Patent Application
20120295866
The present invention relates to methods and compositions for the production and use of pro-drug analogs. This invention relates to a method for the production of a broad group of novel glycoside derivatives of drugs, including but not limited to drugs containing at least one hydroxyl group, such as phenols and alcohols, a primary or secondary amine or a thiol group. The invention also importantly relates to the resulting glycosides as novel compounds of diverse application having desired properties including pharmacodynamic properties; and to medicaments containing the pro-drug compounds.
There are a number of potentially useful drugs with poor water solubility. One approach to imparting better water solubility involves glycosylating the drug. See U.S. Pat. No. 6,093,805 [1]. However, attempts to glycosylate the drug directly often fails or results in yields so low as to be commercially unviable. An approach that would be more compatible with a greater variety of functional groups, allowing easy access to drug analogs containing a carbohydrate in which the pro-drug efficiently and quickly releases the drug in vivo is highly desirable.
The present invention relates to methods and compositions for the production and use of pro-drug analogs. This invention relates to a method for the production of a broad group of novel glycoside derivatives of drugs, including but not limited to drugs containing at least one hydroxyl group, such as phenols and alcohols, a primary or secondary amine or a thiol group. The invention also importantly relates to the resulting glycosides as novel compounds of diverse application having desired properties including pharmacodynamic properties; and to medicaments containing the pro-drug compound.
In one embodiment, the present invention contemplates a glycosylated compound of the formula: CARB-T-L-SUB wherein CARB is the particular carbohydrate connected through the chemical tether T to linking group L which is connected to a substrate (SUB), which in one embodiment is an active drug D, wherein said carbohydrate is selected from the group consisting of a mono-, di- and tri-saccharides, wherein said linker is created by chemical modification of a hydroxyl, amine or thiol group on the substrate. It is not intended that the present invention be limited by the nature of the tether T. In one embodiment, the tether T comprises —(CH2)n— groups, wherein n is a whole number between 1 and 10 and can be branched. In one embodiment, said carbohydrate is a cyclic monosaccharide. In one embodiment, said cyclic monosaccharide is a pyranoside (6 member ring). In one embodiment, said cyclic monosaccharide is a furanoside (5 member ring). In one embodiment, said carbohydrate has additional functional groups that are protected with protecting groups (e.g., wherein said protected functional groups are acetylated) (or wherein the said carbohydrate has its functional group protected with protecting groups). In one embodiment, said carbohydrate containing protecting groups is an acetylated pyranoside. In one embodiment, said carbohydrate is a disaccharide selected from the group consisting of a lactose-derived glycal, and a maltose-derived glycal. In one embodiment, said substrate is a particle (e.g. bead, microbead, nanoparticle, etc.). In one embodiment, said substrate comprises a drug carrier selected from the group consisting of a microsphere, a nanoparticle, a micelle, a liposome, and a biodegradable polymer. In one embodiment, said drug carrier comprises a drug. In one embodiment, CARB-T-L-SUB has the structure:
wherein Z is O or S, Y is O or S, and X is CH2, CHR, CRR′, C(O)O, C(O)NH, C(O)NR, NH, NR, O, or S, wherein SUB is the substrate, and wherein the anomer is either α or β.
In one embodiment, the present invention contemplates a method for making a glycosylated compound of the formula: CARB-T-L-SUB wherein CARB is a carbohydrate connected through the chemical tether T to linking group L which is connected to a substrate SUB, said method comprising: a) providing a substrate and a modified carbohydrate, said modified carbohydrate comprising a tethered functional group, said functional group selected from the group consisting of alcohols, amines and thiol groups; b) modifying a group on the substrate, said group selected from a hydroxyl group, an amino group, and a thiol group, so as to create a modified substrate comprising a linker intermediate, and reacting said modified substrate with said modified carbohydrate, so as to create a glycosylated compound of the formula CARB-T-L-SUB. In one embodiment, said glycosylated compound comprises a chemical group selected from the group consisting of a carbonate, a thiocarbonate, a carbamate, a substituted carbamate, and an ester. In one embodiment, said modified carbohydrate has additional functional groups that are protected with protecting groups. In one embodiment, said protected functional groups are acetylated. In one embodiment, said carbohydrate containing protecting groups is an acetylated pyranoside. In one embodiment, after step c) said protecting groups are removed. In one embodiment, said linker intermediate is a haloformate. In one embodiment, said haloformate is a chloroformate. In one embodiment, the reacting of step c) converts said linker intermediate into said linker.
In one embodiment, the present invention contemplates a method of treating a subject, comprising: a) providing an glycosylated compound of the formula: CARB-T-L-SUB, wherein CARB is the particular carbohydrate connected through the chemical tether T to linking group L which is connected to a substrate SUB, wherein said carbohydrate is selected from the group consisting of a mono-, di- and tri-saccharides, wherein said linker is created by chemical modification of a functional group (e.g. a hydroxyl group, an amino group, a thiol group, etc.) on said substrate, wherein said tether comprises —(CH2)n— and wherein n is a whole number between 1 and 10; and b) administering said glycosylated compound to a subject. In one embodiment, said subject is a human. In one embodiment, said subject is a non-human animal. In one embodiment, said glycosylated compound is in a water-based formulation and wherein said administering comprises intravenous administration. In one embodiment, said formulation is oil-free.
In one embodiment, the present invention contemplates a method for making a glycosylated substrate of the formula: CARB-T-L-SUB wherein CARB is a carbohydrate connected through the chemical tether T to linking group L which is connected to a substrate SUB, said method comprising: a) providing a substrate, said substrate comprising a functional group, and a modified carbohydrate, said modified carbohydrate comprising a tethered functional group, said functional group (for both the substrate and the modified carbohydrate) selected from the group consisting of hydroxyl, amine and thiol groups; b) modifying the functional group on said substrate, so as to create a modified substrate comprising a linker intermediate; and c) reacting said modified substrate with said modified carbohydrate, so as to create a glycosylated compound of the formula CARB-T-L-SUB. In one embodiment, said modified carbohydrate has additional functional groups that are protected with protecting groups. In one embodiment, said protected functional groups are acetylated. In one embodiment, said carbohydrate containing protecting groups is an acetylated pyranoside. In one embodiment, after step c) said protecting groups are removed. In one embodiment, said linker intermediate is a haloformate. In one embodiment, said linker intermediate is a haloformamide. In one embodiment, said haloformate is a chloroformate. In one embodiment, said haloformamide is a chloroformamide. In one embodiment, reacting of step c) converts said linker intermediate into said linker. In one embodiment, after step c) said glycosylated substrate comprises a chemical group selected from the group consisting of a carbonate, a thiocarbonate, a carbamate, a substituted carbamate, and an ester. In one embodiment, said modified carbohydrate is selected from the group consisting of a mono-, di- and tri-saccharides. In one embodiment, said disaccharides are selected from the group consisting of a lactose-derived glycal, and a maltose-derived glycal.
In another embodiment the invention relates to methods of synthesizing derivatives of other functionalities, including aliphatic alcohols, amines and anilines. In some cases it is best to make the chloroformate of the substrate (as in the case of propofol), in others it is best to make the chloroformate of the tethered functional group on the modified carbohydrate. In one embodiment, the present invention contemplates a method for making a glycosylated substrate of the formula: CARB-T-L-SUB wherein CARB is a carbohydrate connected through the chemical tether T to linking group L which is connected to a substrate SUB, said method comprising: a) providing a substrate, said substrate comprising a functional group, and a modified carbohydrate, said modified carbohydrate comprising a tethered functional group, said functional group (for both the substrate and the modified carbohydrate) selected from the group consisting of hydroxyl, amine and thiol groups; b) modifying the tethered functional group on said modified carbohydrate, so as to create a modified tethered functional group comprising a linker intermediate; and c) reacting said modified tethered functional group with said substrate, so as to create a glycosylated compound of the formula CARB-T-L-SUB. In one embodiment, said modified carbohydrate has additional functional groups that are protected with protecting groups. In one embodiment, said protected functional groups are acetylated. In one embodiment, said carbohydrate containing protecting groups is an acetylated pyranoside. In one embodiment, after step c) said protecting groups are removed. In one embodiment, said linker intermediate is a haloformate. In one embodiment, said linker intermediate is a haloformamide. In one embodiment, said haloformate is a chloroformate. In one embodiment, said haloformamide is a chloroformamide. In one embodiment, reacting of step c) converts said linker intermediate into said linker. In one embodiment, after step c) said glycosylated substrate comprises a chemical group selected from the group consisting of a carbonate, a thiocarbonate, a carbamate, a substituted carbamate, and an ester. In one embodiment, said modified carbohydrate is selected from the group consisting of a mono-, di- and tri-saccharides. In one embodiment, said disaccharides are selected from the group consisting of a lactose-derived glycal, and a maltose-derived glycal.
In one embodiment, the present invention contemplates a method for making a glycosylated drug of the formula: CARB-T-L-DRUG wherein GARB is a carbohydrate connected through the chemical tether T to linking group L which is connected to a drug DRUG, said method comprising: a) providing a substrate, said substrate comprising a functional group, and a modified carbohydrate, said modified carbohydrate comprising a tethered functional group, said functional group (for both the substrate and the modified carbohydrate) selected from the group consisting of hydroxyl, amine and thiol groups; b) modifying the functional group on said drug, so as to create a modified drug comprising a linker intermediate; and c) reacting said modified drug with said modified carbohydrate, so as to create a glycosylated compound of the formula CARB-T-L-DRUG. In one embodiment, said modified carbohydrate has additional functional groups that are protected with protecting groups. In one embodiment, said protected functional groups are acetylated. In one embodiment, said carbohydrate containing protecting groups is an acetylated pyranoside. In one embodiment, after step c) said protecting groups are removed. In one embodiment, said linker intermediate is a haloformate. In one embodiment, said haloformate is a chloroformate. In one embodiment, said linker intermediate is a halo formamide. In one embodiment, said haloformamide is a chloroformamide. In one embodiment, the reacting of step c) converts said linker intermediate into said linker. In one embodiment, after step c) said glycosylated drug comprises a chemical group selected from the group consisting of a carbonate, a thiocarbonate, a carbamate, a substituted carbamate, and an ester. In one embodiment, said modified carbohydrate is selected from the group consisting of a mono-, di- and tri-saccharides. In one embodiment, said disaccharides are selected from the group consisting of a lactose-derived glycal, and a maltose-derived glycal.
In another embodiment the invention relates to methods of synthesizing derivatives of other functionalities, including aliphatic alcohols, amines and anilines. In some cases it is best to make the chloroformate of the drug (as in the case of propofol), in others it is best to make the chloroformate of the tethered functional group on the modified carbohydrate. In one embodiment, the present invention contemplates a method for making a glycosylated drug of the formula: CARB-T-L-DRUG wherein CARB is a carbohydrate connected through the chemical tether T to linking group L which is connected to a drug DRUG, said method comprising: a) providing a drug, said drug comprising a functional group, and a modified carbohydrate, said modified carbohydrate comprising a tethered functional group, said functional group (for both the drug and the modified carbohydrate) selected from the group consisting of hydroxyl, amine and thiol groups; b) modifying the tethered functional group on said modified carbohydrate, so as to create a modified tethered functional group comprising a linker intermediate; and c) reacting said modified tethered functional group with said drug, so as to create a glycosylated compound of the formula CARB-T-L-DRUG. In one embodiment, said modified carbohydrate has additional functional groups that are protected with protecting groups. In one embodiment, said protected functional groups are acetylated. In one embodiment, said carbohydrate containing protecting groups is an acetylated pyranoside. In one embodiment, after step c) said protecting groups are removed. In one embodiment, said linker intermediate is a halofottnate. In one embodiment, said linker intermediate is a haloformamide. In one embodiment, said haloformate is a chloroformate. In one embodiment, said haloformamide is a chloroformamide. In one embodiment, reacting of step c) converts said linker intermediate into said linker. In one embodiment, after step c) said glycosylated drug comprises a chemical group selected from the group consisting of a carbonate, a thiocarbonate, a carbamate, a substituted carbamate, and an ester. In one embodiment, said modified carbohydrate is selected from the group consisting of a mono-, di- and tri-saccharides. In one embodiment, said disaccharides are selected from the group consisting of a lactose-derived glycal, and a maltose-derived glycal.
