Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/32—Alcohol-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/36—Opioid-abuse
• • 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
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
  • G01N30/02—Column chromatography
  • G01N2030/022—Column chromatography characterised by the kind of separation mechanism
  • G01N2030/027—Liquid chromatography
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
  • G01R33/00—Arrangements or instruments for measuring magnetic variables
  • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
  • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
  • G01R33/46—NMR spectroscopy

Definitions

• the present invention in various aspects relates to the synthesis of pyrrole-linked bivalent compounds, including but not limited to norBNI, as well as pharmaceutical compositions comprising the same.
• KPR Selective ⁇ Opioid Receptor Antagonists
• norBNI non-binaltorphimine
• norBNI and analogs thereof are considered to act as a bivalent ligand for KOPR, with the pyrrole acting essentially as a spacer.
• the first step involves the synthesis of the azine intermediate by reacting naltrexone with hydrazine, followed by change of solvent for conversion of the azine to norBNI.
• Portoghese PS et al. Binaltorphimine-Related Bivalent Ligands and Their ⁇ Opioid Receptor Antagonist Selectivity. J Med. Chem. 31 :836-841 (1988).
• the yield of the reaction is low (e.g., 40- 60%), and the process is not sufficiently scalable.
• the known synthesis may produce reaction by-products with unintended pharmacological activity, or otherwise include potentially toxic impurities that are difficult to remove.
• the invention provides a process for the chemical synthesis of pyrrole-linked bivalent compounds, such as those of Formula I:
• R a is hydrogen or a substituent; each n is an integer independently selected from 0, 1, 2, 3, and 4; each r is an integer ranging from 0 to (2n + 4); and each R is a substituent wherein two or more neighboring R groups may optionally form a hydrocarbon or heterocyclic ring system.
• An exemplary compound of Formula I is nor-binaltorphimine (norBNI), a selective antagonist of the ⁇ Opioid Receptor (KOPR).
• the reaction takes place as a one-pot synthesis (e.g., without solvent exchange and/or without isolation of an intermediate), thereby improving yield, cost, and simplifying the process.
• the process is scalable. For example, the process can be conducted at small scale (e.g., with 10 g of starting material such as naltrexone), or at a commercial scale (e.g., 100 kg or more of starting material such as naltrexone).
• the reaction can proceed with about 0.1 to about 10 molar equivalents of hydrazine reactant with respect to naltrexone (or compound of Formula II as described herein). In certain embodiments, the reaction contains less than about 2 molar equivalents of hydrazine reactant with respect to naltrexone (or compound of Formula II), or about 0.5 molar equivalents of hydrazine reactant with respect to naltrexone (or compound of Formula II).
• the reaction takes place with an N-aminoimide reactant, such as tert-butyl (2,5-dioxopyrrolidin-l-yl)carbamate, which can be present in the reaction at from about 0.1 to about 10 molar equivalents (with respect to naltrexone or compound of Formula II).
• an N-aminoimide reactant such as tert-butyl (2,5-dioxopyrrolidin-l-yl)carbamate, which can be present in the reaction at from about 0.1 to about 10 molar equivalents (with respect to naltrexone or compound of Formula II).
• a solvent which in various embodiments is a polar solvent, such as a solvent selected from DMF (dimethylformamide), water, and alcohol (e.g., methanol or ethanol).
• a solvent selected from DMF (dimethylformamide), water, and alcohol (e.g., methanol or ethanol).
• the reaction is conducted in the presence of a catalyst.
• the catalyst can be an organic acid, an inorganic acid, or a combination thereof.
• the catalyst comprises methanesulfonic acid (MeS0 3 H) and/or sulfuric acid.
• the method comprises degassing the reaction mixture.
• the method may comprise sparging the reaction mixture with an inert gas, which may be argon or nitrogen in some embodiments.
• Illustrative embodiments of the invention include the production of norBNI from naltrexone and hydrazine, using DMF as the solvent, and MeS0 3 H as a catalyst in a one- pot reaction (e.g., without solvent exchange). Such reactions can involve about 0.5 to about 1 molar equivalents of hydrazine with respect to naltrexone, and from about 3 to about 5 molar equivalents of MeS0 3 H with respect to naltrexone.
