US20210047269A1 - Trigonelline based compounds - Google Patents

Trigonelline based compounds Download PDF

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US20210047269A1
US20210047269A1 US17/001,005 US202017001005A US2021047269A1 US 20210047269 A1 US20210047269 A1 US 20210047269A1 US 202017001005 A US202017001005 A US 202017001005A US 2021047269 A1 US2021047269 A1 US 2021047269A1
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agents
compound
oxy
carbonyl
methylpyridin
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Sundeep Dugar
Dinesh Mahajan
Somdutta SEN
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Sphaera Pharma Pvt Ltd
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Sphaera Pharma Pvt Ltd
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Priority to US17/001,005 priority Critical patent/US20210047269A1/en
Assigned to SPHAERA PHARMA PVT. LTD. reassignment SPHAERA PHARMA PVT. LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DUGAR, SUNDEEP, MAHAJAN, Dinesh, SEN, Somdutta
Publication of US20210047269A1 publication Critical patent/US20210047269A1/en
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
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    • C07D471/00—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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol

Definitions

  • the present invention relates to novel compounds with improved solubility and altered pharmacokinetic properties and a method for altering the pharmacokinetic profile of a compound.
  • Molecular modifications of a drug substance are designed to enhance, amongst other aspects, the specificity for a particular target site, increasing its potency, improving its rate and extent of absorption, modifying the time span in which the drug becomes bio-available in the body while preserving the efficacy and toxicity value of the drug.
  • chemical modifications known which can enhance aqueous solubility of the drug substance independent of pH or which can alter the pharmacokinetic properties of drugs without affecting its efficacy and toxicity.
  • EP0110955 B1 discloses a compound of Formula [D-DHC] for the site specific/sustained delivery of a centrally acting drug species to the brain.
  • the compound on administration gets converted to quaternized salt inside the body where it is locked inside the brain only and the salt entering other parts of the body gets excreted readily from liver and kidney.
  • concentration of quaternary salt is higher in brain as compared to the other parts of the body.
  • An object of the invention is to provide novel compounds with better aqueous solubility independent of pH of the media and improved or altered pharmacokinetic profile by a chemical modification using trigonelline as derivatizing agent,
  • the present invention provides novel compounds with improved solubility and altered pharmacokinetic properties.
  • the compounds of the present invention may be represented by Formula I as below:
  • DX- is an active pharmaceutical ingredient (API) or a drug substance and; X is either O, or NR; or a functionalizable N which is a part of the API or drug substance.
  • Z is selected from Cl—, Br—, I—, mesylate, tosylate, tetrafluoroborate, or phosphate.
  • R is H, CH 3 , lower straight chain or branched chain alykyl; alternatively X can also be part of a 3-7 membered ring when there is a bond present between R and another atom on D.
  • the present invention also discloses a process of preparing the compounds of the present invention and use of the compounds of the present invention and the compound of formula I is not substrate for CYP450.
  • the present invention provides a novel compound with improved solubility and altered pharmacokinetic properties and a method for altering the pharmacokinetic profile of a compound.
  • DX- is an active pharmaceutical ingredient (API) or a drug substance and; X is either O, or NR, or a functionalizable N which is a part of the API or drug substance.
  • API active pharmaceutical ingredient
  • X is either O, or NR, or a functionalizable N which is a part of the API or drug substance.
  • Z is selected from Cl—, Br—, I—, mesylate, tosylate, tetrafluoroborate, or phosphate.
  • R is H, CH 3 , lower straight chain or branched chain alykyl, alternatively X can also be part of a 3-7 membered ring when there is a bond present between R and another atom on D.
  • the active pharmaceutical ingredient (API) or drug substance may be selected from the group of analgesic agents; anesthetic agents; antiarthritic agents; respiratory drugs, including antiasthmatic agents; anticancer agents, including antineoplastic agents; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihelminthics; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents such as antibiotics and antiviral agents; antiinflammatory agents; antimigraine preparations; antinauseants; antiparkinsonism drugs; antipruritics; antipyretics; antispasmodics; antitubercular agents; antiulcer agents; antiviral agents; anxiolytics; appetite suppressants; attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD) drugs; cardiovascular preparations including calcium channel blockers, CNS agents; beta-blockers and antiarrhythmic agents; alpha adrene
  • the active pharmaceutical ingredient (API) or drug substance may preferably be selected from the group of anticancer compounds such as paclitaxel, docetaxel and cabazitaxel; phosphodiestrase 5 inhibitors such as tadafil; vasodilators such as dopamine; narcotic antagonists; opiod modulators; nicotine; nictone/acetylcholine antagonists or agonists; most preferably the active pharmaceutical ingredient is an anticancer compound.
  • anticancer compounds such as paclitaxel, docetaxel and cabazitaxel
  • phosphodiestrase 5 inhibitors such as tadafil
  • vasodilators such as dopamine
  • narcotic antagonists such as narcotic antagonists
  • opiod modulators nicotine
  • nicotine nictone/acetylcholine antagonists or agonists
  • the active pharmaceutical ingredient is an anticancer compound.
  • the present invention discloses compounds of Formula II and Formula III;
  • the drug may be any active pharmaceutical compound or drug substance as mentioned above.
  • the compound of the Formula (II) may be obtained when the active pharmaceutical ingredient or the drug substance is attached to the compound of Formula (IV) through a functionalizable oxygen such as hydroxyl of the active pharmaceutical ingredient or the drug substance by using standard coupling methods for a hydroxyl and an acid.
  • the compound of the Formula (III) may be obtained when the active pharmaceutical ingredient or the drug substance is attached to the compound of Formula (IV) through a functionalizable nitrogen such as amino group of the active pharmaceutical ingredient or the drug substance by using standard coupling methods for a hydroxyl and an acid.
  • the present invention also includes various compounds that fall within the scope of the compound of formula (I).
  • a compound of formula I is not substrate for CYP450.
  • Table 1 shows an exemplary but a non-limiting list of currently existing active pharmaceutical agents or drug substances that can be modified using the methods described in this invention.
  • the compounds of the present invention include but are not limited to:
  • the present invention includes compound of Formula I, which may be represented by Formula V;
  • R 1 is selected from an cyclic or acyclic or branched alkyl, aryl such as methyl, propyl, isopropyl, n-butyl, t-butyl or aralkyl such as benzyl, hydrogen, tertbutoxycarbonylamino or N-phenylcarbamoyl;
  • R 2 is selected from hydrogen, hydroxyl, acyclic, cyclic or branched alkyl, aryl or an aralkyl group;
  • R 3 and R 4 are independently selected from the group of hydrogen, hydroxyl, lower alkyl, lower alkoxy, acetyl or benzyl.
  • the present invention also discloses process for preparing the compound of Formula (I).
  • the compound of Formula (I) may be prepared by the following general schemes described herein below:
  • the method of preparing the compound of Formula (I) may be based on the functional group of the active pharmaceutical ingredient or the drug substance.
  • active pharmaceutical ingredient or the drug substances containing hydroxyl as the functional group may be prepared following the synthetic Scheme 1 or 2 as set out herein below:
  • Y is selected from the group comprising OH, Cl, F, Br or any activated form of acid such as anhydride;
  • the drug may be any active pharmaceutical compound or drug substance as mentioned above.
  • the present invention also discloses a process for synthesis of compounds of Formula (I), wherein the functional group of the active ingredient is —NH—.