In one embodiment, the present invention contemplates a glycosylated compound of the formula: CARB-T-L-DRUG, wherein CARB is a carbohydrate connected through a chemical tether T to linking group L which is connected to a drug, wherein said carbohydrate is selected from the group consisting of a mono-, di- and tri-saccharides, wherein said linker is created by chemical modification of a functional group on the drug, and wherein said tether comprises —(CH2)m— wherein m is a whole number between 1 and 10. In one embodiment, said carbohydrate is a cyclic monosaccharide. In one embodiment, said cyclic monosaccharide is a pyranoside (6 member ring). In one embodiment, said cyclic monosaccharide is a furanoside (5 member ring). In one embodiment, said carbohydrate has additional functional groups that are protected with protecting groups (e.g., wherein said protected functional groups are acetylated) (or wherein the said carbohydrate has its functional group protected with protecting groups). In one embodiment, said carbohydrate containing protecting groups is an acetylated pyranoside. In one embodiment, said carbohydrate is a disaccharide selected from the group consisting of a lactose-derived glycal, and a maltose-derived glycal. In one embodiment, said compound contains a chemical group selected from the group consisting of a carbonate, a thiocarbonate, a carbamate, a substituted carbamate, and an ester. In one embodiment, the functional group on the drug is selected from the group consisting of a hydroxyl group, an amine group and a thiol group. In one embodiment, the compound further comprises a diluent selected from the group consisting of water, saline, dextrose, glycerol, polyethylene glycol, and poly(ethylene glycol methyl ether). In one embodiment, the compound is in a water-based formulation suitable for intravenous administration. It is preferred that the solubility of said glycosylated compound in said formulation is greater than the solubility of an unglycosylated drug (i.e. the same drug that has not been glycosylated).
It is not intended that the present invention be limited by the nature of the drug. In one embodiment, the drug is an analgesic. In one embodiment, said drug is also an antipyretic. In one embodiment, said drug is acetaminophen. In one embodiment, said drug is an anti-cancer drug. In one embodiment, said anti-cancer drug is camptothecin or a derivative thereof. In one embodiment, said anti-cancer drug is betulin.
In one embodiment, CARB-T-L-DRUG has the structure:
wherein Z is O or S, Y is O or S, X is CH2, CHR, CRR′, C(O)O, C(O)NH, C(O)NR, NH, NR, O, or S, wherein D is the drug, wherein R and R′ are independent and can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, wherein n is a whole number between 1 and 10 (and more preferably between 2 and 3) and wherein the anomer is either α or β.
In one embodiment, CARB-T-L-DRUG has the structure:
wherein Z is O or S, Y is O or S, and X is CH2, CHR, CRR′, C(O)O, C(O)NH, C(O)NR, NH, NR, O, or S, wherein D is the drug, wherein R and R′ are independent and can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, wherein n is a whole number between 1 and 10 (and more preferably between 2 and 2), and wherein the anomer is either α or β.
The present invention contemplates method of administering such compounds to humans and animals. For example, in one embodiment, the glycosylated drug derivative is administered prior to, during, or after a medical procedure. In addition, the present invention contemplates methods of synthesizing such compounds.
In one embodiment, the present invention contemplates a glycosylated compound of the formula: CARB-T-L-D wherein CARB is a carbohydrate connected through a chemical tether T to linking group L which is connected to D, a drug, wherein said carbohydrate is selected from the group consisting of a mono-, di- and tri-saccharides, wherein said linker is created by chemical modification of an amine group or thiol group on said drug, and more preferably at least one hydroxyl group, such as phenol and alcohol group on said drug, and wherein said tether comprises —(CH2)m— wherein m is a whole number between 1 and 10.
In one embodiment, the present invention contemplates a glycosylated compound of the formula: CARB-T-L-D wherein CARB is a carbohydrate connected through a chemical tether T to linking group L which is connected to D, a drug, wherein said carbohydrate is selected from the group consisting of a mono-, di- and tri-saccharides, wherein said linker is created by chemical modification of a functional group (e.g. an amine or thiol group, and more preferably at least one hydroxyl group, such as phenol and alcohol group) on said drug, and wherein said tether comprises —(CRR′)m— wherein R and R′ are independent and can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl and wherein m is a whole number between 1 and 10.
In one embodiment, the present invention contemplates a glycosylated compound of the formula: CARB-T-L-D, wherein CARB is a carbohydrate connected through the chemical tether T to linking group L which is connected to D, a drug, wherein said carbohydrate is selected from the group consisting of a mono-, di- and tri-saccharides, wherein said linker is created by chemical modification a functional group (e.g. an amine or thiol group, and more preferably at least one hydroxyl group, such as phenol and alcohol group) on said drug, and wherein said tether comprises —(CR1R2)m(CR3R4)n(CR5R6)p— branched tether, wherein m, n, and p are independent, and where n and p can be a whole number between 0 and 10 and m can be a whole number between 1 and 10 (and in which the sum of m, n and p are preferably 2 or 3), and where R1, R2, R3, R4, R5 and R6 are each independent can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, wherein any of R1, R2, R3, R4, R5 and R6 can be joined to provide a cyclic tether, wherein for simple straight chain tethers, n and p=0, R1 and R2═H, and the tether formula —(CR1R2)m(CR3R4)n(CR5R6)p— collapses to —(CH2)m— where m is a whole number between 1 and 10 (preferably between 1 and 3, and most preferably 2 and 3). In one embodiment, said chemical modification comprises reacting said drug with a reactant selected from the group consisting of phosgene, triphosgene, thiophosgene, and oxalyl chloride so as to create a linker intermediate. In one embodiment, said linker intermediate is a chloroformate. In one embodiment, said linker intermediate is a thionochloroformate. In one embodiment, the linker intermediate is reacted such that said glycosylated compound comprises a carbonate, a thiocarbonate, or a carbamate group. In one embodiment, said carbohydrate is a cyclic monosaccharide. In one embodiment, said cyclic monosaccharide is a pyranoside (6 member ring). In one embodiment, said cyclic monosaccharide is a furanoside (5 member ring). In one embodiment, said carbohydrate has additional functional groups that are protected with protecting groups (e.g., wherein said protected functional groups are acetylated) (or wherein the said carbohydrate has its functional group protected with protecting groups). In one embodiment, said carbohydrate containing protecting groups is an acetylated pyranoside. In one embodiment, said carbohydrate is a disaccharide selected from the group consisting of a lactose-derived glycal, and a maltose-derived glycal.
In one embodiment, said glycosylated compound, CARB-T-L-D has the structure:
wherein Z is O or S, Y is O or S, and X is CH2, CHR, CRR′, OC(O), NHC(O), NRC(O), NH, NR, O, or S, wherein R and R′ are independent and can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, wherein m, n and p are independent and can be whole number between 1 and 10 (the sum n, m, and p are most preferably 2 or 3), where R1, R2, R3, R4, R5 and R6 (and R if X═NR or NRC(O)) are each independent can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, and wherein the anomer is either α or β.
In one embodiment, CARB-T-L-D has the structure:
wherein Z is O or S, q is 1 or 2, Y is O or S, and X is CH2, CHR, CRR′, OC(O), NHC(O), NRC(O), NH, NR, O, or S, wherein R and R′ are independent and can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, wherein m, n and p are independent and can be whole number between 1 and 10 (the sum n, m, and p are most preferably 2 or 3), where R1, R2, R3, R4, R5 and R6 (and R if X═NR or NRC(O)) are each independent can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, and wherein the anomer is either α or β.
In one embodiment, said glycosylated compound, CARB-T-L-D has the structure:
wherein Z is O or S, q is 1 or 2, Y is O or S, and X is CH2, CHR, CRR′, OC(O), NHC(O), NRC(O), NH, NR, O, or S, wherein W and Q are independently selected from O, N—R, S(O), S(O)2, C(O), or S, wherein R and R′ are independent and can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl wherein m, n and p are independent and can be whole number between 1 and 10 (the sum n, m, and p are most preferably 2 or 3), where R1, R2, R3, R4, R5 and R6 (and R if X═NR or NRC(O)) are each independent can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, and wherein the anomer is either α or β.
In one embodiment, said glycosylated compound, CARB-T-L-D has the structure:
wherein Z is O or S, q is 1 or 2, Y is O or S, and X is CH2, CHR, CRR′, OC(O), NHC(O), NRC(O), NH, NR, O, or S, wherein R and R′ are independent and can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, wherein W and Q are independently selected from O, N—R, S(O), S(O)2, C(O), S, or direct bonds (i.e. do not exist or are nothing), wherein m, n and p are independent and can be whole number between 1 and 10 (the sum n, m, and p are most preferably 2 or 3), wherein r is a whole number between 1 and 100, where R1, R2, R3, R4, R5 and R6 (and R if X═NR or NRC(O)) are each independent can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, and wherein the anomer is either α or β. For polyethylene glycol derived tethers, n and m=2, X and Y═O, W═O, Q=O, R1, R2, R3, and R4═H, and p=0, and the tether formula —{Y—(CR1R2)m—W—(CR3R4)n-Q-(CR5R6)p}r— collapses to —{Y—(CH2CH2—O—CH2CH2)}r— where r is a whole number between 1 and 100. In one embodiment, said glycosylated compound, CARB-T-L-D collapses to the structure below wherein Q=direct bond and p=0:
In one embodiment, the structure can then further collapse to the structure wherein X═Y═W═O, R1, R2, R3, and R4═H, and p=0:
In one embodiment, said glycosylated compound, CARB-T-L-D would be one derived from the use of polyethylene glycols (PEG) in place of allyl alcohol described in the procedure (where Z═O and q=1). The use of such a polyethylene glycol tether would aid in compound solubility. The preparation of polyethylene glycol (PEG) tether derivatives should be relatively easy to prepare.
In one embodiment, said glycosylated compound, CARB-T-L-D has a PEG-related tether and has the structure:
wherein Z is O or S, Y is O or S, and X is CH2, CHR, CRR′, OC(O), NHC(O), NRC(O), NH, NR, O, or S, wherein R and R′ are independent and can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, wherein n is a whole number between 1 and 100, and wherein the anomer is either α or β.
In one embodiment, said glycosylated compound, CARB-T-L-D has a PEG-related tether and has the structure:
wherein Z is O or S, Y is O or S, and X is CH2, CHR, CRR, OC(O), NHC(O), NRC(O), NH, NR, O, or S, wherein R and R′ are independent and can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, wherein n is a whole number between 1 and 100, wherein r is a whole number between 1 and 100, where R1 and R2 (and R if X═NR or NRC(O)) are each independent can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, and wherein the anomer is either α or β.
In one embodiment, said glycosylated compound, CARB-T-L-D has the structure:
wherein Z is O or S, q is 1 or 2, Y is O or S, and X is CH2, CHR, CRR′, OC(O), NHC(O), NRC(O), NH, NR, O, or S, wherein W and Q are independently selected from O, N—R, S(O), S(O)2, C(O), S, or direct bonds (i.e. do not exist or are nothing) (i.e. do not exist or are nothing), wherein R and R′ are independent and can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl wherein m, n and p are independent and can be whole number between 0 and 10, where R1, R2, R3, R4, R5 and R6 (and R if X═NR or NRC(O)) are each independent can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, and wherein the anomer is either α or β.
