyl)pyridin-l-ium;
xliii. l-((((4-acetamidophenoxy)carbonyl)oxy)methyl)-3-(dimethylcarbamoyl)pyridin- 1-ium;
xliv. 3-((4-acetamidophenoxy)carbonyl)-l-((isobutyryloxy)methyl)pyridin-l-ium; xlv. 3-(dimethylcarbamoyl)-l-((((4-((lE,3Z,6E)-3-hydroxy-7-(4-hydroxy-3- methoxyphenyl)-5-oxohepta-l,3,6-trien-l-yl)-2- methoxyphenoxy)carbonyl)oxy)methyl)pyridin-l-ium;
xlvi. 3-((4-acetamidophenoxy)carbonyl)-l-
(((diisopropylcarbamoyl)oxy)methyl)pyridin-l-ium;
xlvii. (S)-l-(((isopropylcarbamoyl)oxy)rtiethyl)-3-((((2-(6-methoxynaphthalen-2- yl)propanoyl)oxy)methoxy)carbonyl)pyridin-l-ium; xlviii. (E)-3-(dimethylcarbamoyl)-l-((((2-methoxy-4-((8-methylnon-6- enamido)methyl)phenoxy)carbonyl)oxy)methyl)pyridin-l-ium;
xlix. 3-((((lS;2R)-l-benzamido-3-(((2aR,4S,4aS,6R,9S,llS,12S(12aR,12bS)-6,12b- diacetoxy-12-(benzoyloxy)-4,ll-dihydroxy-4a,8,13 13-tetramethyl-5-oxo-
2a;3,4,4a,5,6,9,10,ll,12/12a,12b-dodecahydro-lH-7,ll- methanocyclodeca[3,4]benzo[l,2-b]oxet-9-yl)oxy)-3-oxo-l-phenylpropan-2- yl)oxy)carbonyl)-l-(((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium;
I. (2aR,4S,4aS,6R,9S,llS,12S/12aR;12bS)-9-(((2R,3S)-3-benzamido-2-
(nicotinoyloxy)-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-4,ll-dihydroxy-
4a,8,13,13-tetramethyl-5-oxo-2a,3A4a,5,6,9,10,ll,12,12a,12b-dodecahydro- lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxete-6,12b-diyl diacetate;
li. (E)-l-(((isopropylcarbamoyl)oxy)methyl)-3-((2-methoxy-4-((8-methylnon-6- enamido)methyl)phenoxy)carbonyl)pyridin-l-ium;
lii. 3,3'-(((((lE,3Z,6E)-3-hydroxy-5-oxohepta-l,3,6-triene-l;7-diyl)bis(2-methoxy-4,l- phenylene))bis(oxy))bis(carbonyl))bis(l-
(((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium);
liii. (S)-3-((((4,ll-diethyl-4-hydroxy-3,14-dioxo-3A12,14-tetrahydro-lH- pyrano[3',4':6 7]indolizino[l,2-b]quinolin-9-yl)oxy)methoxy)carbonyl)-l-
(((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium;
liv. (S)-((4,ll-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-lH- pyrano[3\4':6,7]indolizino[l,2-b]quinolin-9-yl)oxy)methyl nicotinate;
Iv. l-(((morpholine-4-carbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-
1-ium;
Ivi. 3-((2-(nitrooxy)ethyl)carbamoyl)-l-(((pyrrolidine-l-carbonyl)oxy)methyl)pyridin- 1-ium;
Ivii. ((6,7-bis(2-methoxyethoxy)quinazolin-4-yl)(3-ethynylphenyl)amino)methyl
diisopropylcarbamate;
Iviii. 2-(((diisopropylcarbamoyl)oxy)methyl)-5-(2-(l-
(((diisopropylcarbamoyl)oxy)methyl)-6-methylpyridin-l-ium-3-yl)ethyl)-2,8- dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-2-ium; lix. 3-(2-((5-benzamido-2-methylphenyl)amino)pyrimidin-4-yl)-l-
(((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium;
Ix. l-(((tert-butoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l- ium;
Ixi. 3-((((2-acetoxybenzoyl)oxy)methoxy)carbonyl)-l-
(((dimethylcarbamoyl)oxy)methyl)pyridin-l-ium;
Ixii. l-(((isopropylcarbamoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l- ium;
Ixiii. l-(((dimethylcarbamoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l- ium;