  • the compounds containing amino group as the functional group may be prepared the synthetic Scheme 3 or 4 as set out herein below:
  • Y is selected from the group comprising OH, Cl, F, Br or any activated form of acid such as anhydride;
  • the drug may be any active pharmaceutical compound or drug substance as mentioned above.
  • Y is selected from halides such as F, Cl or Br
  • the active pharmaceutical ingredient is dissolved in a solvent and is treated with nicotinic acid or activated form of nicotinic acid such as nicotinoyl chloride or corresponding anhydride in presence of a base and optionally with a catalyst and/or a dehydrating agent at a temperature in the range of 0 to 60° C.
  • the active pharmaceutical ingredient as utilized herein may be selected from paclitaxel, docetaxel, cabazitaxel, tadafil, curcumin.
  • the base may be selected from any base such as DIPEA (N,N-Diisopropylethylamine), triethylamine or pyridine or an inorganic base such NaH (sodium hydride) or carbonate salt of sodium or potassium.
  • the solvent may be selected from dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, dimethylformamide etc.
  • the dehydrating agent may be N,N′-Dicyclohexylcarbodiimide or EDCI etc with or without any co-catalyst such as dimethylaminopyridine.
  • alkyl halide such as MeI in stoichiometric or excess amount.
  • the reaction is then stirred at a temperature in the range of 0° C. to refluxing for a period until maximum consumption of starting material.
  • the solvent is removed under vacuum and the residue obtained is purified with solvent washing or crystallization to afford purified compound.
  • the solvent may be selected from acetonitrile, ether, n-pentane, tetrahydrofuran.
  • the process of the present invention may optionally comprise a co-catalyst such as tetrabutyl ammonium chloride, or other phase transfer catalyst, for example, quaternary ammonium salts, quaternary phosphonium salts, polyethylene glycols, crown ethers, alkyl sulfate salts, and alkyl sulfonates, can be exemplified amphoteric surfactants and the like, typically, tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide, tetrabutylammonium chloride, aliquots 336, hydrogen trioctylmethylammonium sulfate ammonium, 18-crown-6, tetrabutyl phosphonium chloride, sodium dodecylsulfate, although lauryl dimethylamino acetic acid betaine and the like, in addition, also be used as mixtures of two or more
  • M ⁇ is any counterion selected from iodide, chloride, bromide, mesylate, tosylate or tetra fluoroborate or any other pharmaceutically acceptable anion and the counterion is either one or more counterions to balance the charge.
  • the modified pharmaceutical compounds of the present invention have enhanced pharmacokinetic properties as compared to active pharmaceutical ingredient.
  • the modified drugs have more solubility in wide pH ranges.
  • the modified compounds of the present invention have a desirable safety and toxicity profile.
  • the modified compounds of the present invention dissociate into the pharmaceutical compound and a compound of Formula IV in the body.
  • Trigonelline N-methylnicotinate
  • Trigonella foenumgraecum which is also known as Fenugreek or Methi.
  • It is a zwitterion formed by the methylation of the nitrogen atom of niacin (vitamin B 3 ).
  • vitamin B 3 niacin
  • Trigonelline has a GRAS (Generally Recognized as Safe) status by the FDA. Since it is a naturally occurring metabolite found in the plants, it is believed that the body is better able to process the new molecule back into the active, parent drug.
  • GRAS Generally Recognized as Safe
  • the modified compounds of this invention are suitable for use as drugs and/or pharmaceutical agents with improved pharmacokinetic property, while maintaining a desirable safety and toxicity profile.
  • the invention also provides a method of alteration of pharmacokinetic profile of the compounds to render them more soluble in saline and/or at biologically useful pHs.
  • the novel compounds of the present invention may be used for pharmaceutical and neutraceutical purposes.
  • the compounds of the present invention are used to treat different types of cancers, including lymphoma and cancers of the head and neck, breast, esophagus, lungs, stomach, bladder, prostate, ovarian, melanoma and other types of solid tumors; Kaposi's sarcoma; in the treatment of inflammatory disorders such as skin disorders: acne vulgaris, pulmonary arterial hypertension, anxiety, Alzheimer's disease, apoptosis; erectile dysfunction; severe hypotension, bradycardia (slow heart rate), circulatory shock, or cardiac arrest.
  • inflammatory disorders such as skin disorders: acne vulgaris, pulmonary arterial hypertension, anxiety, Alzheimer's disease, apoptosis; erectile dysfunction; severe hypotension, bradycardia (slow heart rate), circulatory shock, or cardiac arrest.
  • Solvates of the compounds of Formula I and Formula VI 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, 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 counter anions are selected from halides, mesylates, tosylates, borates, carbonates, phosphates etc.
  • 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 not be suitable substrates or inhibitors of the cytochrome P450 enzymes, such as CYP3A4, enabling reduction in dose of the active pharmaceutical ingredient or the drug substance and increasing the safety and efficacy.
  • the compounds of the present invention may be administered orally, topically, intranasal, 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 reaction was worked-up by treating the reaction mass with 5% aqueous HCl 2 ⁇ 20 ml, followed by water 2 ⁇ 20 ml, drying over anhydrous Na 2 SO 4 and removing the solvent under vacuum to get the desired product. Yield: 89%.
  • the iodide counterion is converted to the mesylate ion by adding silver (I) methanesulfonate (1.0 eq) at RT.
  • the reaction mixture was stirred at RT for 2 h.
  • the reaction was filtered to remove silver iodide. Filtrate was concentrated under vacuum, which was triturated with dry ether (2 ⁇ 5 ml), ether removed by decantation and product dried under vacuum to get the desired product mesylate. This process yields the final product [1002], [1003], [1004] mesylate as the desired product mesylate.
  • Step 1 Synthesis of (6R,12aR)-6-(benzordin,31dioxol-5-yl)-2-methyl-7-nicotinoyl-hexahydropyrazinori′,2′:1,61pyridor3,4-blindole-1,4-dione
  • Step 2 Synthesis of 3-((6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-7-carbonyl)-1-methylpyridin-1-ium iodide
  • Step 1 Synthesis of ((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperidin-1-yl)(pyridin-3-yl)methanone
  • Step 2 Synthesis of 33-((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperidine-1-carbonyl)-1-methylpyridin-1-ium iodide
  • Solubility profile of the compounds of the present invention Fold increase Concentration in solubility used for for equiv. wt HPLC of DM using Compound RT Solubility analysis HPLC Mefloquine 6.92 Poor 1 mg/ml — solubility 1011 7.03 Completely 1 mg/ml 2.4 fold soluble increase Tadalafil 7.13 Very poor 2 mg/ml — solubility 1005 5.93 Completely 2 mg/ml 80 fold soluble increase
  • Trigonelline modified drug of Paclitaxel (1001) was evaluated for its aqueous solubility. Solubility was checked in different solvent systems. Only those solvents were selected which were found to solubilize the modified drug at the desirable concentrations and maintains the stability of the molecule. Modified drugs were found to be stable in the selected solvents.
  • Solubility of modified drug (1001) was evaluated in normal saline, 5% DMA in normal saline, 9% NMP in normal saline and 5% DMSO in normal saline.
  • Paclitaxel and compound (1001) presented in the present invention was taken in different solvent systems mentioned above, vortexed, centrifuged for 3 min., filtered and loaded on HPLC column (Zorbax Eclipse C18); Waters 2996 HPLC model). Area under the curve for each were determined and based on that fold increase in solubility was determined The results are presented herein below at Table 3.