In one embodiment, said glycosylated compound, CARB-T-L-D has a straight-chain tether and has the structure:
wherein Z is O or S, Y is O or S, X is CH2, CHR, CRR, OC(O), NHC(O), NRC(O), NH, NR, O, or S, wherein R and R′ are independent and can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, wherein m is a whole number between 1 and 10 (preferably between 2 and 10, and most preferably n is 2 or 3) and wherein the anomer is either α or β.
In one embodiment, CARB-T-L-D has the structure:
wherein Z is O or S, Y is O or S, X is CH2, CHR, CRR′, OC(O), NHC(O), NRC(O), NH, NR, O, or S, wherein R and R′ are independent and can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl, wherein m is a whole number between 1 and 10 (preferably between 2 and 10, and most preferably n is 2 or 3) and wherein the anomer is either α or β. In one embodiment, said glycosylated compound has the structure:
In one embodiment, said glycosylated compound has the structure:
In one embodiment, said glycosylated compound has the structure:
In one embodiment, said glycosylated compound has the structure:
In one embodiment, said glycosylated compound has the structure:
In one embodiment, said glycosylated compound has the structure:
In one embodiment, said glycosylated compound has the structure:
In one embodiment, the present invention also contemplates branched tethers. For example, in one embodiment said glycosylated compound has the structure:
In one embodiment, said glycosylated compound has the structure:
In one embodiment, said glycosylated compound has the structure:
In one embodiment, said glycosylated compound has the structure:
In one embodiment, said glycosylated compound has the structure:
In one embodiment, said glycosylated compound has the structure:
In one embodiment, said glycosylated compound has the structure:
In one embodiment, said glycosylated compound has the structure:
In one embodiment, the glycosylated compound further comprises a diluent selected from the group consisting of water, saline, dextrose, glycerol, polyethylene glycol (PEG) and poly(ethylene glycol methyl ether). In one embodiment, the present invention contemplates a water-based formulation comprising the glycosylated compound, wherein said formulation is suitable for intravenous administration. In one embodiment, the water solubility of said glycosylated compound in said formulation is greater than the water solubility of the unglycosylated drug (e.g. the unmodified drug). In one embodiment, the water-based formulation is oil-free.
In one embodiment, the present invention contemplates a method for making a glycosylated compound of the formula: CARB-T-L-D wherein CARB is a carbohydrate connected through a straight chain or branched chemical tether T to linking group L which is connected to said drug, said method comprising: a) providing a drug and a modified carbohydrate, said modified carbohydrate comprising a tethered functional group, said functional group selected from the group consisting of alcohols, amines and thiol groups; b) modifying the hydroxyl group on said drug, so as to create a modified drug comprising a linker intermediate; and c) reacting said modified drug with said modified carbohydrate, so as to create a glycosylated compound of the formula CARB-T-L-D, wherein said linker intermediate is converted to a linker L. In one embodiment, said modifying of step b) comprises reacting said drug with a reactant selected from the group consisting of phosgene, triphosgene, thiophosgene, and oxalyl chloride so as to create a linker intermediate. In one embodiment, said reactant is a halo carbonate. In one embodiment, said linker intermediate is a chloroformate. In one embodiment, said linker intermediate is a thionochloroformate. In one embodiment, the linker intermediate is reacted so as to create glycosylated drug comprising a carbonate, a thiocarbonate, or a carbamate group. In one embodiment, said modified carbohydrate has additional functional groups that are protected with protecting groups (or wherein the said carbohydrate has its functional groups protected with protecting groups). In one embodiment, said protected functional groups are acetylated. In one embodiment, said carbohydrate containing protecting groups is an acetylated pyranoside. In one embodiment, after step c) said protecting groups are removed. In one embodiment, the linker intermediate is converted in step c) above to a linker having the formula C(Z) or C double bonded to Z, wherein Z is O or S. In one embodiment, said modified carbohydrate is selected from the group consisting of a mono-, di- and tri-saccharides. In one embodiment, said monosaccharide is a glucose-derived glycal. In one embodiment, said disaccharide is selected from the group consisting of a lactose-derived glycal and a maltose-derived glycal.
In one embodiment, the present invention contemplates a method for making a glycosylated compound of the formula: CARB-T-L-D wherein CARB is a carbohydrate connected through a straight chain or branched chemical tether T to linking group L which is connected to D, a drug, said method comprising: a) providing D, a drug, and a modified carbohydrate, said modified carbohydrate comprising a tethered functional group, said functional group selected from the group consisting of alcohols, amines and thiol groups; b) modifying the hydroxyl, thiol, or amine group on the tether attached to the carbohydrate, so as to create a modified tether comprising a linker intermediate; and c) reacting said modified tethered carbohydrate with D, a drug, so as to create a glycosylated compound of the formula CARB-T-L-D, wherein said linker intermediate is converted to linker L. In one embodiment, the linker intermediate is reacted so as to create a glycosylated drug comprising a carbonate, a thiocarbonate, or a carbamate group. In one embodiment, said modified carbohydrate has additional functional groups that are protected with protecting groups (wherein the said carbohydrate has its functional group protected with protecting groups). In one embodiment, said protected functional groups are acetylated. In one embodiment, said carbohydrate containing protecting groups is an acetylated pyranoside. In one embodiment, after step c) said protecting groups are removed. In one embodiment, said modified carbohydrate is selected from the group consisting of a mono-, di- and tri-saccharides. In one embodiment, said monosaccharide is a glucose-derived glycal. In one embodiment, said disaccharide is selected from the group consisting of a lactose-derived glycal and a maltose-derived glycal.
In one embodiment, the carbohydrate unit (CARB) or units attached to the drug are exemplified but not limited to 2,3-desoxy-2,3-dehydroglucose, glucoside, mannoside, galactoside, alloside, guloside, idoside, taloside, rhamnoside, maltoside, 2,3-desoxy-2,3-dehydromaltoside, 2,3-desoxymaltoside, lactoside, 2,3-desoxy-2,3-dehydro-lactoside, 2,3-desoxylactoside, glucouronate, glucosamine, galactosamine, mannosamine, N-acetylglucosamine, N-acetylgalactosamine, and N-acetylmannosamine. In one embodiment, the present invention contemplates the use of carbohydrate unit or units having five-membered rings, known as furanoses. In one embodiment, the present invention contemplates the use of carbohydrate unit or units having six-membered rings, known as pyranoses. Combinations of furanoses and pyranoses are also contemplated.
In one embodiment, the carbohydrate unit (CARB) or units attached to the drug contain acetate protecting group are exemplified but not limited to 2,3-desoxy-2,3-dehydroglucose diacetate, glucoside tetraacetate, mannoside tetraacetate, galactoside tetraacetate, alloside tetraacetate, guloside tetraacetate, idoside tetraacetate, taloside tetraacetate, rhamnoside triacetate, maltoside heptaacetate, 2,3-desoxy-2,3-dehydromaltoside pentaacetate, 2,3-desoxymaltoside pentaacetate, lactoside tetraacetate, 2,3-desoxy-2,3-dehydrolactoside pentaacetate, 2,3-desoxylactoside pentaacetate, glucouronate triacetate, N-acetylglucosamine triacetate N-acetylgalactosamine triacetate, and N-acetylmannosamine triacetate. In one embodiment, the present invention contemplates the use of carbohydrate unit or units having five-membered rings, known as furanoses. In one embodiment, the present invention contemplates the use of carbohydrate unit or units having six-membered rings, known as pyranoses. Combinations of furanoses and pyranoses are also contemplated.
In one embodiment, the carbohydrate unit (CARB) or units attached to the drug contain protecting groups exemplified but not limited to an acetyl group, including acetyl (Ac), chloroacetyl (ClAc), propionyl, benzoyl (Bz), and pivalyl (Piv). Non-acyl protecting groups include but not limited to benzyl (Bn), β-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), methylthiomethyl ether, tetrahydropyran (THP), silyl ethers (including but not limited to trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), and triisopropylsilyl (TIPS) ethers), methyl ethers, and ethoxyethyl ethers (EE). In one embodiment, the carbohydrate unit (CARB) or units attached to the drug contain a protecting group exemplified but not limited to amine protecting groups: carbobenzyloxy (Cbz) group, p-methoxybenzyl carbonyl (Moz or MeOZ) group, tert-butyloxycarbonyl (BOC) group, 9-fluorenylmethyloxycarbonyl (FMOC) group, benzyl (Bn) group, p-methoxybenzyl (PMB), dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP) group, tosyl (Ts) group, and other sulfonamides (Nosyl & Nps) groups. In one embodiment, the carbohydrate unit (CARB) or units attached to the drug contain a protecting group exemplified but not limited to carbonyl protecting groups: acetals, ketals, acylals, and dithianes. Carboxylic acid protecting groups: alkyl esters, aryl esters, silyl esters.
It can also be contemplated that branched tethered analogs be prepared as well. These branched tethers can be prepared in a similar manner as those described above. The branching could be aliphatic, cyclic, contain other functionalities to aid in making the compound more water-soluble, or it could contain another carbohydrate. For example, in one embodiment, the present invention contemplates a non-carbohydrate functionality which increases water solubility. Non-limiting examples of such functionalities include sodium carboxylate and sodium sulfate.
In a preferred embodiment, the present invention contemplates that the tether T is branched and comprises another carbohydrate, wherein said carbohydrate is selected from the group consisting of a mono-, di- and tri-saccharides. Thus it is quite possible that analogs similar to that shown below would have characteristics superior to those that have been prepared and described herein.
Since the analogs above contain two monosaccharides, it is expected that their water solubility would be more comparable to that of disaccharide analogs SCD1 and SCD2 than those containing just one monosaccharide moiety.
It is not intended that the present invention be limited by the medical uses for the glycosylated compounds described herein. In one embodiment, the present invention contemplates a method of treating a subject, comprising: a) providing an glycosylated compound of the formula: CARB-T-L-D, wherein CARB is a carbohydrate connected through a chemical tether T to linking group L which is connected to D, a drug, wherein said carbohydrate is selected from the group consisting of a mono-, di- and tri-saccharides, and b) administering said glycosylated compound to a subject. In one embodiment, said tether comprises —(CR1R2)m(CR3R4)n(CR5R6)p—, wherein m, n, and p are independent and can be a whole numbers between 0 and 10 (preferably when the sum of m, n and p are between 1 and 3) and where R1, R2, R3, R4, R5 and R6 are each independent can be hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, heteroarylalkyl, or substituted heteroarylalkyl. Any of R1, R2, R3, R4, R5 and R6 (including R when X═NR) can be joined to provide a cyclic tether. It should be noted that in one embodiment of simple straight chain tethers, n and p=0, R1 and R2═H, and the tether formula —(CR1R2)m(CR3R4)n(CR5R6)p— collapses to —(CH2)m—); The subject can be a human or non-human animal. In one embodiment, said linker is created by chemical modification of a hydroxyl group on D, a drug, so as to create a linker intermediate. In one embodiment, said linker intermediate is a chloroformate. In one embodiment, the linker intermediate is converted to a linker upon reaction with a modified carbohydrate so as to generate the glycosylated drug. In one embodiment, the glycosylated drug comprises a carbonate, a carbamate, or thiocarbonate group.
It is not intended that the present invention be limited by the timing of administration or the nature of subject's condition. In one embodiment, the subject has cancer and a glycosylated anti-cancer drug is administered to treat the cancer. It is not intended that the present invention be limited to treatment that cures cancer. It is sufficient if growth of the cancer is slowed or inhibited.