Ixiv. l-(((isopropoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l- ium;
Ixv. 3-(2-((5-benzamido-2-methylphenyl)amino)pyrimidin-4-yl)-l-
((pivaloyloxy)methyl)pyridin-l-ium;
Ixvi. l-(((ethoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l-iurn; Ixvii. 3-((2-(nitrooxy)ethyl)carbamoyl)-l-(((piperidine-l-carbonyl)oxy)methyl)pyridin-
1-ium;
Ixviii. l-(((diisopropylcarbamoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin- 1-ium;
Ixix. l-((isobutyryloxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l-ium;
Ixx. l-methyl-4-(4-((4-methyl-3-((4-(l-((pivaloyloxy)methyl)pyridin-l-ium-3- yl)pyrimidin-2-yl)amino)phenyl)carbamoyl)benzyl)-l-
((pivaloyloxy)methyl)piperazin-l-ium;
Ixxi. l-(((3-methylbutanoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-l- ium;
Ixxii. 2-methyl-l-((9-methyl-4-oxo-2,3,4;9-tetrahydro-lH-carbazol-3-yl)methyl)-3-
((pivaloyloxy)methyl)-lH-imidazpl-3-ium;
Ixxiii. l-(((3,3-dimethylbutanoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-
1-ium;
Ixxiv. l-methyl-4-(4-((4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2- yl)amino)phenyl)carbamoyl)benzyl)-l-((pivaloyloxy)methyl)piperaz'm-l-ium; Ixxv. 3-((2-(nitrooxy)ethyl)carbamoyl)-l-((pivaloyloxy)methyl)pyridin-l-ium; and Ixxvi. Compound 502.
Figure imgf000155_0001
24. A modified compound as claimed in claim 1, and their intermediates wherein the compound is: i. 2-(((diisopropylcarbamoyl)oxy)methyl)-2,8-dimethyl-5-(2-(6- methylpyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-2-ium iodide;
ii. 2-(((diisopropylcarbamoyl)oxy)methyl)-5-(2-(l- (((diisopropylcarbamoyl)oxy)methyl)-6-methylpyridin-l-ium-3-yl)ethyl)-
2,8-dimethyl-2,3A5-tetrahydro-lH-pyrido[4,3-b]indol-2-ium diiodide ; iii. l-(((isopropylcarbamoyl)oxy)methyl)-l-methyl-4-(2-methyl-10H- benzo[b]thieno[2,3-e][l,4]diazepin-4-yl)piperazin-l-ium iodide ;
iv. l-(acetoxymethyl)-4-((4-ethoxy-3-(l-methyl-7-oxo-3-propyl-4,7-dihydro- lH-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)sulfonyl)-l-methylpiperazin-l- ium iodide ;
v. 4-acetamidophenyl nicot'inate ;
vi. 3-((4-acetamidophenoxy)carbonyl)-l- (((diisopropylcarbamoyl)oxy)methyl)pyridin-l-ium iodide; vii. 4-acetamidophenyl 2-bromoacetate ; viii. l-(2-(4-acetamidophenoxy)-2-oxoethyl)-3-(dimethylcarbamoyl)pyridin-l- ium iodide;
ix. 4-acetamidophenyl (chloromethyl) carbonate ;
x. 4-acetamidophenyl (iodomethyl) carbonate ;
xi. l-((((4-acetamidophenoxy)carbonyl)oxy)methyl)-3- (dimethylcarbamoyl)pyridin-l-ium iodide;
xii. (S)-((4,H-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-lH- pyrano[3^4^6,7]indolizino[l,2-b]quinolin-9-yl)oxy)methyl nicotinate; xiii. (S)-3-((((4,ll-diethyl-4-hydroxy-3,14-dioxo-3,4 12,14-tetrahydro-lH- pyrano[3',4':6,7]indolizino[l,2-b]quinolin-9-yl)oxy)methoxy)carbonyl)-l- (((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium iodide;
xiv. 4-((lE,4Z,6E)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-3-oxohepta- l,4,6-trien-l-yl)-2-methoxyphenyl nicotinate;
xv. ((lE,3Z,6E)-3-hydroxy-5-oxohepta-l,3,6-triene-l 7-diyl)bis(2-methoxy- 4,1-phenylene) dinicotinate;