• the process allows simple recovery of the product.
• the recovery of norBNI does not comprise chromatography and/or chemical extraction.
• the recovery of norBNI in some embodiments comprises collecting a precipitant of the reaction product, and converting the product to a pharmaceutically acceptable salt.
• the salt is a dichloride salt, or alternatively is a tartrate, citrate, diacetate, sulfate, or phosphate salt, or a mixed salt.
• the invention provides a composition prepared by the methods as described herein, such as norBNI compositions, or other compositions based on compounds of Formula I.
• the compositions avoid impurities in the prior processes.
• the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable salt of norBNI selected from tartrate, citrate, diacetate, sulfate or phosphate, and a pharmaceutically acceptable carrier or excipient.
• FIG. 1 shows various compounds of Formula 1 that may be synthesized in accordance with the processes described herein.
• FIG. 2(A-C) are example UPLC spectra for production of norBNI free base, as well as chloride and sulfate salts according to embodiments of the invention.
• the UPLC spectra show that the products are near 100% pure.
• the present invention provides a process for chemical synthesis of a compound having the structure of Formula I or salt thereof:
• R a is hydrogen or a substituent; each n is an integer independently selected from 0, 1, 2, 3, and 4; each r is an integer ranging from 0 to (2n + 4); and each R is a substituent wherein two or more neighboring R groups may optionally form a hydrocarbon or heterocyclic ring system.
• An exemplary compound of Formula I is nor-binaltorphimine (norBNI). norBNI and related compounds are selective antagonists of the ⁇ Opioid Receptor (KOPR), and are promising therapeutic candidates for Attention Deficit/Hyperactivity Disorder (ADHD). See US 2014/0113924, the entire disclosure of which is hereby incorporated by reference.
• the present invention provides processes for the chemical synthesis of norBNI and related compounds (e.g., which may be defined in some embodiments as bivalent receptor ligands, linked by a pyrrole). Such processes provide substantial improvements in yield, cost, and scalability, and in some embodiments, avoid the production of toxic impurities and/or reaction by-products that have undesirable pharmacological activity.
• norBNI and related compounds e.g., which may be defined in some embodiments as bivalent receptor ligands, linked by a pyrrole.
• the invention provides compounds and compositions prepared by the methods described herein.
• the invention further provides pharmaceutical compositions of norBNI or related compounds, including pharmaceutically-acceptable salts.
• the process for synthesizing a compound of Formula I or a salt thereof comprises the step of reacting a compound of Formula II with a hydrazine reactant of Formula III or a salt thereof under reaction conditions sufficient to produce the compound of Formula I.
• R d and R e are independently hydrogen or a substituent
• Z is O, S, or NR f , wherein R f is hydrogen or a substituent. All other groups are as defined above for Formula I.
• the process for synthesizing a compound of Formula I or salt thereof comprises the step of reacting an N-aminoimide reactant with a compound of Formula II, under reaction conditions sufficient to produce a compound of Formula I.
• N-aminoimide reactants include (2,5-dioxopyrrolidin-l-yl)carbamate, including protected derivatives (e.g., tert-butyl (2,5-dioxopyrrolidin-l-yl)carbamate).
• Alternative N-aminoimide reactants include aminomaleimide or aminoglutarimide, or salts thereof (e.g., hydrochloride salt).
• the invention provides yields of about 75% or greater, or about 85% or greater, such as 90% or greater.
• these embodiments may employ methane sulfonic acid as a catalyst.
• the method produces a compound of Formula 1(A), where each of R la to R 9a is independently selected from hydrogen or a substituent:
• the compound of Formula 1(A) is symmetrical, with the 6- membered rings containing identical substituents.
• the product of the process is a salt of Formula 1(B) or a free base of Formula 1(C):
• each of R ⁇ -R 13 or R ⁇ -R 11 is independently hydrogen or a substituent as defined herein;
• X 1 and X 2 are independently any heteroatom, such as O, N, S, P, or B.
• Y is a negatively charged counter-ion.