In one embodiment, the compound can be administered before, during or after a medical procedure (e.g. a diagnostic or surgical procedure). In one embodiment, the procedure can involve the insertion of medical devices or tubes into the subject. For example, in one embodiment, the human is mechanically ventilated (e.g. the compound is administered to calm the patient in order to better tolerate mechanical ventilation). The procedure can be for minor surgery (e.g. removing teeth) or more complicated surgery.
It is not intended that the present invention be limited by the route of administration; all routes of administration (e.g. oral, nasal, etc.) can be employed. However, in a preferred embodiment, the administering is by intravenous administration. In a preferred embodiment, the compound is in a water-based (and preferably oil-free) formulation. In one embodiment, said human after said administering is sedated (typically indicated by a reduction of alertness, sensitivity, irritability or agitation). In one embodiment, the subject experiences reduced pain. In one embodiment, the subject is soporous.
The present invention relates to methods and compositions for the production and use of pro-drug analogs. This invention relates to a method for the production of a broad group of novel glycoside derivatives of drugs, including but not limited to drugs containing an amine or thiol group, and more preferably at least one hydroxyl group, such as phenols and alcohols. The invention also importantly relates to the resulting glycosides as novel compounds of diverse application having desired properties including pharmacodynamic properties; and to medicaments containing the pro-drug compounds.
It is not intended that the present invention be limited by the nature of the drug. In one embodiment, the invention relates to methods of synthesizing derivatives of drugs containing hydroxyl groups. In other embodiments, the drug is glycosylated utilizing a secondary and/or tertiary aliphatic alcohol. In other embodiments, the drug is glycosylated utilizing an amine. In another embodiment, the drug is glycosylated utilizing a secondary amine (pyrrolidine). In still another embodiment, the drug is glycosylated utilizing a primary amine or an aniline with an additional reactive functionality (4-aminophenol). In some cases it is best to make the chloroformate (or chloroformamide) of the drug (as in the case of propofol); in others it is best to make the chloroformate (or chloroformamide) of the tethered sugar. Additional preferred drugs are described below.
In one embodiment, the present invention contemplates glycosylated propofol. Propofol is a short-acting, intravenously administered sedative agent and is approved for use in more than 50 countries. Its uses include the induction and maintenance of general anesthesia, sedation for mechanically ventilated adults, and procedural sedation for both adults and children. Propofol is also commonly used in veterinary medicine. McKeage (2003) is an excellent review on use of propofol [2] with discussions on dosage, formulation (issues with), human pharmacokinetics and pharmacodynamics. Ellett (2010) is an excellent review on propofol use [3, 4]. Lamond (2010) is a very good review on the increasing use of propofol in pediatric procedural sedation [5]. Symington (2006) details the use of propofol in procedural sedation in the emergency department [6].
Propofol has very little water solubility so its formulation has been problematic. The standard formulation currently used is 1% or 2% propofol in 10% soya bean oil as long chain triglycerides with EDTA. Another major issue is that the administration causes great pain 80% of the time that it is used. The current solution for this is pretreatment with local anesthetics (e.g. lidocaine) (also see Table 2 in Sneyd (2004) [7]. Also, the lipid based formulation of propofol is susceptible to bacterial and fungal infection. Use of EDTA has been somewhat effective in curbing this serious contamination.
Sneyd (2004) is a good review on i.v. anesthetics with major focus on propofol [7]. Table 1 delineates different formulations both on the market as well as those tried in the clinic, including cyclodextrin-based and polysorbate-based ones [7].
Harris (2009) addresses issues with current formulation of propofol [8] and Egan (2003) compares a cyclodextrin-based formulation (Captisol®) versus propofol in the current lipid-based formulation [9]. Ravenelle (2007) describes a novel polymer-based formulation of propofol using amphiphilic block copolymers of poly-(N-vinyl-2-pyrrolidone) and poly-(D,L-lactide), PVP-PLA [10].
Fospropofol disodium (Aquavan®, Lusedra), approved by the FDA in 2008 and does not cause pain upon injection, is a phosphorylated prodrug of propofol, which upon hydrolysis in vivo by alkaline phosphatases releases the active drug propofol, formaldehyde and phosphate. However, there is significant time-lag to reach peak-effect when compared with propofol and patient recovery is correspondingly slower. Thus, fospropofol has a slower pharmacokinetic and pharmacodynamic profile than propofol lipid emulsion. On the other hand the advantage is that its slower profile may allow for an ease of administration that requires less frequent administration of medication for brief procedures. Moreover, fospropofol has side-effects not associated with propofol, which include perineal pain or paraesthesia. It should also be noted that fospropofol is approved for use only by persons trained in the administration of general anesthesia.
Sneyd (2010) is an updated review and includes a section on fospropofol that outlines its advantages and disadvantages [11]. Levitzky (2008) reviews on the use of fospropofol for the sedation of patients undergoing colonoscopy, highlighting the pharmacokinetics, pharmacodynamics, risks, and common adverse events associated with fospropofol [12]. Harris (2009) gives a good overview of the pharmacokinetics, pharmacodynamics and clinical use of fospropofol [8]. Yavas (2008) describes an interactive web-based simulation for propofol and fospropofol and their pharmacokinetics and pharmacodynamics [13].
The ‘ideal’ anesthetic should, like propofol, have a rapid onset (<30 sec) and a short duration of action (˜5 min), but it should also have a good safety margin. Regarding an ‘ideal’ prodrug of an anesthetic such as propofol, it is desirable that it has a rapid onset—close to that of propofol. Thus the prodrug should release propofol in vivo in a rapid, facile and near quantitative manner. Also, the prodrug should be devoid of any toxic or undesired side effects and a fast clearance of the prodrug would also be advantageous.
In one embodiment, the present invention contemplates glycosylating acetaminophen. Acetaminophen is a widely used over-the-counter analgesic (pain reliever) and antipyretic (fever reducer). It is commonly used for the relief of fever, headaches, and other minor aches and pains, and is a major ingredient in numerous cold and flu remedies. In combination with non-steroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics, acetaminophen is used also in the management of more severe pain (such as postoperative pain).
One of the problems in the development of an injectable acetaminophen is its poor solubility in water. One approach to improve solubility is to glycosylate acetaminophen. For example, glycosylated acetaminophen pro-drug analogs that with an olefin at the 2,3 position of the carbohydrate are described in U.S. Pat. No. 5,693,767 [14] shown in
Acetaminophen is most stable at pH 6, and the analogs with the olefin at the 2,3 position, will hydrolyze easily at this and lower pH's. Thus, new acetaminophen analogs are needed that are more water soluble than acetaminophen itself, stable to pH's lower than 7, and release acetaminophen in the blood quickly.
Table 1 shows different formulations of propofol.
Table 2 shows methods to alleviate or modify pain on injection with propofol which have been evaluated in randomized controlled trials from Sneyd 2004 [7].
Table 3 shows the structure and solubility determination of propofol analogs.
Table 4 shows clinical observations of rats during Administration of propofol analogs during pharmacokinetics study as described in Example 36.
Table 5A shows pharmacokinetics study details for propofol, and compounds 9, 12, and 17 as described in Example 36.
Table 5B shows pharmacokinetics study details for compounds 24, 25, 32 and 33 as described in Example 36.
Table 6 shows the mean concentration of pro-drug and propofol in rat plasma after intravenous infusion administration as described in Example 36.
Table 7 shows mean concentration of propofol in rat plasma after intravenous infusion of each pro-drug of propofol as described in Example 36.
Table 8 shows examples of compounds contemplated and how they correspond to one embodiment of the general formula.
To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.
As used herein, “acetaminophen” refers to a compound represented by the following chemical structure:
where R is H. It is not intended that the invention be limited to any particular derivative, analog or isomer of acetaminophen or salt thereof. Examples of derivatives of acetaminophen include but are in no way limited to acetaminophen or glycoside derivatives of acetaminophen. It is not intended that the present invention be limited by the type of chemical substituent or substituents that is or are coordinated to acetaminophen. Examples of chemical substituents include but are in no way limited to hydrogen, methyl, ethyl, formyl, acetyl, phenyl, chloride, bromide, hydroxyl, methoxyl, ethoxyl, methylthiol, ethylthiol, propionyl, carboxyl, methoxy carbonyl, ethoxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, butylthiocarbonyl, dimethylcarbamyl, diethylcarbamyl, N-piperidinylcarbonyl, N-methyl-N′-piperazinylcarbonyl, 2-(dimethylamino)ethylcarboxyl, N-morpholinylcarbonyl, 2-(dimethylamino)ethylcarbamyl, 1-piperidinylcarbonyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, 2-piperidinylethyl, 2-morpholinylethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, butylthiol, dimethylamino, diethylamino, piperidinyl, pyrrolidinyl, imidazolyl, pyrazolyl, N-methylpiperazinyl and 2-(dimethylamino)ethylamino.
Camptothecin (CPT) is a cytotoxic quinoline alkaloid which inhibits the DNA enzyme topoisomerase I (topo I). As used herein, “camptothecin” refers to a compound represented by the following chemical structure:
where R is H. Camptothecin also has the formal name (S)-4-ethyl-4-hydroxy-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione. It is not intended that the invention be limited to any particular derivative, analog or isomer of camptothecin or salt thereof. Examples of derivatives of camptothecin include but are in no way limited to camptothecin or glycoside derivatives of camptothecin.
In one embodiment derivatives of camptothecin have the following structure:
Some examples of camptothecin derivatives of this formula include:
It is not intended that the present invention be limited by the type of chemical substituent or substituents that is or are coordinated to camptothecin. Examples of chemical substituents include but are in no way limited to hydrogen, methyl, ethyl, formyl, acetyl, phenyl, chloride, bromide, hydroxyl, methoxyl, ethoxyl, methylthiol, ethylthiol, propionyl, carboxyl, methoxy carbonyl, ethoxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, butylthiocarbonyl, dimethylcarbamyl, diethylcarbamyl, N-piperidinylcarbonyl, N-methyl-N′-piperazinylcarbonyl, 2-(dimethylamino)ethylcarboxyl, N-morpholinylcarbonyl, 2-(dimethylamino)ethylcarbamyl, 1-piperidinylcarbonyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, 2-piperidinylethyl, 2-morpholinylethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, butylthiol, dimethylamino, diethylamino, piperidinyl, pyrrolidinyl, imidazolyl, pyrazolyl, N-methylpiperazinyl and 2-(dimethylamino)ethylamino.
Irinotecan is a drug used for the treatment of cancer. Irinotecan is a topoisomerase 1 inhibitor, which prevents DNA from unwinding. In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin. As used herein, “irinotecan” refers to a compound represented by the following chemical structure:
where R is H. Irinotecan also has the formal name (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4′bipiperidine]-1′-carboxylate. It is not intended that the invention be limited to any particular derivative, analog or isomer of irinotecan or salt thereof. Examples of derivatives of irinotecan include but are in no way limited to irinotecan or glycoside derivatives of irinotecan. It is not intended that the present invention be limited by the type of chemical substituent or substituents that is or are coordinated to irinotecan. Examples of chemical substituents include but are in no way limited to hydrogen, methyl, ethyl, formyl, acetyl, phenyl, chloride, bromide, hydroxyl, methoxyl, ethoxyl, methylthiol, ethylthiol, propionyl, carboxyl, methoxy carbonyl, ethoxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, butylthiocarbonyl, dimethylcarbamyl, diethylcarbamyl, N-piperidinylcarbonyl, N-methyl-N′-piperazinylcarbonyl, 2-(dimethylamino)ethylcarboxyl, N-morpholinylcarbonyl, 2-(dimethylamino)ethylcarbamyl, 1-piperidinylcarbonyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, 2-piperidinylethyl, 2-morpholinylethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, butylthiol, dimethylamino, diethylamino, piperidinyl, pyrrolidinyl, imidazolyl, pyrazolyl, N-methylpiperazinyl and 2-(dimethylamino)ethylamino.