  • Example 9 Comparative PK Profile of Paclitaxel Modified Drug (1001) with Parent Drug Paclitaxel
  • the modified compound (1001) of the present invention has more than 80 folds increase in the Cmax and more than 10 fold increase in the AUC. Hence, the compound (1001) of the present invention has increased pharmacokinetic and solubility over the API compounds.
  • Example 10 Pharmacokinetic Profile of the Compounds (1008) of the Present Invention (Docetaxel)
  • Docetaxel modified drug (1008) was found to have significantly higher exposure as compared to the parent drug as shown in table
  • modified drug of Docetaxel displayed better aqueous solubility.
  • 3 mpk IV dosing was done for the modified drug (1008) and 10 mpk IV for Docetaxel parent drug.
  • IV dosing of the modified drug blood was collected by serial bleeding at different time points in heparinized tubes. Blood samples were centrifuged at 10,000 rpm for 5 min. at 4° C. to obtain the plasma, which were aspirated into separate labeled tubes and stored at ⁇ 80° C. Extraction solvent was added to plasma, was vortexed and shaken on shaker for 10 minutes, centrifuged at 10,000 rpm for 10 minutes at 4° C. Supernatant was kept for analysis.

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Abstract

The present invention provides novel compounds with improved solubility and altered pharmacokinetic properties. The compounds of the present invention may be represented by Formula I as below:
Figure US20210047269A1-20210218-C00001

Description

    FIELD OF INVENTION
  • The present invention relates to novel compounds with improved solubility and altered pharmacokinetic properties and a method for altering the pharmacokinetic profile of a compound.
    • BACKGROUND OF THE INVENTION
  • Many compounds of pharmaceutical interest face challenges during the process of drug development because of their pharmacokinetic or pharmacodynamic properties and also due to their poor solubility.
  • Molecular modifications of a drug substance are designed to enhance, amongst other aspects, the specificity for a particular target site, increasing its potency, improving its rate and extent of absorption, modifying the time span in which the drug becomes bio-available in the body while preserving the efficacy and toxicity value of the drug. There are limited number of chemical modifications known which can enhance aqueous solubility of the drug substance independent of pH or which can alter the pharmacokinetic properties of drugs without affecting its efficacy and toxicity.
  • It is interesting to note that, attempts to improve solubility of pharmaceutical compounds such as taxanes based on molecular modification have not resulted in any successful clinical products. Certain prodrugs of Taxol have been prepared which are purported to undergo in vivo transformation into Taxol and some other product. For instance, PCT patent publication no. WO 1997044063 discloses certain prodrugs but appears that these compounds still do not have the desired pharmacokinetic properties. Pharmaceutical industry majorly depends on novel formulations or excipients to generate a desirable solubility profile for molecules of biological interest to develop them for clinical use.
  • Some alkaloids having a purine or pyrimidine base type structures have been known in the prior art for the molecular modification of drug species for site specific drug delivery. For instance, EP0110955 B1 discloses a compound of Formula [D-DHC] for the site specific/sustained delivery of a centrally acting drug species to the brain. The compound on administration gets converted to quaternized salt inside the body where it is locked inside the brain only and the salt entering other parts of the body gets excreted readily from liver and kidney. Thus, the concentration of quaternary salt is higher in brain as compared to the other parts of the body.
  • There is still a need to develop better prodrugs or modified compounds having improved solubility and/or pharmacokinetic properties for the effective drug delivery without loss of therapeutic efficacy and increase in toxicity of active molecule or drug.
    • OBJECT OF THE INVENTION
  • An object of the invention is to provide novel compounds with better aqueous solubility independent of pH of the media and improved or altered pharmacokinetic profile by a chemical modification using trigonelline as derivatizing agent,
    • SUMMARY OF THE INVENTION
  • The present invention provides novel compounds with improved solubility and altered pharmacokinetic properties. The compounds of the present invention may be represented by Formula I as below:
  • Figure US20210047269A1-20210218-C00002
  • wherein DX- is an active pharmaceutical ingredient (API) or a drug substance and;
    X is either O, or NR; or a functionalizable N which is a part of the API or drug substance. Z is selected from Cl—, Br—, I—, mesylate, tosylate, tetrafluoroborate, or phosphate.
  • R is H, CH3, lower straight chain or branched chain alykyl; alternatively X can also be part of a 3-7 membered ring when there is a bond present between R and another atom on D.
  • The present invention also discloses a process of preparing the compounds of the present invention and use of the compounds of the present invention and the compound of formula I is not substrate for CYP450.
    • DETAILED DESCRIPTION OF THE INVENTION
  • Accordingly, the present invention provides a novel compound with improved solubility and altered pharmacokinetic properties and a method for altering the pharmacokinetic profile of a compound.
  • Figure US20210047269A1-20210218-C00003
  • wherein DX- is an active pharmaceutical ingredient (API) or a drug substance and;
    X is either O, or NR, or a functionalizable N which is a part of the API or drug substance.
  • Z is selected from Cl—, Br—, I—, mesylate, tosylate, tetrafluoroborate, or phosphate.
  • R is H, CH3, lower straight chain or branched chain alykyl, alternatively X can also be part of a 3-7 membered ring when there is a bond present between R and another atom on D.
  • The active pharmaceutical ingredient (API) or drug substance may be selected from the group of analgesic agents; anesthetic agents; antiarthritic agents; respiratory drugs, including antiasthmatic agents; anticancer agents, including antineoplastic agents; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihelminthics; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents such as antibiotics and antiviral agents; antiinflammatory agents; antimigraine preparations; antinauseants; antiparkinsonism drugs; antipruritics; antipyretics; antispasmodics; antitubercular agents; antiulcer agents; antiviral agents; anxiolytics; appetite suppressants; attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD) drugs; cardiovascular preparations including calcium channel blockers, CNS agents; beta-blockers and antiarrhythmic agents; alpha adrenergic antagonists or agonists; cough and cold preparations, including decongestants; antitussives; diuretics; gastrointestinal (GI) motility agents; hormones; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; leukotriene inhibitors; mitotic inhibitors; phosphodiesterase inhibitors; muscle relaxants; narcotic antagonists; opiod modulators; nicotine; nictone/acetylcholine antagonists or agonists; psychostimulants; sedatives; steroids; tranquilizers; and vasodilators including general coronary, peripheral and cerebral.
  • The active pharmaceutical ingredient (API) or drug substance may preferably be selected from the group of anticancer compounds such as paclitaxel, docetaxel and cabazitaxel; phosphodiestrase 5 inhibitors such as tadafil; vasodilators such as dopamine; narcotic antagonists; opiod modulators; nicotine; nictone/acetylcholine antagonists or agonists; most preferably the active pharmaceutical ingredient is an anticancer compound.
  • The present invention discloses compounds of Formula II and Formula III;
  • Figure US20210047269A1-20210218-C00004
  • Wherein the drug may be any active pharmaceutical compound or drug substance as mentioned above.
  • The compound of the Formula (II) may be obtained when the active pharmaceutical ingredient or the drug substance is attached to the compound of Formula (IV) through a functionalizable oxygen such as hydroxyl of the active pharmaceutical ingredient or the drug substance by using standard coupling methods for a hydroxyl and an acid.