• the method produces nor-binaltorphimine (norBNI) or salt thereof, by reacting naltrexone or salt thereof with hydrazine in a polar solvent.
• naltrexone or salt thereof
• hydrazine in a polar solvent.
• the process can take place according to the following scheme, using DMF as an exemplary solvent:
• the reaction takes place as a one-pot synthesis (e.g., without solvent exchange and/or without isolation of an intermediate), thereby improving yield, cost, and simplifying the process.
• the process for production of the compound or composition described herein starts with the compound of Formula II
• the product of the reaction is at least about 70% norBNI, or is at least about 75% norBNI, or is at least about 80%> norBNI, or is at least about 85%> norBNI, or is at least about 90% norBNI, or is at least about 95% norBNI, or is at least about 96% norBNI, or is at least about 97% norBNI, or is at least 98% norBNI, or is at least 99% norBNI, or is at least 99.5% norBNI.
• the product of the reaction may contain fewer reaction byproducts, such as the corresponding azine.
• the azine corresponding to norBNI which has been considered to be an intermediate, can have the following structure (shown as a di chloride salt): ⁇ ⁇
• the reaction product contains the corresponding azine at less than about 30%, or less than about 25%, or less than about 20%, or less than about 15%), or less than about 10%>, or less than about 5%, or less than about 4%, or less than about 3%), or less than about 2%, or less than about 1% of total product, or less than about 0.5%) of total product.
• the azine is not detectable as a reaction product.
• the process of the invention in various embodiments does not require a long reaction time.
• the reaction generally proceeds for less than about 15 hours, or less than about 12 hours, or less than about 10 hours, or less than about 8 hours, or less than about 6 hours, or less than about 4 hours, or less than about 3 hours, or less than about 2 hours.
• the reaction proceeds for 1 to about 5 hours, or for 1 to about 4 hours.
• the reaction in various embodiments may be conducted with at least about lOg of a compound of Formula II (e.g., naltrexone), or at least about 50g of a compound of Formula II (e.g., naltrexone), or at least about lOOg of a compound of Formula II (e.g., naltrexone), or at least about 500g of a compound of Formula II (e.g., naltrexone), or at least about 1kg of a compound of Formula II (e.g., naltrexone), or at least about 20 kg of a compound of Formula II (e.g., naltrexone), or at least about 50 kg of a compound of Formula II (e.g., naltrexone), or at least about 100 kg of a compound of Formula II (e.g., naltrexone), or at least about 200 kg of a compound of Formula II (e.g., n
• the method does not rely on high concentrations of hydrazine to drive the reaction, and in such embodiments, the invention may employ higher molar equivalents of the compound of Formula II.
• concentration of naltrexone (or related compound of Formula II) in the reaction is about 0.3M or greater, about 0.4M or greater, or about 0.5M or greater.
• concentration of naltrexone or compound of Formula II in the reaction will be from about 0. IM to about IM (e.g., from 0.4M to IM or from 0.5M to IM).
• the reaction contains from about 0.1 to about 10 molar equivalents of hydrazine reactant (Formula III) with respect to naltrexone (or compound of Formula II), such as from about 0.2 to about 5 molar equivalents of hydrazine reactant with respect to naltrexone (or compound of Formula II). In certain embodiments, the reaction contains less than about 2 molar equivalents of hydrazine reactant with respect to naltrexone (or compound of Formula II), or about 0.5 molar equivalents of hydrazine reactant with respect to naltrexone (or compound of Formula II).
• the reaction is conducted in a solvent, which in various embodiments is organic, inorganic, polar, or nonpolar.
• the solvent can be protic or aprotic.
• the reaction is performed in an organic solvent, which may be an aprotic organic solvent.
• the reaction is performed in a solvent having both high dielectric constant and/or high dipole moment.
• the solvent is a polar solvent selected from DMF (dimethylformamide), water, alcohol (e.g., methanol, ethanol, isopropanol, butanol, tert-butanol etc.), acetonitrile, DMSO, or mixtures thereof.
• the solvent is DMF. Examples of solvents that can be used in the present invention and their relative polarities are detailed in Table 1 :
• the reaction is conducted in the presence of a catalyst.