Topotecan hydrochloride (trade name Hycamtin) is a chemotherapy agent that is a topoisomerase I inhibitor. It is the water-soluble derivative of camptothecin. It is used to treat ovarian cancer and lung cancer, as well as other cancer types. As used herein, “topotecan” refers to a compound represented by the following chemical structure:
where R is H. Topotecan also has the formal name (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione monohydrochloride. It is not intended that the invention be limited to any particular derivative, analog or isomer of topotecan or salt thereof. Examples of derivatives of topotecan include but are in no way limited to topotecan or glycoside derivatives of topotecan. It is not intended that the present invention be limited by the type of chemical substituent or substituents that is or are coordinated to topotecan. Examples of chemical substituents include but are in no way limited to hydrogen, methyl, ethyl, formyl, acetyl, phenyl, chloride, bromide, hydroxyl, methoxyl, ethoxyl, methylthiol, ethylthiol, propionyl, carboxyl, methoxy carbonyl, ethoxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, butylthiocarbonyl, dimethylcarbamyl, diethylcarbamyl, N-piperidinylcarbonyl, N-methyl-N′-piperazinylcarbonyl, 2-(dimethylamino)ethylcarboxyl, N-morpholinylcarbonyl, 2-(dimethylamino)ethylcarbamyl, 1-piperidinylcarbonyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, 2-piperidinylethyl, 2-morpholinylethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, butylthiol, dimethylamino, diethylamino, piperidinyl, pyrrolidinyl, imidazolyl, pyrazolyl, N-methylpiperazinyl and 2-(dimethylamino)ethylamino.
As used herein, “propofol” refers to a compound represented by the following chemical structure:
where R is H. Propofol also has the formal name 2,6-diisopropylphenol. It is not intended that the invention be limited to any particular derivative, analog or isomer of propofol or salt thereof. Examples of derivatives of propofol include but are in no way limited to propofol or glycoside derivatives of propofol. It is not intended that the present invention be limited by the type of chemical substituent or substituents that is or are coordinated to propofol. Examples of chemical substituents include but are in no way limited to hydrogen, methyl, ethyl, formyl, acetyl, phenyl, chloride, bromide, hydroxyl, methoxyl, ethoxyl, methylthiol, ethylthiol, propionyl, carboxyl, methoxy carbonyl, ethoxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, butylthiocarbonyl, dimethylcarbamyl, diethylcarbamyl, N-piperidinylcarbonyl, N-methyl-N-piperazinylcarbonyl, 2-(dimethylamino)ethylcarboxyl, N-morpholinylcarbonyl, 2-(dimethylamino)ethylcarbamyl, 1-piperidinylcarbonyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, 2-piperidinylethyl, 2-morpholinylethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, butylthiol, dimethylamino, diethylamino, piperidinyl, pyrrolidinyl, imidazolyl, pyrazolyl, N-methylpiperazinyl and 2-(dimethylamino)ethylamino.
As used herein, “betulin” refers to a compound represented by the following chemical structure:
where R is H. Betulin is also known as lup-20(29)-ene-3β, 28 diol and also has the formal name (1R,3aS,5aR,5bR,9S,11aR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-ol. It is not intended that the invention be limited to any particular derivative, analog or isomer of betulin or salt thereof. Examples of derivatives of betulin include but are in no way limited to betulin or glycoside derivatives of betulin. It is not intended that the present invention be limited by the type of chemical substituent or substituents that is or are coordinated to betulin. Examples of chemical substituents include but are in no way limited to hydrogen, methyl, ethyl, formyl, acetyl, phenyl, chloride, bromide, hydroxyl, methoxyl, ethoxyl, methylthiol, ethylthiol, propionyl, carboxyl, methoxy carbonyl, ethoxycarbonyl, methylthiocarbonyl, ethylthiocarbonyl, butylthiocarbonyl, dimethylcarbamyl, diethylcarbamyl, N-piperidinylcarbonyl, N-methyl-N′-piperazinylcarbonyl, 2-(dimethylamino)ethylcarboxyl, N-morpholinylcarbonyl, 2-(dimethylamino)ethylcarbamyl, 1-piperidinylcarbonyl, methylsulfonyl, ethylsulfonyl, phenylsulfonyl, 2-piperidinylethyl, 2-morpholinylethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, butylthiol, dimethylamino, diethylamino, piperidinyl, pyrrolidinyl, imidazolyl, pyrazolyl, N-methylpiperazinyl and 2-(dimethylamino)ethylamino.
Betulin (lup-20(29)-ene-3β,28-diol) is an abundant naturally occurring triterpene. It is commonly isolated from the bark of birch trees and forms up to 30% of the dry weight of the extractive [15]. The purpose of the compound in the bark is not known. It can be converted to betulinic acid (the alcohol group replaced by a carboxylic acid group), which is biologically more active than betulin itself.
“Epimers” refer to diastereomers that differ in configuration of only one stereogenic center. Diastereomers are a class of stereoisomers that are non-superposable, non-mirror images of one another, unlike enantiomers that are non-superposable mirror images of one another.
“Anomers” refer to a special type of epimer. It is a stereoisomer (diastereomer, more precisely) of a cyclic saccharide that differs only in its configuration at the hemiacetal or hemiketal carbon, also called the anomeric carbon.
Anomers are identified as “α” or “β” based on the relation between the stereochemistry of the exocyclic oxygen atom at the anomeric carbon and the oxygen attached to the configurational atom (defining the sugar as
For example in the case of α-
Unless otherwise stated, it can be assumed the current invention contemplates both α and β anomers described.
“Sugar” refers to a monosaccharide, disaccharide, trisaccharides, or polysaccharides. Monosaccharides have the general formula (CH2O)n, in which n is an integer larger than 2. Disaccharides have the general formula Cn(H2O)n-1, with n larger than 5. Polysaccharides include such substances as cellulose, dextrin, glycogen, and starch.
A “pharmaceutically acceptable monosaccharide” is a pharmaceutically acceptable aldose sugar, a pharmaceutically acceptable ketose sugar, or other specified sugar. Among the pharmaceutically acceptable aldose sugars within the contemplation of the present invention are erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose and talose. Among the pharmaceutically acceptable ketose sugars preferred for use in the composition of the present invention are erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, and sedoheptulose. Among the other specified sugars preferred for use in the composition of the present invention are fucose, fuculose, rhamnose, or any other deoxy sugar. Although either (
The present disaccharide derivatives are preferably derived from disaccharides of the general formula C12H22O11 and may suitably be chosen from the group consisting of cellobiose, gentiobiose, lactose, lactulose, maltose, melibiose, sucrose, trehalose, and turanose. Preferably, the novel disaccharide derivatives are derived from lactose, maltose or sucrose.
The pharmaceutical compositions of the present invention may be prepared by formulating them in dosage forms which are suitable for peroral, rectal or non-parenteral administration, the last-mentioned including intravenous injection and administration into the cerebrospinal fluid. For this purpose, common carriers and routine formulation techniques may be employed.
“API” or “active pharmaceutical ingredient” means the substance in a pharmaceutical drug that is biologically active.
“Common carriers” means those which are employed in standard pharmaceutical preparations and includes excipients, binders and disintegrators the choice of which depends on the specific dosage form used. Typical examples of the excipient are starch, lactose, sucrose, glucose, mannitol, and cellulose; illustrative binders are polyvinylpyrrolidone, starch, sucrose, hydroxypropyl cellulose and gum arabic; illustrative disintegrators include starch, agar, gelatin powder, cellulose, and CMC. Any other common excipients, binders and disintegrators may also be employed.
In addition of the carriers described above, the pharmaceutical composition of the present invention preferably contains antioxidants for the purpose of stabilizing the effective ingredient. Appropriate antioxidants may be selected from among those which are commonly incorporated in pharmaceuticals and include ascorbic acid, N-acetylcysteine,
The term “substrate” is used herein to mean something to which molecules can be attached (e.g. to which a linker can be attached), including but not limited to something that can be chemically modified (e.g. something with functional groups that can be modified) for the attachment of molecules. A substrate can be a pharmaceutical (i.e. drug). However, a substrate can also serve as a drug platform or drug carrier. It may take the form of a solid support, such as nanoparticles, beads and the like. However, it may also simply be a molecule, such as a polymer, including polymers which hydrolyze in the body so as to release the attached drug.
Formulations of the pharmaceutical composition of the present invention which are suitable for peroral administration may be provided in the form of tablets, capsules, powders, granules, or suspensions in non-aqueous solutions such as syrups, emulsions or drafts, each containing one or more of the active compounds in predetermined amounts.
The granule may be provided by first preparing an intimate mixture of one or more of the active ingredients with one or more of the auxiliary components shown above, then granulating the mixture, and classifying the granules by screening through a sieve.
The tablet may be prepared by compressing or otherwise forming one or more of the active ingredients, optionally with one or more auxiliary components.
The capsule may be prepared by first making a powder or granules as an intimate mixture of one or more of the active ingredients with one or more auxiliary components, then charging the mixture into an appropriate capsule on a packing machine, etc.
The pharmaceutical composition of the present invention may be formulated as a suppository (for rectal administration) with the aid of a common carrier such a cocoa butter. The pharmaceutical composition of the present invention may also be formulated in a dosage form suitable for non-parenteral administration by packaging one or more active ingredients as dry solids in a sterile nitrogen-purged container. The resulting dry formulation may be administered to patients non-parenterally after being dispersed or dissolved in a given amount of aseptic water.
The dosage forms are preferably prepared from a mixture of the active ingredients, routine auxiliary components and one or more of the antioxidants listed above. If desired, the formulations may further contain one or more auxiliary components selected from among excipients, buffers, flavoring agents, binders, surfactants, thickening agents, and lubricants.
The dose of the various pro-drugs will of course vary with the route of administration, the severity of the disease to be treated, and the patient to be treated, but the exact dose ultimately chosen should be left to the good discretion of the doctor responsible for the treatment. If a desired dose is determined, the active ingredient may be administered once a day or, alternatively, it may be administered in up to as many portions as deemed appropriate at suitable intervals. The active ingredient may be straightforwardly administered without being mixed with any other components. However, for several reasons, typically for the purpose of providing ease in controlling the dose level, the active compound is preferably administered in a pharmaceutical dosage form.
The term “salts”, as used herein, refers to any salt that complexes with identified compounds contained herein while retaining a desired function, e.g., biological activity. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as, but not limited to, acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic, acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and polygalacturonic acid. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Suitable pharmaceutically-acceptable base addition salts include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, and trimethylamine. All of these salts may be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of the invention. Unless otherwise specifically stated, the present invention contemplates pharmaceutically acceptable salts of the considered pro-drugs.
As used herein, “hydrogen” means —H; “hydroxy” means —OH; “oxo” means ═O; “halo” means independently —F, —Cl, —Br or —I; “amino” means —NH2 (see below for definitions of groups containing the term amino, e.g., alkylamino); “hydroxyamino” means —NHOH; “nitro” means —NO2; “imino” means ═NH (see below for definitions of groups containing the term imino, e.g., alkylamino); “cyano” means —CN; “azido” means —N3; “mercapto” means —SH; “thio” means ═S; “sulfonamido” means —NHS(O)2— (see below for definitions of groups containing the term sulfonamido, e.g., alkylsulfonamido); “sulfonyl” means —S(O)2— (see below for definitions of groups containing the term sulfonyl, e.g., alkylsulfonyl); and “silyl” means —SiH3 (see below for definitions of group(s) containing the term silyl, e.g., alkylsilyl).