xvi. 3,3'-(((((lE,3Z,6E)-3-hydroxy-5-oxohepta-l,3,6-triene-l,7-diyl)bis(2- methoxy-4,l-phenylene))bis(oxy))bis(carbonyl))bis(l- (((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium) diiodide;
xvii. (2aR,4S,4aS,6R,9S,llS/12Si12aR,12bS)-9-(((2R 3S)-3-benzamido-2- (nicotinoyloxy)-3-phenylpropanoyl)oxy)-12-(benzoyloxy)-4,ll-dihydroxy- 4a;8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12/12a,12b- dodecahydro-lH-7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxete-6,12b- diyl diacetate;
xviii. 3-((((lS,2R)-l-benzamido-3-(((2aR,4S;4aS,6R,9S/llS,12S,12aR,12bS)- 6,12b-diacetoxy-12-(benzoyloxy)-4 ll-dihydroxy-4a,8,13,13-tetramethyl- 5-oxo-2a,3,4,4a,5,6,9,10,ll,12 12a,12b-dodecahydro-lH-7(ll- methanocyclodeca[3,4]benzo[l,2-b]oxet-9-yl)oxy)-3-oxo-l- phenylpropan-2-yl)oxy)carbonyl)-l- (((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium iodide;
xix. (2aR,4S,4aS,6R 9S,llS,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2- (((chloromethoxy)carbonyl)oxy)-3-phenylpropanoyl)oxy)-12- (benzoyloxy)-4-(((chloromethoxy)carbonyl)oxy)-ll-hydroxy-4a, 8,13,13- tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH- 7,ll-methanocyclodeca[3,4]benzo[l,2-b]oxete-6,12b-diyl diacetate; xx. (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2- (((iodomethoxy)carbonyl)oxy)-3-phenylpropanoyl)oxy)-12-(benzoyloxy)- ll-hydroxy-4-(((iodomethoxy)carbonyl)oxy)-4a,8,13,13-tetramethyl-5- oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll- methanocyclodeca[3,4]benzo[l,2-b]oxete-6,12b-diyl diacetate;
xxi. mono(l-((((((lS,2R)-l-benzamido-3- (((2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-6,12b-diacetoxy-12- (benzoyloxy)-4-((((3-(dimethylcarbamoyl)pyridin-l-ium-l- yl)methoxy)carbonyl)oxy)-ll-hydroxy-4a,8,13,13-tetramethyl-5-oxo- 2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll- methanocyclodeca[3,4]benzo[l,2-b]oxet-9-yl)oxy)-3-oxo-l- phenylpropan-2-yl)oxy)carbonyl)oxy)methyl)-3- (dimethylcarbamoyl)pyridin-l-ium) doiodide;
xxii. (2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)-9-(((2R,3S)-3-benzamido-2- (((chloromethoxy)carbonyl)oxy)-3-phenylpropanoyl)oxy)-12- (benzoyloxy)-4,ll-dihydroxy-4a,8,13,13-tetramethyl-5-oxo- 2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll- methanocyclodeca[3,4]benzo[l,2-b]oxete-6,12b-diyl diacetate ;
xxiii. l-((((((lS,2R)-l-benzamido-3-(((2aR,4S,4aS,6R,9S,llS,12S,12aR,12bS)- 6,12b-diacetoxy-12-(benzoyloxy)-4,ll-dihydroxy-4a,8,13,13-tetramethyl- 5-oxo-2a,3,4,4a,5,6,9,10,ll,12,12a,12b-dodecahydro-lH-7,ll- methanocyclodeca[3,4]benzo[l,2-b]oxet-9-yl)oxy)-3-oxo-l- phenylpropan-2-yl)oxy)carbonyl)oxy)methyl)-3-
(dimethylcarbamoyl)pyridin-l-ium iodide iodomethyl 2-(4- isobutylphenyl) propanoate ;
xxiv. ((2-acetoxybenzoyl)oxy)methyl nicotinate;
xxv. 3-((((2-acetoxybenzoyl)oxy)methoxy)carbonyl)-l- (((dimethylcarbamoyl)oxy)methyl)pyridin-l-ium iodide ; xxvi. Chloromethyl 2-acetoxybenzoate;
xxvii. l-(((2-acetoxybenzoyl)oxy)-3-carboylpyridin-l-ium iodide ;