• the catalyst can be an organic acid, an inorganic acid, or a combination thereof.
• the catalyst comprises a Lewis acid alone or in combination with other acids.
• the catalyst comprises organic sulfonic acid such as alkylsulfonic acid, arylsulfonic acid, and cycloalkylsulfonic acid.
• organic sulfonic acids include methanesulfonic acid and ethanesulfonic acid.
• the catalyst comprises a mineral acid.
• Exemplary mineral acids include, but are not limited to, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and combinations thereof.
• the catalyst comprises methanesulfonic acid (MeS0 3 H) and/or sulfuric acid.
• the acid catalyst in the reaction is from about 0.5 to about 5 molar equivalents with respect to the compound of Formula II. In some embodiments using less than 2 or less than 1 molar equivalent of hydrazine reactant (e.g. with respect to the compound of Formula II), the reaction includes from about 3 to about 5 (e.g., about 4) molar equivalents of MeS0 3 H (with respect to the compound of Formula II).
• reaction conditions in the process of the present invention are selected appropriately depending on the identity of the compound of Formula II as the starting material, the kind of hydrazine reactant of Formula III (or kind of N-aminoimide reactant in alternative embodiments), or the kind of catalysts or solvents used.
• the molar ratio of hydrazine reactant to the compound of Formula II in some embodiments is in the range of about 0.5 to about 1, but in consideration of catalyst to be used in combination with the hydrazine reactant, it may be desirable to maintain the ratio of the hydrazine reactant at about 0.5, while varying the ratio of the catalyst in the range of about 0.5 to about 5 (with respect to the compound of Formula II).
• the method comprises degassing the reaction mixture, such as by sparging the reaction mixture with an inert gas, which may be argon, nitrogen, or helium in some embodiments.
• an inert gas which may be argon, nitrogen, or helium in some embodiments.
• reaction conditions can vary, in some embodiments, the reaction is maintained within the temperature of from about 50 °C to about 110 °C, and optionally from about 95 °C to about 105 °C.
• Illustrative embodiments include the production of a compound of Formula I from a compound of Formula II, with the hydrazine reactant of Formula III, using DMF as the solvent, and MeS0 3 H as a catalyst.
• the process produces norBNI from naltrexone and hydrazine in a one-pot synthesis. Such reactions can involve about 0.5 to about 1 molar equivalent of hydrazine with respect to naltrexone, and from about 3 to about 5 molar equivalents of MeS0 3 H with respect to naltrexone.
• the process allows simple recovery of the product. While the recovery of the product (e.g., norBNI) can comprise purifying the product from one or more secondary reaction products or reactants, such steps are not be necessary in some embodiments. For example, in some embodiments, the recovery of norBNI does not comprise chromatography and/or extraction.
• the recovery of norBNI in some embodiments comprises collecting a precipitant of the reaction product (e.g., by filtration), and converting the product (having a yield as already described) to a pharmaceutically acceptable salt.
• the salt is a dichloride salt, or alternatively is a tartrate, citrate, diacetate, sulfate, or phosphate salt, or a mixed salt.
• the reaction is monitored to avoid the addition of excess acid.
• the reaction may be monitored for an abrupt change in the trend between increasing volume of acid added, verses conductance or pH of the reaction mixture, indicating the equivalence point of the reaction.
• the salt formation reaction may be monitored with a conductivity meter, pH meter, ion-sensitive electrode, or other suitable means.
• the reactant of Formula II is a cycloalkanone where Z is O.
• exemplary cycloalkanones include, but are not limited to substituted and unsubstituted cyclobutanones, substituted and unsubstituted cyclopentanones, substituted and unsubstituted cyclohexanones, substituted and unsubstituted cycloheptanones, and substituted and unsubstituted cyclooctanones.
• Two or more adjacent or distal R groups of the compound of Formula II may optionally form a hydrocarbon or heterocyclic ring system.