As used herein, “olefin” means any of a class of unsaturated hydrocarbon containing one or more pairs of carbon atoms linked by a double bond (see covalent bond, saturation). Olefins may be classified by whether the double bond is in a ring (cyclic) or a chain (acyclic, or aliphatic) or by the number of double bonds (monoolefin, diolefin, etc.).
As used herein, “methylene” means a chemical species in which a carbon atom is bonded to two hydrogen atoms. The —CH2— group is considered to be the standard methylene group. Methylene groups in a chain or ring contribute to its size and lipophilicity. In this context dideoxy also refers the methylene groups. In particular a 2,3-dideoxy compound is the same as 2,3-methylene (2,3-methylene-glycoside=2,3-dideoxy-glycoside).
For the groups below, the following parenthetical subscripts further define the groups as follows: “(Cn)” defines the exact number (n) of carbon atoms in the group; “(C≦n)” defines the maximum number (n) of carbon atoms that can be in the group; (Cn-n′) defines both the minimum (n) and maximum number (n′) of carbon atoms in the group. For example, “alkoxy(C≦10)” designates those alkoxy groups having from 1 to 10 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or any range derivable therein (e.g., 3-10 carbon atoms)). Similarly, “alkyl(C2-10)” designates those alkyl groups having from 2 to 10 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, or any range derivable therein (e.g., 3-10 carbon atoms)).
The term “alkyl” when used without the “substituted” modifier refers to a non-aromatic monovalent group with a saturated carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups, —CH3 (Me), —CH2CH3 (Et), —CH2CH2CH3 (n-Pr), —CH(CH3)2 (iso-Pr or i-Pr), —CH(CH2)2 (cyclopropyl), —CH2CH2CH2CH3 (n-Bu), —CH(CH3)CH2CH3 (sec-butyl or sec-Bu), —CH2CH(CH3)2 (iso-butyl or i-Bu), —C(CH3)3 (tert-butyl or t-Bu), —CH2C(CH3)3 (neo-pentyl), cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexylmethyl are non-limiting examples of alkyl groups. The term “substituted alkyl” refers to a non-aromatic monovalent group with a saturated carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The following groups are non-limiting examples of substituted alkyl groups: —CH2OH, —CH2Cl, —CH2Br, —CH2SH, —CF3, —CH2CN, —CH2C(O)H, —CH2C(O)OH, —CH2C(O)OCH3, —CH2C(O)NH2, —CH2C(O)NHCH3, —CH2C(O)CH3, —CH2OCH3, —CH2OCH2CF3, —CH2OC(O)CH3, —CH2NH2, —CH2NHCH3, —CH2N(CH3)2, —CH2CH2Cl, —CH2CH2OH, —CH2CF3, —CH2CH2OC(O)CH3, —CH2CH2NHCO2C(CH3)3, and —CH2Si(CH3)3.
The term “alkanediyl” when used without the “substituted” modifier refers to a non-aromatic divalent group, wherein the alkanediyl group is attached with two σ-bonds, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups, —CH2-(methylene), —CH2CH2—, —CH2C(CH3)2CH2—, —CH2CH2CH2—, and
are non-limiting examples of alkanediyl groups. The term “substituted alkanediyl” refers to a non-aromatic monovalent group, wherein the alkenediyl group is attached with two σ-bonds, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The following groups are non-limiting examples of substituted alkanediyl groups: —CH(F)—, —CF2—, —CH(Cl)—, —CH(OH)—, —CH(OCH3)—, and —CH2CH(Cl)—.
The term “alkenyl” when used without the “substituted” modifier refers to a monovalent group with a nonaromatic carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples of alkenyl groups include: —CH═CH2 (vinyl), —CH═CHCH3, —CH═CHCH2CH3, —CH2CH═CH2 (allyl), —CH2CH═CHCH3, and —CH═CH—C6H5. The term “substituted alkenyl” refers to a monovalent group with a nonaromatic carbon atom as the point of attachment, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, a linear or branched, cyclo, cyclic or acyclic structure, and at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The groups, —CH—CHF, —CH═CHCl and —CH═CHBr, are non-limiting examples of substituted alkenyl groups.
The term “alkenediyl” when used without the “substituted” modifier refers to a non-aromatic divalent group, wherein the alkenediyl group is attached with two σ-bonds, with two carbon atoms as points of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. The groups, —CH═CH—, —CH═C(CH3)CH2—, —CH═CHCH2—, and
are non-limiting examples of alkenediyl groups. The term “substituted alkenediyl” refers to a non-aromatic divalent group, wherein the alkenediyl group is attached with two σ-bonds, with two carbon atoms as points of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The following groups are non-limiting examples of substituted alkenediyl groups: —CF═CH—, —C(OH)═CH—, and —CH2CH═C(Cl)—.
The term “alkynyl” when used without the “substituted” modifier refers to a monovalent group with a nonaromatic carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. The groups, —C≡CH, —C≡CCH3, —C≡CC6H5 and —CH2C≡CCH3, are non-limiting examples of alkynyl groups. The term “substituted alkynyl” refers to a monovalent group with a nonaromatic carbon atom as the point of attachment and at least one carbon-carbon triple bond, a linear or branched, cyclo, cyclic or acyclic structure, and at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The group, —C≡CSi(CH3)3, is a non-limiting example of a substituted alkynyl group.
The term “alkynediyl” when used without the “substituted” modifier refers to a non-aromatic divalent group, wherein the alkynediyl group is attached with two σ-bonds, with two carbon atoms as points of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. The groups, —C≡C—, —C≡CCH2—, and —C≡CCH(CH3)— are non-limiting examples of alkynediyl groups. The term “substituted alkynediyl” refers to a non-aromatic divalent group, wherein the alkynediyl group is attached with two σ-bonds, with two carbon atoms as points of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one carbon-carbon triple bond, and at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The groups —C≡CCFH— and —C≡CCH(Cl)— are non-limiting examples of substituted alkynediyl groups.
The term “aryl” when used without the “substituted” modifier refers to a monovalent group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a six-membered aromatic ring structure wherein the ring atoms are all carbon, and wherein the monovalent group consists of no atoms other than carbon and hydrogen. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, C6H3(CH3)2 (dimethylphenyl), —C6H4—CH2CH3 (ethylphenyl), —C6H4CH2CH2CH3 (propylphenyl), —C6H4CH(CH3)2, —C6H4CH(CH2)2, —C6H3(CH3)CH2CH3 (methylethylphenyl), —C6H4CH═CH2 (vinylphenyl), —C6H4CH═CHCH3, —C6H4C≡CH, —C6H4C≡CCH3, naphthyl, and the monovalent group derived from biphenyl. The twit “substituted aryl” refers to a monovalent group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a six-membered aromatic ring structure wherein the ring atoms are all carbon, and wherein the monovalent group further has at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S, Non-limiting examples of substituted aryl groups include the groups: —C6H4F, —C6H4Cl, —C6H4Br, —C6H4I, —C6H4OH, —C6H4OCH3, —C6H4OCH2CH3, —C6H4OC(O)CH3, —C6H4NH2, C6H4NHCH3, —C6H4N(CH3)2, —C6H4CH2OH, —C6H4CH2OC(O)CH3, —C6H4CH2NH2, —C6H4CF3, —C6H4CN, —C6H4CHO, —C6H4CHO, —C6H4C(O)CH3, —C6H4C(O)C6H5, —C6H4CO2H, —C6H4CO2CH3, —C6H4CONH2, —C6H4CONHCH3, and —C6H4CON(CH3)2.
The term “arenediyl” when used without the “substituted” modifier refers to a divalent group, wherein the arenediyl group is attached with two σ-bonds, with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structure(s) wherein the ring atoms are all carbon, and wherein the monovalent group consists of no atoms other than carbon and hydrogen. Non-limiting examples of arenediyl groups include:
The term “substituted arenediyl” refers to a divalent group, wherein the arenediyl group is attached with two σ-bonds, with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic rings structure(s), wherein the ring atoms are all carbon, and wherein the divalent group further has at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
The term “aralkyl” when used without the “substituted” modifier refers to the monovalent group -alkanediyl-aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above. Non-limiting examples of aralkyls are: phenylmethyl (benzyl, Bn), 1-phenyl-ethyl, 2-phenyl-ethyl, indenyl and 2,3-dihydro-indenyl, provided that indenyl and 2,3-dihydro-indenyl are only examples of aralkyl in so far as the point of attachment in each case is one of the saturated carbon atoms. When the term “aralkyl” is used with the “substituted” modifier, either one or both the alkanediyl and the aryl is substituted. Non-limiting examples of substituted aralkyls are: (3-chlorophenyl)-methyl, 2-oxo-2-phenyl-ethyl(phenylcarbonylmethyl), 2-chloro-2-phenyl-ethyl, chromanyl where the point of attachment is one of the saturated carbon atoms, and tetrahydroquinolinyl where the point of attachment is one of the saturated atoms.
The term “heteroaryl” when used without the “substituted” modifier refers to a monovalent group with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of an aromatic ring structure wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the monovalent group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. Non-limiting examples of aryl groups include acridinyl, furanyl, imidazoimidazolyl, imidazopyrazolyl, imidazopyridinyl, imidazopyrimidinyl, indolyl, indazolinyl, methylpyridyl, oxazolyl, phenylimidazolyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, tetrahydroquinolinyl, thienyl, triazinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrroloimidazolyl, chromenyl (where the point of attachment is one of the aromatic atoms), and chromanyl (where the point of attachment is one of the aromatic atoms). The term “substituted heteroaryl” refers to a monovalent group with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of an aromatic ring structure wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the monovalent group further has at least one atom independently selected from the group consisting of non-aromatic nitrogen, non-aromatic oxygen, non aromatic sulfur F, Cl, Br, I, Si, and P.
The term “heteroarenediyl” when used without the “substituted” modifier refers to a divalent group, wherein the heteroarenediyl group is attached with two σ-bonds, with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom two aromatic atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structure(s) wherein the ring atoms are all carbon, and wherein the monovalent group consists of no atoms other than carbon and hydrogen. Non-limiting examples of heteroarenediyl groups include:
The term “substituted heteroarenediyl” refers to a divalent group, wherein the heteroarenediyl group is attached with two σ-bonds, with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic rings structure(s), wherein the ring atoms are all carbon, and wherein the divalent group further has at least one atom independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.
The term “heteroaralkyl” when used without the “substituted” modifier refers to the monovalent group -alkanediyl-heteroaryl, in which the terms alkanediyl and heteroaryl are each used in a manner consistent with the definitions provided above. Non-limiting examples of aralkyls are: pyridylmethyl, and thienylmethyl. When the term “heteroaralkyl” is used with the “substituted” modifier, either one or both the alkanediyl and the heteroaryl is substituted.