  • Figure US20210047269A1-20210218-C00005
  • The compound of the Formula (III) may be obtained when the active pharmaceutical ingredient or the drug substance is attached to the compound of Formula (IV) through a functionalizable nitrogen such as amino group of the active pharmaceutical ingredient or the drug substance by using standard coupling methods for a hydroxyl and an acid.
  • The present invention also includes various compounds that fall within the scope of the compound of formula (I). A compound of formula I is not substrate for CYP450.
  • The compounds of formula (I) are illustrated herein below at Table 1. Table 1, shows an exemplary but a non-limiting list of currently existing active pharmaceutical agents or drug substances that can be modified using the methods described in this invention.
  • TABLE 1
    Illustrative compounds of the present invention
    Compound
    no. Structure/Name IUPAC nomenclature
    1001
    Figure US20210047269A1-20210218-C00006
         		3-((((1R,2R)-1-benzamido- 3-(((2aR,4S,6R,9S,11S, 12S,12bS)-6,12b-diacetoxy- 12-(benzoyloxy)-4,11- dihydroxy-4a,8,13,13- tetramethyl-5-oxo-2a,3,4, 4a,5,6,9,10,11,12,12a,12b- dodecahydro-1H-7,11- methanocyclodeca[3,4]- benzo[1,2-b]oxet-9-yl)- oxy)-3-oxo-1-phenylpropan- 2-yl)oxy)carbonyl)-1- methylpyridin-1-ium iodide
    1002
    Figure US20210047269A1-20210218-C00007
         		3-((((1R,2R)-1-benzamido- 3-(((2aR,4S,6R,9S,11S, 12S,12bS)-6,12b-diacetoxy- 12-(benzoyloxy)-4,11- dihydroxy-4a,8,13,13- tetramethyl-5-oxo-2a,3,4, 4a,5,6,9,10,11,12,12a,12b- dodecahydro-1H-7,11- methanocyclodeca[3,4]- benzo[1,2-b]oxet-9-yl)- oxy)-3-oxo-1-phenyl- propan-2-yl)oxy)carbonyl)- 1-methylpyridin-1-ium Mesylate
    1003
    Figure US20210047269A1-20210218-C00008
         		3-((((1R,2R)-1-benzamido- 3-(((2aR,4S,6R,9S,11S, 12S,12bS)-6,12b-diacetoxy- 12-(benzoyloxy)-4,11- dihydroxy-4a,8,13,13- tetramethyl-5-oxo-2a,3,4, 4a,5,6,9,10,11,12,12a,12b- dodecahydro-1H-7,11- methanocyclodeca[3,4]- benzo[1,2-b]oxet-9-yl)- oxy)-3-oxo-1-phenyl- propan-2-yl)oxy)carbonyl)- 1-methylpyridin-1-ium Tetrafluoroborate
    1004
    Figure US20210047269A1-20210218-C00009
         		3-((((1R,2R)-1-benzamido- 3-(((2aR,4S,6R,9S,11S, 12S,12bS)-6,12b-diacetoxy- 12-(benzoyloxy)-4,11- dihydroxy-4a,8,13,13- tetramethyl-5-oxo-2a,3,4, 4a,5,6,9,10,11,12,12a,12b- dodecahydro-1H-7,11- methanocyclodeca[3,4]- benzo[1,2-b]oxet-9-yl)- oxy)-3-oxo-1-phenyl- propan-2-yl)oxy)carbonyl)- 1-methylpyridin-1-ium Tosylate
    1005
    Figure US20210047269A1-20210218-C00010
         		3-((6R,12aR)-6-(benzo[d]- [1,3]dioxol-5-yl)-2-methyl- 1,4-dioxo-1,2,3,4,6,7,12, 12a-octahydropyrazino- [1′,2′:1,6]pyrido[3,4-b]- indole-7-carbonyl)-1- methylpyridin-1-ium iodide;
    1006
    Figure US20210047269A1-20210218-C00011
         		3-((4-((1E,4Z,6E)-5- hydroxy-7-(4-hydroxy- 3-methoxyphenyl)-3- oxohepta-1,4,6-trien-1- yl)-2-methoxyphenoxy)- carbonyl)-1-methylpyridin- 1-ium iodide
    1007
    Figure US20210047269A1-20210218-C00012
         		3,3′-(((((1E,3Z,6E)-3- hydroxy-5-oxohepta- 1,3,6-triene-1,7-diyl)- bis(2-methoxy-4,1- phenylene))bis(oxy))- bis(carbonyl))bis(1- methylpyridin-1-ium) iodide
    1008
    Figure US20210047269A1-20210218-C00013
         		3-((((2R,3S)-1-(((2aR,4S, 4aS,6R,9S,11S,12S,12aR, 12bS)-12b-acetoxy-12- (benzoyloxy)-4,6,11- trihydroxy-4a,8,13,13- tetramethyl-5-oxo-2a,3,4, 4a,5,6,9,10,11,12,12a,12b- dodecahydro-1H-7,11- methanocyclodeca[3,4]- benzo[1,2-b]oxet-9-yl)- oxy)-3-((tert-butoxy- carbonyl)amino)-1-oxo- 3-phenylpropan-2-yl)oxy)- carbonyl)-1-methylpyridin- 1-ium iodide
    1009
    Figure US20210047269A1-20210218-C00014
         		3-((1-((2R,4R,5R)-3,3- difluoro-4-hydroxy-5- (hydroxymethyl)tetra- hydrofuran-2-yl)-2-oxo- 1,2-dihydropyrimidin-4- yl)carbamoyl)-1-methyl- pyridin-1-ium iodide
    1010
    Figure US20210047269A1-20210218-C00015
         		3-((((2R,3R,5R)-5-(4- amino-2-oxopyrimidin- 1(2H)-yl)-4,4-difluoro-2- (hydroxymethyl)tetra- hydrofuran-3-yl)oxy)- carbonyl)-1-methyl- pyridin-1-ium iodide
    1011
    Figure US20210047269A1-20210218-C00016
         		3-((R)-2-((S)-(2,8-bis- ((trifluoromethyl)quinolin- 4 yl)(hydroxy)methyl)- piperidine-1-carbonyl)-1- methylpyridin-1-ium
    1012
    Figure US20210047269A1-20210218-C00017
         		(R)-3-(((1-(4-((2-(5- chloro-2-fluorophenyl)- 5-isopropylpyrimidin- 4-yl)amino)nicotin- amido)propan-2-yl)oxy)- carbonyl)-1-methylpyrin- 1-ium
    1013
    Figure US20210047269A1-20210218-C00018
         		(S)-3-(((1-(4-((2-(5- chloro-2-fluorophenyl)- 5-isopropylpyrimidin-4- yl)amino)nicotinamido)- propan-2-yl)oxy)carbonyl)- 1-methylpyrin-1-ium iodide
  • The compounds of the present invention include but are not limited to:
    • i. 3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium iodide;
    • ii. 3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium Mesylate;
    • iii. 3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium Tetrafluoroborate;
    • iv. 3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium Tosylate;
    • v. 3-((6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-7-carbonyl)-1-methylpyridin-1-ium iodide;
    • vi. 3-((4-((1E,4Z,6E)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-3-oxohepta-1,4,6-trien-1-yl)-2-methoxyphenoxy)carbonyl)-1-methylpyridin-1-ium iodide;
    • vii. 3,3′-(((((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(2-methoxy-4,1-phenylene))bis(oxy))bis(carbonyl))bis(1-methylpyridin-1-ium) iodide;
    • viii. 3-((((2R,3S)-1-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-acetoxy-12-(benzoyloxy)-4,6,11-trihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl)oxy)-3-((tert-butoxycarbonyl)amino)-1-oxo-3-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium iodide;
    • ix. 3-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)-1-methylpyridin-1-ium iodide;
    • x. 3-((((2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)carbonyl)-1-methylpyridin-1-ium iodide.