• two neighboring R groups form a ring system independently selected from phenyl, thienyl, furanyl, pyrimidinyl, oxazoyl, thiazolyl, pyridyl, naphthyl, quinolinyl, indolyl, benzothiophenyl, benzofuranyl, pyrrolyl, imidazolyl, pyrazole, triazolyl, isoxazolyl, pyridazinyl, pyzazinyl, pyrimidinyl, oxadiazolyl, benzimidazolyl, and triazinyl, each of which may contain substituents.
• two or more neighboring R groups form a heterocyclic system containing one or more heteroatoms selected from the group consisting of as oxygen, sulfur, nitrogen, and combinations thereof.
• R d and R e of the hydrazine reactant of the Formula III are both hydrogen, or in some embodiments, one or both of R d and R e is a lower alkyl (e.g., methyl or ethyl) or alkoxy, hydroxyl, a halogen, or an amine.
• the hydrazine reactant comprises hydrazine sulfate, hydrazine hydrochloride, hydrazine dihydrochloride, hydrazine monohydrochloride, hydrazine monohydrobromide, hydrazine acetate, hydrazine sulfate, and mixtures thereof.
• R d or R e have the same identity as R a of Formula I.
• Substituents as identified for compounds of Formulas I-III may be independently selected from any suitable substituent.
• suitable substituents include, but are not limited to acyl, acyloxy, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, alkoxy, alkoxycarbonyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, and trimethylsilanyl.
• substituents include those independently selected from ethers, esters, sulfides, disulfides, sulfonyl, sulfinyl, sulfonamidyl, sulfonate, sulfoxyl, phosphate esters, phosphines, borate esters, halogens, carbonyl, carboxylate, carbamate, amines, imides, and quanidines.
• exemplary substituents include CI, F, Br,— OR b , -SR b , -OC(0)-R b , -N(R b )2, -C(0)R b , -C(0)OR b , -OC(0)N(R b )2, -C(0)N(R b )2, -N(R b )C(0)OR b , -N(R b )C(0)R b , -N(R b )C(0)N(R b )2, N(R b )C( R b )N(R b )2, -N(R b )S(0) 2 R b , -S(0)OR b , -S(0) 2 OR b , -S(0)N(R b ) 2 , -S(0) 2 N(R b ) 2 , or P0 3 (R b ) 2 where each R b is independently hydrogen, alkyl, hal
• Alkyl substituents may be straight or branched, and may be substituted or unsubstituted (e.g., haloalkyl).
• the alkyl group may have from 1 to 12 carbon atoms, e.g. 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms etc., up to and including about 12 carbon atoms.
• alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl.
• the alkyl substituent may be attached to the rest of the molecule by a single bond.
• Alkenyl substituents may be straight or branched, and may be substituted or unsubstituted.
• the alkenyl group may contain from 2 carbon atoms to about 12 carbon atoms, e.g., the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms etc., up to and including about 12 carbon atoms.
• the alkenyl substituent may be attached to the rest of the molecule by a single bond or by a double bond.
• Alkynyl substituents may be straight or branched, and may be substituted or unsubstituted.
• the alkynyl group contains from 2 to about 12 carbon atoms (e.g., 2, 3, or 4 carbon atoms).
• the alkynyl may be attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl.
• Cycloalkyl substituents may be monocyclic or polycyclic substituents, which may be saturated, or partially unsaturated, and may be substituted or unsubstituted. In some embodiments, cycloalkyl substituents are selected from those having from 3 to 12 ring atoms. Illustrative examples of cycloalkyl substituents include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like.
• Alkoxy substituents are defined by the group— O-alkyl.
• the alkoxy group contains from 1 to 12 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen.
• Exemplary alkoxy substituents include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyl oxy.
• the alkoxy is a lower alkoxy (containing one to six carbon atoms). The alkoxy substituent is optionally substituted.
• the alkoxycarbonyl group contain from 1 to 12 carbon atoms, e.g., C(l-12)-alkoxycarbonyl group. In some embodiments, the alkoxycarbonyl is a lower alkoxycarbonyl (containing 1 to 6 carbon atoms). The alkoxycarbonyl may be substituted or unsubstituted.
• Acyl substituents include substituents of the formula Rx— C(O)— , where Rx is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each as described herein.
• Amino or "amine" substituents include those of the formula— N(R b ) 2 , where Rb is hydrogen, alkyl, (halo)alkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl heteroarylalkyl, or other substituent described herein.