xxviii. Chloromethyl 2-(-l-(4-chlorobenzoyl)-5methoxy-2-methyl-lH-indol-3yl) acetate;
xxix. 3-carbamoyl-l-((2-(-l-(4-chlorobenzoyl)-5methbxy-2-methyl-lH-indol- 3yl)acetoxy)methyl)pyridine-l-ium iodide ;
xxx. chloromethyl 2-(4-isobutylphenyl)propanoate;
xxxi. iodomethyl 2-(4-isobutylphenyl) propanoate;
xxxii. 3-(dimethylcarbamoyl)-l-(((2-(4- isobutylphenyl)propanoyl)oxy)methyl)pyridin-l-ium iodide ;
xxxiii. chloromethyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate;
xxxiv. iodomethyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate;
xxxv. l-((2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)methyl)-3- (dimethylcarbamoyl)pyridin-l-ium iodide;
xxxvi. Com ound [337];
Figure imgf000158_0001
xxxvii. (3-(4-amino-l-oxoisoindolin-2-yl)-2,6-dioxopiperidin-l-yl)methyl
nicotinate;
xxxviii. 3-(((3-(4-amino-l-oxoisoindolin-2-yl)-2,6-dioxopiperidin-l- yl)methoxy)carbonyl)-l-(((isopropylcarbamoyl)oxy)methyl)pyridin-l-ium iodide;
xxxix. l-methyl-4-(4-((4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2- yl)amino)phenyl)carbamoyl)benzyl)-l-((pivaloyloxy)methyl)piperazin-l- ium iodide;
xl. l-methyl-4-(4-((4-methyl-3-((4-(l-((pivaloyloxy)methyl)pyridin-l-ium-3- yl)pyrimidin-2-yl)amino)phenyl)carbamoyl)benzyl)-l- ((pivaloyloxy)methyl)piperazin-l-ium diiodide ; and Compound 502.
Figure imgf000159_0001
25. The compound of claim 21, wherein the modified chemical compound is present as its counter ion.
26. The compound of claim 24, wherein the counter ion is mesylate or iodide.
27. The use of a derivatizing agent of compound 1 to modify pharmaceutical agents and/ or biologically active substances to alter the physicochemical, biological and/ or pharmacokinetic properties of the resulting compound from the unmodified original pharmaceutical agent and/ or biologically active substance:
Where:
Figure imgf000159_0002
X is selected from CI, Br, I, OTs, OMs;
Y is selected from R2, OR2, or N(R2)2 ;
R and R1 can independently be H, Ci-C8 straight or branched chain alkyl - optionally containing 1-3 heteroatoms selected from O, N, S, SO, or S02; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from O, N, S, SO, or S02 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl;
R and R1 can also be joined to substituted methyl formyl to form a 3-7 membered carbocyclic ring optionally containing 1-2 heteroatoms selected from, O, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI;
R2 can independently be H, Ci-Cg straight or branch chain alkyl - optionally containing 1-3 heteroatoms selected from O, N, S, SO, or S02; 3-7 membered cycloalkyl optionally containing 1-3 heteroatoms selected from O, N, S, SO, or S02 and or lower alkyl, straight or branched alkyl, alkoxy; alkaryl, aryl, heteroaryl, or alkheteroaryl; and
R2 can also be part of a 3-7 membered ring optionally containing additional 1-2 heteroatoms selected from, O, N, S, SO, S02 and also be optionally substituted with alkoxy, F or CI.
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