    • xi. 3-((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4 yl)(hydroxy)methyl) piperidine-1-carbonyl)-1-methylpyridin-1-ium
    • xii. (R)-3-(((1-(4-((2-(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin-4-yl)amino)nicotinamido)propan-2-yl)oxy)carbonyl)-1-methylpyrin-1-ium;
    • xiii. (S)-3-(((1-(4-((2-(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin-4-yl)amino)nicotinamido)propan-2-yl)oxy)carbonyl)-1-methylpyrin-1-ium iodide
  • In an aspect, the present invention includes compound of Formula I, which may be represented by Formula V;
  • Figure US20210047269A1-20210218-C00019
  • wherein R1 is selected from an cyclic or acyclic or branched alkyl, aryl such as methyl, propyl, isopropyl, n-butyl, t-butyl or aralkyl such as benzyl, hydrogen, tertbutoxycarbonylamino or N-phenylcarbamoyl; R2 is selected from hydrogen, hydroxyl, acyclic, cyclic or branched alkyl, aryl or an aralkyl group; R3 and R4 are independently selected from the group of hydrogen, hydroxyl, lower alkyl, lower alkoxy, acetyl or benzyl.
  • The present invention also discloses process for preparing the compound of Formula (I). The compound of Formula (I) may be prepared by the following general schemes described herein below:
  • The method of preparing the compound of Formula (I) may be based on the functional group of the active pharmaceutical ingredient or the drug substance.
  • For instance for active pharmaceutical ingredient or the drug substances containing hydroxyl as the functional group may be prepared following the synthetic Scheme 1 or 2 as set out herein below:
    • General Synthetic Scheme of Modification of Drugs or Molecules of Biological Interests Having —OH as One of the Functional Group.
  • Figure US20210047269A1-20210218-C00020
  • Figure US20210047269A1-20210218-C00021
  • wherein Y is selected from the group comprising OH, Cl, F, Br or any activated form of acid such as anhydride;
  • Wherein the drug may be any active pharmaceutical compound or drug substance as mentioned above.
  • The present invention also discloses a process for synthesis of compounds of Formula (I), wherein the functional group of the active ingredient is —NH—.
  • For instance, the compounds containing amino group as the functional group may be prepared the synthetic Scheme 3 or 4 as set out herein below:
    • General Synthetic Scheme of Modification of Drugs or Molecules of Biological Interests Having —NH— as One of the Functional Group.
  • Figure US20210047269A1-20210218-C00022
  • Figure US20210047269A1-20210218-C00023
  • wherein Y is selected from the group comprising OH, Cl, F, Br or any activated form of acid such as anhydride;
  • Wherein the drug may be any active pharmaceutical compound or drug substance as mentioned above.
  • The Synthesis of compounds of Formula I may consist of the following steps;
    • Step 1
  • Figure US20210047269A1-20210218-C00024
  • wherein Y is selected from halides such as F, Cl or Br, and OH and X is selected from O, N, and, n=0 to 2 depending on the allowable valency of X. The active pharmaceutical ingredient is dissolved in a solvent and is treated with nicotinic acid or activated form of nicotinic acid such as nicotinoyl chloride or corresponding anhydride in presence of a base and optionally with a catalyst and/or a dehydrating agent at a temperature in the range of 0 to 60° C.
  • The active pharmaceutical ingredient as utilized herein may be selected from paclitaxel, docetaxel, cabazitaxel, tadafil, curcumin. The base may be selected from any base such as DIPEA (N,N-Diisopropylethylamine), triethylamine or pyridine or an inorganic base such NaH (sodium hydride) or carbonate salt of sodium or potassium. The solvent may be selected from dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, dimethylformamide etc. The dehydrating agent may be N,N′-Dicyclohexylcarbodiimide or EDCI etc with or without any co-catalyst such as dimethylaminopyridine.
    • Step 2: Synthesis of Compound of Formula I
  • Figure US20210047269A1-20210218-C00025
  • To the product of Step 1 in a suitable solvent is added alkyl halide such as MeI in stoichiometric or excess amount. The reaction is then stirred at a temperature in the range of 0° C. to refluxing for a period until maximum consumption of starting material. The solvent is removed under vacuum and the residue obtained is purified with solvent washing or crystallization to afford purified compound. The solvent may be selected from acetonitrile, ether, n-pentane, tetrahydrofuran.
  • In another embodiment, the process of the present invention may optionally comprise a co-catalyst such as tetrabutyl ammonium chloride, or other phase transfer catalyst, for example, quaternary ammonium salts, quaternary phosphonium salts, polyethylene glycols, crown ethers, alkyl sulfate salts, and alkyl sulfonates, can be exemplified amphoteric surfactants and the like, typically, tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide, tetrabutylammonium chloride, aliquots 336, hydrogen trioctylmethylammonium sulfate ammonium, 18-crown-6, tetrabutyl phosphonium chloride, sodium dodecylsulfate, although lauryl dimethylamino acetic acid betaine and the like, in addition, also be used as mixtures of two or more thereof.
    • Step 3
  • Optionally, reacting an active pharmaceutical ingredient (API) of formula D-XHn with 3,3′-(oxybis(carbony))bis(1-methylpyridin-1-ium)iodide to obtain compound (300);
  • Figure US20210047269A1-20210218-C00026
    • Step 4
  • Optionally, converting the iodine counter ion of compound (300) to another counter ion by adding a catalyst and appropriate counter ion to obtain the compound (400);
  • Figure US20210047269A1-20210218-C00027
  • Wherein M⊖ is any counterion selected from iodide, chloride, bromide, mesylate, tosylate or tetra fluoroborate or any other pharmaceutically acceptable anion and the counterion is either one or more counterions to balance the charge.
  • The modified pharmaceutical compounds of the present invention have enhanced pharmacokinetic properties as compared to active pharmaceutical ingredient. The modified drugs have more solubility in wide pH ranges. The modified compounds of the present invention have a desirable safety and toxicity profile. The modified compounds of the present invention dissociate into the pharmaceutical compound and a compound of Formula IV in the body.
  • Figure US20210047269A1-20210218-C00028
  • Attorney Ref. No. 15985-002US1
  • The compound of Formula IV is generically known as Trigonelline. Trigonelline (N-methylnicotinate) is a pyridine alkaloid with chemical formula C7H7NO2 mostly reported from family Fabaceae. It is generally found in the seeds of the plant, Trigonella foenumgraecum, which is also known as Fenugreek or Methi. It is a zwitterion formed by the methylation of the nitrogen atom of niacin (vitamin B3). It is a hypocholesterolemic agent and has nutritional benefits and glucose lowering activity.
  • Trigonelline has a GRAS (Generally Recognized as Safe) status by the FDA. Since it is a naturally occurring metabolite found in the plants, it is believed that the body is better able to process the new molecule back into the active, parent drug.