• Rb is hydrogen, alkyl, (halo)alkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl heteroarylalkyl, or other substituent described herein.
• Rb is hydrogen, alkyl, (halo)alkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, aryl,
• Amide or "amido" substituents include those of the formula— C(0)N(R y ) 2 or — HC(0)R y , where R y is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, cycloalkyl, aryl, heteroaryl, or other substituent described herein.
• R y of— N(R y ) 2 of the amide may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring.
• a substituent is aromatic, meaning that the substituent is an unsaturated, cyclic and planar hydrocarbon group with a delocalized conjugated ⁇ system having 4n + 2 ⁇ electrons, where n is an integer having a value of 0, 1, 2, 3, and so on.
• the aromatic group is an "aryl", which refers to an aromatic radical with six to ten ring atoms. That is, an aryl substituent has at least one ring having a conjugated pi electron system which is carbocyclic.
• Aryl includes monocyclic or fused- ring polycyclic groups. Aryl may include substituents as described herein, for example, "aralkyl" or "arylalkyl".
• Aryl includes carbocyclic and heterocyclic ring systems.
• An "ester” as used herein refers to a chemical radical of formula— COOR z , where R z includes, but is not limited to, alkyl, alkenyl, alkynyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl, or other substituent described herein.
• the substituent is a halogen (e.g., fluoro, chloro, bromo or iodo).
• substituents include haloalkyl, haloalkenyl, haloalkynyl and haloalkoxy.
• a substituent is sulfanyl, which refers to substituents that include — S-(optionally substituted alkyl), — S— (optionally substituted aryl), — S— (optionally substituted heteroaryl) and— S-(optionally substituted heterocycloalkyl).
• at least one substituent is a sulfinyl, which refers to substituents that include — S(0)-H, — S(0)-(optionally substituted alkyl), — S(0)-(optionally substituted amino),— S(0)-(optionally substituted aryl),— S(0)-(optionally substituted heteroaryl) and — S(0)-(optionally substituted heterocycloalkyl).
• At least one substituent is sulfonyl, which refers to substituents that include — S(0 2 )-H, — S(0 2 )- (optionally substituted alkyl),— S(0 2 )-(optionally substituted amino),— S(0 2 )-(optionally substituted aryl), — S(0 2 )-(optionally substituted heteroaryl), and — S(0 2 )-(optionally substituted heterocycloalkyl).
• Heteroalkyl, heteroalkenyl, and heteroalkynyl substituents include optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
• the compound of Formula I is a salt of Formula 1(B) or free base of Formula 1(C):
• each of X and X is O, N, or S, and each of R to R or R to R is independently selected from hydrogen, hydroxide, amino, halogen.
• Formula II may have the structure of Formula II (A):
• Exemplary compounds of Formula I which may be synthesized in accordance with the invention, include those shown in FIG 1.
• the invention includes methods of making and compositions of various isomers and stereoisomers (including enantiomers, diasteriomers, and racemic mixtures) of norBNI and related compounds.
• the term "( ⁇ )" is used to designate a racemic mixture where appropriate.
• a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by either (R) or (S).
• Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
• Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (S).
• the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
• Optically active (R)- and (S)-isomers can be prepared using chiral reagents, or resolved using conventional techniques.
• the invention provides a composition prepared by the method as described herein, such as norBNI compositions, or other compositions based on compounds of Formula I.
• the compositions avoid impurities in the prior process, such as, for example, DMSO and/or corresponding azine compounds. While DMSO has been used to convert an azine intermediate to norBNI, the present invention provides a direct (one-pot) synthesis from naltrexone to norBNI (for example) and which does not require solvent exchange to DMSO.
• the invention provides norBNI compositions that are highly pure, without reaction impurities, such as compositions that are at least 99% norBNI or salt thereof, with respect to norBNI and reaction impurities as 100%, or at least 99.5% norBNI or salt thereof.
• the compositions may be scaled batches of active ingredient, and thus contain at least 100 g of norBNI or salt thereof, or at least 500 g of norBNI or salt thereof, or at least 1 kg of norBNI or salt thereof.