The term “acyl” when used without the “substituted” modifier refers to a monovalent group with a carbon atom of a carbonyl group as the point of attachment, further having a linear or branched, cyclo, cyclic or acyclic structure, further having no additional atoms that are not carbon or hydrogen, beyond the oxygen atom of the carbonyl group. The groups, —CHO, —C(O)CH3, —C(O)CH2CH3, —C(O)CH2CH2CH3, —C(O)CH(CH3)2, —C(O)CH(CH2)2, —C(O)C6H5, —C(O)C6H4CH3, —C(O)C6H4CH2CH3, —COC6H3(CH3)2, and —C(O)CH2C6H5, are non-limiting examples of acyl groups. The term “acyl” therefore encompasses, but is not limited to groups sometimes referred to as “alkyl carbonyl” and “aryl carbonyl” groups. The term “substituted acyl” refers to a monovalent group with a carbon atom of a carbonyl group as the point of attachment, further having a linear or branched, cyclo, cyclic or acyclic structure, further having at least one atom, in addition to the oxygen of the carbonyl group, independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The groups, —C(O)CH2CF3, —C(O)CH2Cl, —CO2H (carboxyl), —CO2CH3 (methylcarboxyl), —CO2CH2CH3, —CO2CH2CH2CH3, —CO2C6H5, —CO2CH(CH3)2, —CO2CH(CH2)2, —C(O)NH2 (carbamoyl), —C(O)NHCH3, —C(O)NHCH2CH3, —CONHCH(CH3)2, —CONHCH(CH2)2, —CON(CH3)2, —CONHCH2CF3, —CO-pyridyl, —CO-imidazoyl, and —C(O)N3, are non-limiting examples of substituted acyl groups. The term “substituted acyl” encompasses, but is not limited to, “heteroaryl carbonyl” groups.
The term “alkylidene” when used without the “substituted” modifier refers to the divalent group ═CRR′, wherein the alkylidene group is attached with one σ-bond and one π-bond, in which R and R′ are independently hydrogen, alkyl, or R and R′ are taken together to represent alkanediyl. Non-limiting examples of alkylidene groups include: ═CH2, ═CH(CH2CH3), and ═C(CH3)2. The term “substituted alkylidene” refers to the group ═CRR′, wherein the alkylidene group is attached with one σ-bond and one π-bond, in which R and R′ are independently hydrogen, alkyl, substituted alkyl, or R and R′ are taken together to represent a substituted alkanediyl, provided that either one of R and R′ is a substituted alkyl or R and R′ are taken together to represent a substituted alkanediyl.
The term “alkoxy” when used without the “substituted” modifier refers to the group —OR, in which R is an alkyl, as that term is defined above. Non-limiting examples of alkoxy groups include: —OCH3, —OCH2CH3, —OCH2CH2CH3, —OCH(CH3)2, —OCH(CH2)2, —O-cyclopentyl, and —O-cyclohexyl. The term “substituted alkoxy” refers to the group —OR, in which R is a substituted alkyl, as that term is defined above. For example, —OCH2CF3 is a substituted alkoxy group.
In addition, atoms making up the compounds of the present invention are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13C and 14C. Similarly, it is contemplated that one or more carbon atom(s) of a compound of the present invention may be replaced by a silicon atom(s). Furthermore, it is contemplated that one or more oxygen atom(s) of a compound of the present invention may be replaced by a sulfur or selenium atom(s).
In structures wherein stereochemistry is not explicitly indicated, it is assumed that either stereochemistry is considered and both isomers are claimed.
Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to the atom.
The term “protecting group,” as that term is used in the specification and/or claims, is used in the conventional chemical sense as a group, which reversibly renders unreactive a functional group under certain conditions of a desired reaction and is understood not to be H. After the desired reaction, protecting groups may be removed to deprotect the protected functional group. All protecting groups should be removable (and hence, labile) under conditions which do not degrade a substantial proportion of the molecules being synthesized. In contrast to a protecting group, a “capping group” permanently binds to a segment of a molecule to prevent any further chemical transformation of that segment. It should be noted that the functionality protected by the protecting group may or may not be a part of what is referred to as the protecting group.
Protecting groups include but are not limited to: alcohol protecting groups: acetoxy group, acetate (AC), β-methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyran (THP), silyl ethers (including but not limited to trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), and triisopropylsilyl (TIPS) ethers), methyl ethers, and ethoxyethyl ethers (EE). Amine protecting groups: carbobenzyloxy (Cbz) group, p-methoxybenzyl carbonyl (Moz or MeOZ) group, tert-butyloxycarbonyl (BOC) group, 9-fluorenylmethyloxycarbonyl (FMOC) group, benzyl (Bn) group, p-methoxybenzyl (PMB), dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP) group, tosyl (Ts) group, and other sulfonamides (Nosyl & Nps) groups. Carbonyl protecting groups: acetals, ketals, acylals, and dithianes. Carboxylic acid protecting groups: alkyl esters, aryl esters, silyl esters. Protection of terminal alkynes protected as propargyl alcohols in the Favorskii reaction. These and other considered protecting groups are described in the book on protecting groups by Wuts and Greene [16].
The term “leaving group,” as that term is used in the specification and/or claims, is an atom or group (charged or uncharged) that becomes detached from an atom in what is considered to be the residual or main part of the substrate in a specified reaction.
Leaving groups include, but are not limited to: NH2− (amine), CH3O− (methoxy), HO− (hydroxyl), CH3COO− (carboxylate), H2O (water), F−, Cl−, Br−, I−, N3− (azide), SCN− (thiocyanate), NO2 (nitro), tosyl (Ts) groups, and protecting groups.
The term “effective,” as that term is used in the specification and/or claims, means adequate to accomplish a desired, or hoped for result.
The term “hydrate” when used as a modifier to a compound means that the compound has less than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) water molecules associated with each compound molecule, such as in solid forms of the compound.
An “isomer” of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs.
As used herein, the term “patient” or “subject” refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human subjects are adults, juveniles, infants and fetuses.
As used herein, the term “pro-drug” refers to a pharmacological substance (drug) that is administered in an inactive (or significantly less active) form. Once administered, the pro-drug is metabolized in vivo into an active metabolite. The rationale behind the use of a pro-drug is generally for absorption, distribution, metabolism, and excretion (ADME) optimization. Pro-drugs are usually designed to improve oral bioavailability, with poor absorption from the gastrointestinal tract usually being the limiting factor. Additionally, the use of a pro-drug strategy increases the selectivity of the drug for its intended target.
“Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
“Pharmaceutically acceptable salts” means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002) [17]. Unless otherwise specifically stated, the present invention contemplates pharmaceutically acceptable salts of the considered pro-drugs.
As used herein, “predominantly one enantiomer” means that a compound contains at least about 85% of one enantiomer, or more preferably at least about 90% of one enantiomer, or even more preferably at least about 95% of one enantiomer, or most preferably at least about 99% of one enantiomer. Similarly, the phrase “substantially free from other optical isomers” means that the composition contains at most about 15% of another enantiomer or diastereomer, more preferably at most about 10% of another enantiomer or diastereomer, even more preferably at most about 5% of another enantiomer or diastereomer, and most preferably at most about 1% of another enantiomer or diastereomer.
As used herein, “predominantly one anomer” means that a compound contains at least about 85% of one anomer, or more preferably at least about 90% of one anomer, or even more preferably at least about 95% of one anomer, or most preferably at least about 99% of one anomer. Similarly, the phrase “substantially free from other optical isomers” means that the composition contains at most about 15% of another anomer, more preferably at most about 10% of another anomer, even more preferably at most about 5% of another anomer, and most preferably at most about 1% of another anomer.
“Prevention” or “preventing” includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomotology of the disease, and/or (2) slowing the onset of the pathology or symptomotology of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomotology of the disease.
The term “saturated” when referring to an atom means that the atom is connected to other atoms only by means of single bonds.
A “stereoisomer” or “optical isomer” is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs. “Enantiomers” are stereoisomers of a given compound that are mirror images of each other, like left and right hands. “Diastereomers” are stereoisomers of a given compound that are not enantiomers.
Enantiomers are compounds that individually have properties said to have “optical activity” and consist of molecules with at least one chiral center, almost always a carbon atom. If a particular compound is dextrorotary, its enantiomer will be levorotary, and vice-versa. In fact, the enantiomers will rotate polarized light the same number of degrees, but in opposite directions. “Dextrorotation” and “levorotation” (also spelled laevorotation) refer, respectively, to the properties of rotating plane polarized light clockwise (for dextrorotation) or counterclockwise (for levorotation). A compound with dextrorotation is called “dextrorotary,” while a compound with levorotation is called “levorotary”.
A standard measure of the degree to which a compound is dextrorotary or levorotary is the quantity called the “specific rotation” “[α]”. Dextrorotary compounds have a positive specific rotation, while levorotary compounds have negative. Two enantiomers have equal and opposite specific rotations. A dextrorotary compound is prefixed “(+)-” or “d-”. Likewise, a levorotary compound is often prefixed “(−)-” or “l-”. These “d-” and “l-” prefixes should not be confused with the “
The invention contemplates that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, S form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures.
The present invention contemplates the above-described compositions in “therapeutically effective amounts” or “pharmaceutically effective amounts”, which means that amount which, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease or to ameliorate one or more symptoms of a disease or condition (e.g. ameliorate pain).
As used herein, the terms “treat” and “treating” are not limited to the case where the subject (e.g. patient) is cured and the disease is eradicated. Rather, the present invention also contemplates treatment that merely reduces symptoms, improves (to some degree) and/or delays disease progression. It is not intended that the present invention be limited to instances wherein a disease or affliction is cured. It is sufficient that symptoms are reduced.
“Subject” refers to any mammal, preferably a human patient, livestock, or domestic pet.
In a specific embodiment, the term “pharmaceutically acceptable” means approved by a regulatory agency of the federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, adjuvant, excipient or vehicle with which the active compound is administered. Such pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents can be used. When administered to a subject, the pharmaceutically acceptable vehicles are preferably sterile. Water can be the vehicle when the active compound is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions. Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
Pharmaceutically acceptable sugars include but are not limited to sucrose, dextrose, maltose, galactose, rhamnose, and lactose. Pharmaceutically acceptable sugar alcohols include but are not limited to mannitol, xylitol, and sorbitol.
C0—Initial concentration at time 0, extrapolated.
t1/2—Half-life of the pro-drug analog.
CLp—Estimate of total body clearance, CLp=dose/AUCinf
Vdss—Estimate of the volume of distribution; Vdss=dose/AUCinf
AUClast—Area under the curve of time versus concentration, to the last detected concentration
AUCinf—Area under the curve of time versus concentration, with concentration extrapolated to infinity
MRTinf—Mean Residence Time when the drug concentration profile is extrapolated to infinity.
LLOQ—Low limit of quantitation
n.d.—Not detected
Due to the administration problems that propofol has, we decided to make glycosylated pro-drugs of propofol. It was considered that these analogs would have greater water solubility, and with the phenol glycosylated, the pain experienced by patients due to the drug's acidity would be mitigated. Initial attempts to directly glycosylate propofol under a variety of conditions failed, likely due to sterics imparted by the 2,6 di-isopropyl groups on the phenyl ring system (
Employing less sterically demanding glycals such as tri-O-acetyl glucal also failed, but in this case providing the unexpected C-glycosylated product at C-4 of propofol with an approximated 3:1 ratio of anomers (
With the prospects of direct appearing to be poor, it was decided to design propofol analogs that would have the following attributes: 1) contain a carbohydrate and 2) would be connected to propofol using an agent that would be small in order to minimize the steric effects of propofol's isopropyl groups
After in vivo enzymatic hydrolysis of the carbohydrate, the remaining moiety used to connect the carbohydrate to propofol would quickly eliminate itself, thus liberating propofol itself.