  • The modified compounds of this invention are suitable for use as drugs and/or pharmaceutical agents with improved pharmacokinetic property, while maintaining a desirable safety and toxicity profile. The invention also provides a method of alteration of pharmacokinetic profile of the compounds to render them more soluble in saline and/or at biologically useful pHs.
  • The novel compounds of the present invention may be used for pharmaceutical and neutraceutical purposes. The compounds of the present invention are used to treat different types of cancers, including lymphoma and cancers of the head and neck, breast, esophagus, lungs, stomach, bladder, prostate, ovarian, melanoma and other types of solid tumors; Kaposi's sarcoma; in the treatment of inflammatory disorders such as skin disorders: acne vulgaris, pulmonary arterial hypertension, anxiety, Alzheimer's disease, apoptosis; erectile dysfunction; severe hypotension, bradycardia (slow heart rate), circulatory shock, or cardiac arrest.
  • The present invention includes within its scope the salts, solvates and isomers. Solvates of the compounds of Formula I and Formula VI 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 active pharmaceutical ingredient or the drug substance, 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, 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 counter anions are selected from halides, mesylates, tosylates, borates, carbonates, phosphates etc.
  • 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.
  • Without being limited by theory, the compounds of the present invention may not be suitable substrates or inhibitors of the cytochrome P450 enzymes, such as CYP3A4, enabling reduction in dose of the active pharmaceutical ingredient or the drug substance and increasing the safety and efficacy.
  • For these purposes the compounds of the present invention may be administered orally, topically, intranasal, 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
  • The following examples are representative of the disclosure, and provide detailed methods for preparing the compounds of the disclosure, including the preparation of the intermediate compounds. The preparation of particular compounds of the embodiments is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other agents of the various embodiments. For example, the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions.
  • As used herein the symbols and conventions used in these process, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of American Chemical Society or the Journal of Biological Chemistry.
    • Example 1: Synthesis of 1001
  • Figure US20210047269A1-20210218-C00029
    • Synthesis of 2′-Nicotinate Ester of Paclitaxel Step-1
  • To a solution of Paclitaxel [1.0 g, 1.1709 mmol, 1.0 mol eq] in dry DCM 25 ml under nitrogen atmosphere, at 0° C. was added DIPEA [0.755 g, d=0.756, 5.8527 mmol, 5.0 eq] and the reaction stirred for 15 min at the same temperature. To the above reaction was added Nicotinoyl chloride hydrochloride salt [0.625 g, 3.0 eq] all at once, while maintaining the temperature 0° C. The reaction was stirred at 0° C. for another 30 min and at RT for 24h. The reaction was worked-up by treating the reaction mass with 5% aqueous HCl 2×20 ml, followed by water 2×20 ml, drying over anhydrous Na2SO4 and removing the solvent under vacuum to get the desired product. Yield: 89%.
  • MS: ink at 959 and 960,
    • Step-2 Synthesis of Trigonelline Ester
  • To a solution of 2′-Nicotinate ester of Paclitaxel [0.03 g, 0.03125 mmol] in dry ACN 5 ml at RT was added Methyl Iodide in large excess [0.5 ml]. The reaction was stirred at RT for 24h. ACN was removed under vacuum and the yellow residue is treated with 1:1 mixture of pentane/diethyl ether 5 ml and triturated to get free flowing yellow-brown crystals. This process yields the final product 1001 and yield is −60%.
    • Examples 2-4: Synthesis of 1002, 1003 and 1004 were Done Exploiting Procedure of Synthetic Scheme 1 Above
  • Figure US20210047269A1-20210218-C00030
  • MS: ink 974, 975 and 976
  • The iodide counterion is converted to the mesylate ion by adding silver (I) methanesulfonate (1.0 eq) at RT. The reaction mixture was stirred at RT for 2 h. The reaction was filtered to remove silver iodide. Filtrate was concentrated under vacuum, which was triturated with dry ether (2×5 ml), ether removed by decantation and product dried under vacuum to get the desired product mesylate. This process yields the final product [1002], [1003], [1004] mesylate as the desired product mesylate.
  • The above procedure is used to synthesize a derivative of curcumin compound (1006) and compound (1007), docetaxel (1008) and Gemcitabine (1009) and compound (1010) as below:
  • Figure US20210047269A1-20210218-C00031
    • Example 5: Synthesis of 3-((6R.12aR)-6-(benzordin.31dioxol-5-yl)-2-methyl-1.4-dioxo-1,2,3,4,6J,12.12a-octahydropyrazinori′,2′:1,61pyridor3,4-blindole-7-carbonyD-1-methylpyridin-1-ium iodide Compound (1005) Step 1: Synthesis of (6R,12aR)-6-(benzordin,31dioxol-5-yl)-2-methyl-7-nicotinoyl-hexahydropyrazinori′,2′:1,61pyridor3,4-blindole-1,4-dione
  • Figure US20210047269A1-20210218-C00032
  • To a solution of tadalafil [0.05 g, 0.128 mmol] in dry THF at 0° C. was added NaH [0.020 g, 0.257 mmol, 2.0 eq] and reaction stirred until turned to yellow; another portion of NaH [0.020 g, 0.257 mmol, 2.0 eq] was added followed by addition of nicotinoyl chloride hydrochloride [0.045, 0.257, 2.0 eq] at 0° C. The reaction was stirred for another 1h at 0° C. and then at 30° C. for 30 min, followed by addition of catalytic amounts of 18-crown-6. The reaction was heated to 55° C. (external) and reaction stirred for 36h. The reaction was poured in water and extracted with ethyl acetate 10 ml×2times, dried and ethyl acetate removed under vacuum to get yellow product. Yield 38 mg. m/z at 494.
    • Step 2: Synthesis of 3-((6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-7-carbonyl)-1-methylpyridin-1-ium iodide
  • Figure US20210047269A1-20210218-C00033
  • To a solution of 6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-7-nicotinoyl-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione [0.038 g] in dry ACN at 30° C. was added MeI [0.5 ml]. The reaction was stirred at the given temperature for 24h. ACN was removed under vacuum, 1:1 ether:n-pentane added and triturated to get a yellow precipitate, which was isolated by filtration under suction and drying. This process yields the final product 1005 and yield is 10 mg. m/z at 509.
    • Example 6: Synthesis of 33-((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperidine-1-carbonyl)-1-methylpyridin-1-ium iodide (1011) Step 1: Synthesis of ((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperidin-1-yl)(pyridin-3-yl)methanone
  • Figure US20210047269A1-20210218-C00034
  • To a solution of Mefloquine[0.150 g, 0.39 mmol, 1 eq] in DMF 2 ml was added EDC [0.090 g, 0.47 mmol, 1.2 eq] and HOBt [0.069 g, 0.51 mmol, 1.3 eq] then stirred at RT for 20 mins. Now NMM [0.1 ml, 0.79 mmol, 2 eq] and nicotinic acid [0.058 g, 0.47 mmol, 1.2 eq] then stirred at RT for 24 hr. Ice cold water was slowly added into the reaction mass, solid so formed was filtered and washed with cold water and dried over vacuum to obtain ((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperidin-1-yl)(pyridin-3-yl)methanone (Yield; 0.100 g, 67%). m/z at 484
    • Step 2: Synthesis of 33-((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperidine-1-carbonyl)-1-methylpyridin-1-ium iodide
  • Figure US20210047269A1-20210218-C00035
  • To a solution of ((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperidin-1-yl)(pyridin-3-yl)methanone [0.050g] was added MeI [0.1 ml]. The reaction was stirred at the given temperature for 24h. Reaction mass was evaporated under vacuum, 1:1 ether:n-pentane added and triturated to get a brown solid 33-((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperidine-1-carbonyl)-1-methylpyridin-1-ium iodide, This process yields the final product 1011 and yield is 0.035 g, 70%). m/z at 498.