• the norBNI composition is a pharmaceutical composition comprising a pharmaceutically effective amount of norBNI or salt thereof.
• the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable salt of norBNI selected from tartrate, citrate, diacetate, sulfate or phosphate, and a pharmaceutically acceptable carrier.
• compositions can take any suitable form depending on the desired administration route (e.g., oral), including tablets, capsules, aerosols, biodegradable matrices for sublingual or buccal administration, topical composition or transdermal patch, suppositories, or injectable solutions.
• Various pharmaceutical carriers and excipients may be used according to standard practice in the industry.
• the composition does not contain more than 1% reaction impurities with respect to the amount of norBNI, or does not contain more than 0.5% reaction impurities with respect to the amount of norBNI.
• the process is a two-step procedure via an intermediate azine.
• norBNI is produced directly from naltrexone and hydrazine, without solvent exchange, according to Scheme 2:
• the resulting precipitate is collected by filtration and washed with a further 200 mL of water and allowed to dry to give crude norBNI contaminated with DMF as a beige solid.
• the crude product is dissolved in a minimum quantity of methanol (400 mL) and to this solution water (600 mL) is slowly added, with stirring, to re-precipitate the product.
• the suspension is then stirred at room temperature for 3 hours, before the precipitate is collected by filtration, washed with a further volume of water (200 mL) and allowed to dry, to give norBNI (free base) as a beige/off white amorphous solid (42 g, 96% yield, 96.8% purity).
• addition of at least one catalyst e.g.
• Naltrexone used purchased from AK Scientific.
• Methanol was also shown to be an acceptable solvent, preferably including 1 equivalent of methanesulfonic acid, and providing yields of around 80% at a 1.6 mmol scale.
• the reaction was also successfully carried out in water, but proceeds at a slower rate.
• the solvent is polar, such that reaction components sufficiently dissolve.
• reaction was also successfully carried out with sulfonic acid as the catalyst, which also required a longer reaction time.
• the process described herein is commercially scalable. It advantageously simplifies synthesis of the pyrrole-containing compound by eliminating isolation of intermediate compounds and/or also eliminating any solvent changing steps. Thus, the process can advantageously be carried out as a one-pot, one-solvent process. Moreover, the process leads to improvements in yields of the reaction product, and work-up procedure (e.g. eliminates use of expensive extraction techniques and chromatography).
• the product precipitate (basified with aqueous ammonium hydroxide) is collected by filtration, dissolved in organic solvent such as methanol, re-precipitated with water, and the precipitate collected again by filtration.
• the free base can be converted to the desired salt, e.g., the di chloride salt by addition to HC1- ethyl acetate solution.
• Naltrexone used purchased from AK Scientific except for entry 4 (Siegfried).
• Table 4 above shows reaction yield is concentration invariant. Varying naltrexone from 0.16 M-0.56 M has little, if any, impact on the yield or rate of the reaction. At a 50 g scale the reaction was conducted at a 0.56 M concentration in a DMF (200 mL)/methanesulfonic acid (35 mL) solution.
• reaction solvent was sparged with an inert gas (nitrogen or argon) for 30 minutes at >200 mL/min for a 100 g scale reaction to remove dissolved oxygen.
• inert gas nitrogen or argon
• Absolute ethanol was used in place of methanol for the reaction work up and in the salt formation process.
• FIG. 2(A-C) are example HPLC spectra of high purity norBNI free base, chloride salt and sulfate salt obtained from this process. The HPLC spectra show that the products are near 100% pure.
• methane sulfonic acid (0.78 mL, 12.00 mmol) was added via syringe in one portion and the reaction was heated to 70 °C. The reaction was then left for 4 h, during which time the reaction mixture was seen to turn black. The reaction mixture was then removed from the heat and allowed to cool to r.t. An aliquot of the reaction material analyzed by 1H NMR indicated 100% conversion of the starting material. The cooled reaction mixture was then diluted with 22 mL of deionized water, and excess ammonium hydroxide (Aqueous 29%, 99 mL) was added to basify the mixture and precipitate the free base.

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• 2016
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