    • Example 7: Evaluation of Solubility Profile of the Compounds of the Present Invention
  • 1 mg/ml and 2 mg/ml solution of Mefloquine and Tadanafil respectively and equivalent weight of respective trigonelline modified compound (1011), compound (1005) of the present invention was taken in miliQ water, vortexed, centrifuged for 3 min., filtered and loaded on HPLC column (Zorbax Eclipse C18; Mobile Phase: A: 0.1% TFA, B: ACN; run time 15 min, Waters 2996 HPLC model). Area under the curve for each was determined and based on that fold increase in solubility was determined. The results are presented herein below at Table 2.
  • TABLE 2
    Solubility profile of the compounds of the present invention
    Fold increase
    Concentration in solubility
    used for for equiv. wt
    HPLC of DM using
    Compound RT Solubility analysis HPLC
    Mefloquine 6.92 Poor 1 mg/ml —
    solubility
    1011 7.03 Completely 1 mg/ml 2.4 fold
    soluble increase
    Tadalafil 7.13 Very poor 2 mg/ml —
    solubility
    1005 5.93 Completely 2 mg/ml 80 fold
    soluble increase
  • As shown above in table 2, both modified compound (1011) and compound (1005) of the present invention showed significant increase in aqueous solubility over their parent drugs.
    • Example 8: Solubility of Paclitaxel Modified Drug
  • Trigonelline modified drug of Paclitaxel (1001) was evaluated for its aqueous solubility. Solubility was checked in different solvent systems. Only those solvents were selected which were found to solubilize the modified drug at the desirable concentrations and maintains the stability of the molecule. Modified drugs were found to be stable in the selected solvents.
  • Solubility of modified drug (1001) was evaluated in normal saline, 5% DMA in normal saline, 9% NMP in normal saline and 5% DMSO in normal saline.
  • Paclitaxel and compound (1001) presented in the present invention was taken in different solvent systems mentioned above, vortexed, centrifuged for 3 min., filtered and loaded on HPLC column (Zorbax Eclipse C18); Waters 2996 HPLC model). Area under the curve for each were determined and based on that fold increase in solubility was determined The results are presented herein below at Table 3.
  • TABLE 3
    Solubility results of Paclitaxel and compound 1001
    Solvent
    5% DMA 9% NMP 5% DMSO
    Normal in normal in Normal in Normal
    Compound saline saline Saline saline
    Paclitaxel 0.1 ug/ml Not soluble Not soluble Not soluble
    1001 >500 ug/ml ~1 mg/ml >1.5 mg/ml >1.2 mg/ml
      • Fold increase in solubility:
        • >5000× in Normal Saline
        • >10,000× in Normal Saline with 5% Dimethylacetamide
        • >12,000× in Normal Saline with 5% Dimethylsulfoxide
        • 15,000× in Normal Saline with 9% N-Methylpyrrolidone
  • From Table 3 above, it can be seen that the compound (1001) of the present invention demonstrate increased solubility.
    • Example 9: Comparative PK Profile of Paclitaxel Modified Drug (1001) with Parent Drug Paclitaxel
  • Pharmacokinetics studies were carried out to evaluate the plasma exposure of modified drug of Paclitaxel in SD rats when dosed intravenously (IV). The results were compared with exposure of Paclitaxel using the same dosing vehicle. The dosing vehicle that was used in this study was PEG400 and Normal saline in fixed composition. The compound of the present invention (1001) was found to be stable and soluble in the given solvent. As reported in solubility data, (1001) displayed better aqueous solubility. This resulted in easier IV dosing in case of modified drugs. 3 mpk and 1 mpk IV dosing was done for the modified drug and 3 mpk IV for Paclitaxel parent drug. After IV dosing of the modified drug blood was collected by serial bleeding at different time points in heparinized tubes. Blood samples were centrifuged at 10,000 rpm for 5 min. at 4° C. to obtain the plasma, which were aspirated into separate labeled tubes and stored at −80° C. Extraction solvent was added to plasma, was vortexed and shaken on shaker for 10 minutes, centrifuged at 10,000 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 spectrometer (API3000 LC-MS/MS). Cmax, Tmax, AUC and t½ were calculated using Graph Pad PRISM version 5.04 and the results are depicted in Table 4
  • TABLE 4
    Pharmacokinetic profile of the compounds
    of the present invention (Paclitaxel)
    Dose
    (mg/ Kg, T1/2 Cmax AUC
    Formulation Compound iv) (hr) (nM) (nM*hr)
    PEG/Normal Paclitaxel 3  2.5 104 67
    Saline 1001 3* 0.6 8620 874
    1001 1* 1.2 2384 301
    *3 mpk 1001 = 2.1 mpk Paclitaxel delivered
    *1 mpk 1001 = 0.71 mpk Paclitaxel delivered
  • It can be seen from Table 4 that the modified compound (1001) of the present invention has more than 80 folds increase in the Cmax and more than 10 fold increase in the AUC. Hence, the compound (1001) of the present invention has increased pharmacokinetic and solubility over the API compounds.
    • Example 10: Pharmacokinetic Profile of the Compounds (1008) of the Present Invention (Docetaxel)
  • Pharmacokinetics studies were carried out to evaluate the plasma exposure of modified drug of Docetaxel (1008) in SD rats when dosed intravenously (IV). The results were compared with exposure of Docetaxel (10 mpk) using the same dosing vehicle. The dosing vehicle that was used in this study was PEG400 and Normal saline in fixed composition. Modified drug of Docetaxel was found to be stable and soluble in the given solvent.
  • Docetaxel modified drug (1008) was found to have significantly higher exposure as compared to the parent drug as shown in table
  • As reported in solubility data, modified drug of Docetaxel (1008) displayed better aqueous solubility. 3 mpk IV dosing was done for the modified drug (1008) and 10 mpk IV for Docetaxel parent drug. After IV dosing of the modified drug blood was collected by serial bleeding at different time points in heparinized tubes. Blood samples were centrifuged at 10,000 rpm for 5 min. at 4° C. to obtain the plasma, which were aspirated into separate labeled tubes and stored at −80° C. Extraction solvent was added to plasma, was vortexed and shaken on shaker for 10 minutes, centrifuged at 10,000 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 spectrometer (API3000 LC-MS/MS). Cmax, Tmax, AUC and t½ were calculated using Graph Pad PRISM version 5.04 and the results are depicted in Table 5
  • TABLE 5
    Pharmacokinetic profile of the compound
    (1008) of the present invention
    Docetaxel
    Parameters 10 mpk IV 1008
    Cmax(nM) 494.96 6924.21
    Tmax(hr) 0.08 0.08
    AUC(nM*hr) 897.47 1035.34
    T1/2 elimination (hr) 2.06 1.78
  • From table 5 above, it can be seen that the compound (1008) of the present invention has enhanced pharmacokinetics than the original compound.

Claims (11)

1. A compound according to formula I with improved solubility and altered pharmacokinetic properties
Figure US20210047269A1-20210218-C00036
wherein DX- is an active pharmaceutical ingredient (API) or a drug substance and;
X is either O, or NR;
Z is selected from Cl—, Br—, I—, mesylate, tosylate, tetrafluoroborate, carbonate or phosphate.
R is H, CH3, lower straight chain or branched chain alkyl, alternatively X can also be part of a 3-7 membered ring when there is a bond present between R and another atom on D.
2. The compound of claim 1, wherein the active pharmaceutical ingredient (API) is selected from the group comprising analgesic agents; anesthetic agents; antiarthritic agents; respiratory drugs, including antiasthmatic agents; anticancer agents, including antineoplastic agents; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihelminthics; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents such as antibiotics and antiviral agents; antiinflammatory agents; antimigraine preparations; antinauseants; antiparkinsonism drugs; antipruritics; antipyretics; antispasmodics; antitubercular agents; antiulcer agents; antiviral agents; anxiolytics; appetite suppressants; attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD) drugs; cardiovascular preparations including calcium channel blockers, CNS agents; beta-blockers and antiarrhythmic agents; alpha adrenergic antagonists or agonists; cough and cold preparations, including decongestants; antitussives; diuretics; gastrointestinal (GI) motility agents; hormones; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; leukotriene inhibitors; mitotic inhibitors; phosphodiesterase inhibitors; muscle relaxants; narcotic antagonists; opiod modulators; nicotine; nictone/acetylcholine antagonists or agonists; psychostimulants; sedatives; steroids; tranquilizers; and vasodilators including general coronary, peripheral and cerebral, preferably selected from the group of anticancer compounds such as paclitaxel, docetaxel and cabazitaxel; phosphodiestrase 5 inhibitors such as tadafil; vasodilators such as dopamine; narcotic antagonists; opiod modulators; nicotine; nictone/acetylcholine antagonists or agonists; most preferably the active pharmaceutical ingredient is an anticancer compound.
3. The compound of claim 1, having Formula (II) and Formula (III)
Figure US20210047269A1-20210218-C00037
4. The compound of claim 1, wherein the compound is
i. 3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium iodide;
ii. 3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium Mesylate;
iii. 3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium Tetrafluoroborate;
iv. 3-((((1R,2R)-1-benzamido-3-(((2aR,4S,6R,9S,11S,12S,12bS)-6,12b-diacetoxy-12-(benzoyloxy)-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl)oxy)-3-oxo-1-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium Tosylate;
v. 3-((6R,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-7-carbonyl)-1-methylpyridin-1-ium iodide;
vi. 3-((4-((1E,4Z,6E)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-3-oxohepta-1,4,6-trien-1-yl)-2-methoxyphenoxy)carbonyl)-1-methylpyridin-1-ium iodide;
vii. 3,3′-(((((1E,3Z,6E)-3-hydroxy-5-oxohepta-1,3,6-triene-1,7-diyl)bis(2-methoxy-4,1-phenylene))bis(oxy))bis(carbonyl))bis(1-methylpyridin-1-ium) iodide;
viii. 3-((((2R,3S)-1-(((2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-acetoxy-12-(benzoyloxy)-4,6,11-trihydroxy-4a,8,13,13-tetramethyl-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benzo[1,2-b]oxet-9-yl)oxy)-3-((tert-butoxycarbonyl)amino)-1-oxo-3-phenylpropan-2-yl)oxy)carbonyl)-1-methylpyridin-1-ium iodide;
ix. 3-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)-1-methylpyridin-1-ium iodide;
x. 3-((((2R,3R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4,4-difluoro-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)carbonyl)-1-methylpyridin-1-ium iodide.
xi. 3-((R)-2-((S)-(2,8-bis(trifluoromethyl)quinolin-4-yl)(hydroxy)methyl)piperidine-1-carbonyl)-1-methylpyridin-1-ium;
xii. (R)-3-(((1-(4-((2-(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin-4-yl)amino)nicotinamido)propan-2-yl)oxy)carbonyl)-1-methylpyrin-1-ium;
xiii. (S)-3-(((1-(4-((2-(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin-4-yl)amino)nicotinamido)propan-2-yl)oxy)carbonyl)-1-methylpyrin-1-ium iodide
5. The compound of claim 1, having Formula V;
Figure US20210047269A1-20210218-C00038
wherein R1 is selected from an cyclic or acyclic or branched alkyl, aryl such as methyl, propyl, isopropyl, n-butyl, t-butyl or aralkyl such as benzyl, hydrogen, tertbutoxycarbonylamino or N-phenylcarbamoyl;
R2 is selected from hydrogen, hydroxyl, acyclic, cyclic or branched alkyl, aryl or an aralkyl group;
R3 and R4 are independently selected from the group of hydrogen, hydroxyl, lower alkyl, lower alkoxy, acetyl or benzyl.
6. A process for the preparation of compound of formula (I) and intermediates, salts thereof as claimed in claim 1 comprising the steps of:
i) reacting an active pharmaceutical ingredient (API) of formula D-XHn with nictotine acid derivative of (100) in the presence of a base and optionally with a catalyst and/or a dehydrating agent to obtain the compound of (200)
Figure US20210047269A1-20210218-C00039
wherein Y is selected from halides such as F, Cl or Br, and OH and X is selected from O, N, S or P; and, n=0 to 3 depending on the valency of X
ii) reacting (200) with alkyl halide and optionally with a catalyst as counter ion to obtain compound of (300)
Figure US20210047269A1-20210218-C00040
iii) Optionally, reacting an active pharmaceutical ingredient (API) of formula D-XHn with 3,3′-(oxybis(carbony))bis(1-methylpyridin-1-ium)iodide to obtain compound (300);
Figure US20210047269A1-20210218-C00041
iv) Optionally, converting the iodine counter ion of compound (300) to another counter ion by adding a catalyst and appropriate counter ion to obtain the compound (400);
Figure US20210047269A1-20210218-C00042
Wherein M⊖ is any counter ion selected from iodide, chloride, bromide, mesylate, tosylate or tetra fluoroborate or any other pharmaceutically acceptable anion and the counterion is either one or more counter ions to balance the charge.
7. The process as claimed in claim 6, wherein the base used in step (I) is selected from the group comprising DIPEA (N, N-Diisopropylethylamine), triethylamine or pyridine, inorganic base such NaH (sodium hydride) or carbonate salt of sodium or potassium and the solvent used in step (I) is selected from the group comprising DCM (dichloromethane), THF (tetrahydrofuran), ACN (acetonitrile), ethyl acetate etc.
8. The process as claimed in claim 6, wherein the catalyst used in step (I) is selected from the group comprising DMAP (4-Dimethylaminopyridine), TBAC (Tert-Butyl Acetate), and the dehydrating agent used in step (I) is selected from the group comprising DCC (N,N′-Dicyclohexylcarbodiimide) or EDC (dichloroethane).
9. The process as claimed in claim 6, wherein the alkyl halide used in step (I) is selected from the group comprising methyl halide, methyl chloride, methyl bromide and the catalyst in step (iv) is selected from the group comprising silver methane sulphonate.
10. The process as claimed in claim 6, wherein the catalyst used in step (II) is selected from the group comprising 18-crown-6, 12crown-4, DMAP (4-dimethylaminopyridine), TBAC (Tert-Butyl Acetate).
11. The compound of claim 1, wherein the compound is not a substrate for CYP450.
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