A simple example of the design can be seen in
Thus, a variety of analogs could be prepared from this basic design. As shown in
Initial attempt to prepare analogs of the type described above (in
Propofol was attached to tethered carbohydrate 7 by first treating propofol with triphosgene in pyridine and CH2Cl2 to form, in situ, the chloroformate of propofol (
The propyl version of analog 9 could be prepared by first preparing the propyl version of 7,1-(propan-3-ol)tetra-O-acetyl-β-
In a similar vein for the ethyl tethered analog 9, the chloroformate of propofol was made in situ, followed by addition of 1-(propan-3-ol)-tetra-O-acetyl-β-
Carbamate analogs can be made using a similar approach. 1-(2-bromoethyl)-tetra-O-acetyl-β-
Disaccharide versions of the propofol carbonate analogs 9 and 12 described above could similarly be made by starting with 1-allyl hepta-O-acetyl-β-maltose 18 (
Preparation of the tethered disaccharide analogs of propofol were prepared in the same manner as the monosaccharide analogs 9 and 12 described above. Formation of the chloroformate of propofol preceded treatment with either alcohol 20 or 21 to provide carbonates 22 or 23, respectively (
Finally, all of the tethered glycosylated analogs of propofol have all been of the β configuration at the carbohydrate; α analogs can also be prepared by this approach with a few subtle changes (
Formation of the carbonates 30 and 31 from tethered monosaccharides 28 and 29 proved uneventful (
Table 3 shows the structure of each of the propofol analogs prepared and the solubility of each in D2O using 1H NMR with 3-(trimethylsilyl)-1-propanesulfonic acid sodium salt (DSS) as an internal standard. Unfortunately, while preparing saturated solutions, all but two of the analogs (17 and 33) including propofol itself provided solutions that were not filterable. Thus the soapy-like solutions obtained were diluted until opalescent and diluted further until the opalescence visually disappeared. Qualitatively, inspection of the solubility data shows that carbamate functionality serves as a detriment as compared to its corresponding carbonate; the shorter ethyl tether is more beneficial than its propyl counterpart (9 vs. 12 and 32 vs. 33) and that the α configuration seems to have a better water solubility over its β counterpart (9 vs. 32; 12 vs. 33).
During the pharmacokinetics study on rats, a number of encouraging observations were made of the rats' behavior (Table 4). The control, propofol, was administered i.m. at 30 mg/kg (0.168 mM/kg) in a 5% cremaphor solution; For all of the carbonate analogs, the rats were all soporous between 3 and 7 minutes post the 10 minute infusion and recovered 26-35 minutes post infusion, comparing very favorably to propofol at twice the molar concentration. Due to its poor water solubility, carbamate 17 had to have a cosolvent (10% tween 80) and poor results were obtained for this analog in its vehicle.
The results from the pharmacokinetics details of the study on male Sprague-Dawley rats (Table 5 A & B, Table 6, and Table 7) show the concentration of prodrug in the rats' blood (Table 6) and the concentration of propofol (Table 7) over time. It is apparent that the carbonate analogs 9, 12, 24, 25, 32 and 33 all act as very efficient pro-drugs, releasing the propofol in a matter of minutes after infusion.
In one embodiment, the invention relates to methods of synthesizing derivatives of propofol. In another embodiment the invention relates to methods of synthesizing derivatives of other functionalities, including aliphatic alcohols, amines and anilines. A few important examples are provided and include one each of a secondary and tertiary aliphatic alcohol, and a secondary amine (pyrrolidine) and an aniline with an additional reactive functionality (4-aminophenol). In some cases it is best to make the chloroformate of the drug (as in the case of propofol), in others it is best to make the chloroformate of the tethered sugar.
The potential impact on camptothecin analogs may very well not be overstated. Forming an ester/carbonate/carbamate at the C-20 hydroxyl stabilizes the E-ring lactone, thus retaining its anticancer activity. The method considered in this invention can easily: A) increase the lactone/E-ring stability of many camptothecin analogs on the market or being investigated, including topotecan and irinotecan; B) increase the water-solubility of these same camptothecin analogs on the market or being investigated, again including topotecan and irinotecan; C) potentially increase the efficacy of any of these camptothecin analogs due to the tumor-enhanced uptake of carbohydrate-containing drugs that we have seen with our other camptothecin analogs, as well as some others (including the Bayer drug that was pursued until only recently).
The additional work, described below and in the experimental section, was all done once and is thus unoptimized. The yields stated should be considered as a minimum.
The potential versatility of the method developed can be seen in the following examples. For example, the method works well on aliphatic alcohols as well, as can be seen with functionalization of the secondary hydroxyl of cholesterol (
It might be necessary or desirable to introduce the possibility that the drug needs to have a functional group protected. For example, there are a number of compounds that have both primary and secondary hydroxyls. One such compound is betulin (
The potential versatility of the method developed can be seen in
Aliphatic tertiary hydroxyls can also be functionalized in a similar manner. The formation of the carbonate of the hydroxyl at C-20 of camptothecin (36) did proceed with some difficulty (40% yield) due to the poor solubility of camptothecin in the solvent CH2Cl2. It should be noted that, although a glycosylate of camptothecin at C-20 is known to occur naturally, direct chemical glycosylation of this hydroxyl is extremely difficult. Removal of the acetates proceeds to provide the tethered glucose analog in 21% overall yield of compound 37 (
Functional glycosylation of amines and anilines can also be accomplished with this method.
Finally, it was found that this process could potentially be applied to acetaminophen. As with case of both pyrrolidine and 4-aminophenol, formation of the chloroformate of 7 was more efficient in forming the chloroformate of acetaminophen, compound 42. However, unlike in the case of the phenol propofol, removing the acetates of the carbonate of the phenol 4-acetamidophenol was not successful; only 4-acetamidophenol was isolated. This would be a case in which it would be best to utilize amine 15 for the formation of a carbamate that would be more stable to hydrolysis conditions (
The preparation of branched-tethered analogs of this type should be fairly straight-forward by applying the methodology already described. Bis-glycosylation of 2-methylene 1,3-propane diol under acidic conditions similar to those described herein for allyl alcohol should provide the bis adduct shown in
As in the case for allyl alcohol, this intermediate is set up to provide tethered analogs of two different lengths. Hydroboration under similar conditions as described herein, followed by oxidative work-up should provide the longer of the two branched tethered bis-glycosylates
Alternatively, oxidative cleavage of the alkene (with ozone or with OsO4/NaIO4, as shown in
Finally, preparation of the propofol carbonates from the branched tethered carbohydrates should proceed under similar conditions already described. In situ preparation of the chloroformate of propofol, followed by addition of the branched tethered carbohydrate should provide the penultimate corresponding carbonates of propofol. Removal of the acetate protecting groups on the carbohydrate under mild conditions (in this case with sodium bicarbonate in warm methanol) should provide the target branched tethered analogs, as shown in
The following examples are provided in order to demonstrate and further illustrate certain preferred embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof.
General.
1H and 13C NMR spectra were taken on a Varian Mercury 300 or 400 MHz spectrometer. Chemical shifts are reported in parts per million (ppm) from an internal standard; either 2,2-dimethyl-2-silapentane-5-sulfonate sodium salt (DSS, 0.00 ppm, used for D2O), tetramethylsilane (TMS, 0.00 ppm for all other solvents), or from the solvent residual peak (CDCl3, 7.26 ppm in 1H NMR, 77.23 ppm in 13C NMR; acetone, 2.05 ppm in 1H, 29.84 ppm in 13C; DMSO, 2.50 ppm in 1H, 39.52 ppm in 13C ppm; D2O 4.79 ppm in 1H; methanol 3.31 ppm in 1H, 49.00 in 13C) [Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem., 1997, 62, 7512-7515] as an internal standard [19]. 1H NMR is reported in the following manner chemical shift; multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broadened, dd=doublet of doublets, etc.); coupling constant (in order of the multiplicity). Coupling constants (J values) are given in hertz (Hz). The multiplicity (from attached protons) of each 13C chemical shift is reported as follows, q (a methyl carbon, i.e., CH3), t (CH2), d (CH), and s (quaternary carbon). All chemicals were purchased from Sigma-Aldrich; all solvents were purchased from Pharmco-AAPER. THF was dried over sodium benzophenone ketyl and distilled, CH2Cl2 was dried over CaSO4 and distilled. All reactions were monitored by thin-layer chromatography on silica gel 60 F254 (Merck); detection was carried out by UV and by charring after spraying with a solution made from 4.7 g Ceric ammonium sulfate and 5.6 mL concentrated sulfuric acid diluted to 100 mL. For flash column chromatography, silica gel 60, 230-400 mesh from Mallinckrodt was used. Optical rotations were obtained using a Bellingham+Stanley ADP-220 POLARIMETER. LC-MS experiments were performed using an Agilent 1600 Series LC/MS ion-trap mass spectrometer coupled to an Agilent 1200 Series HPLC system. The mass spectrometer was operated with the electrospray ionization (ESI) source in the positive ion mode. The HPLC system was equipped with an Eclipse XDB-C18 column (Agilent; ID 4.6 mm, length 50 mm, particle size 1.8 μM). Solvents used as eluants were: water with 0.2% formic acid and acetonitrile with 0.2% formic acid.
Propofol 1 (0.430 g) and tri-O-acetyl glucal (0.720 g) were dissolved in CH2Cl2, the solution cooled to −78° C. and BF3OEt2 (0.025 g) was added. The solution was stirred for 1 hr before slowly warming to 0° C. over the course of another hr. The reaction was quenched with 2 mL saturated NaHCO3 and the reaction diluted with CH2Cl2 (50 mL) the aqueous discarded, the organic washed once with NaHCO3 (50 mL), brine (25 mL), dried (Na2SO4), filtered, and concentrated. The crude was then purified by silica gel column chromatography (25% ethyl acetate/hexanes) to provide 0.390 g (41%) 3 as a yellow syrup. 1H NMR (300 MHz, CDCl3) δ 1.26 (d, J=6.9 Hz, 12H), 2.07 (s, 3H), 2.12 (s, 3H), 3.15 (qq, J=6.9, 6.9 Hz, 2H), 3.93 (ddd, J=2.6, 6.1, 9.2 Hz, 1H), 4.18 (1H) and 4.28 (1H) (ABq, JAB=12.0 Hz, the peaks at 4.18 and 4.28 are further split into d, J=6.1 Hz and 2.6 Hz, respectively), 5.04 (s, 1H, OH), 5.13 (br s, 1H), 5.44 (ddd, J=1.4, 1.4, 9.2 Hz, 1H), 5.83 (1H) and 5.93 (1H) (ABq, JAB=10.2 Hz; the peaks at 5.83 and 5.93 are further split into dd, J=1.4, 2.2 Hz and 1.4, 1.7 Hz, respectively), 7.00 (s, 2H); 13C NMR (75.4 MHz, CDCl3) δ 21.1 (q), 21.3 (q), 22.9 (q, 4C), 27.4 (d, 2C), 64.1 (t), 65.9 (d), 75.0 (d), 78.1 (d), 123.2 (d), 124.8 (d), 131.7 (s), 133.4 (d, 2C), 134.0 (s, 2C), 150.5 (s), 170.7 (s), 171.3 (s).
1-Allyl 2,3,4,6-tetra-O-acetyl-β-
1-(2′-oxyethyl) 2,3,4,6-tetra-O-acetyl-β-
Triphosgene (0.416 g) was dissolved in 3 mL CH2Cl2 and cooled to −78° C. A solution of propofol (0.812 g), pyridine (1.661 g) and CH2Cl2 (2 mL) was prepared and added to the triphosgene solution. The reaction mixture was then slowly warmed to room temperature and stirred for 30 min. The mixture was then cooled back down to −78° C., and 1-(ethan-2′-ol)-2,3,4,6-tetra-O-acetyl-β-
1-((2′,6′-diisopropylphenoxy)carbonyloxy)ethyl-2,3,4,6-tetra-O-acetyl-β-
1-((2′,6′-Diisopropylphenoxy)carbonyloxy)ethyl-2,3,4,6-tetra-O-acetyl-β-
1-Allyl 2,3,4,6-tetra-O-acetyl-β-
Triphosgene (0.320 g) was dissolved in 10 mL CH2Cl2 and cooled to −78° C. Propofol (0.577 g) was dissolved in 7 mL CH2Cl2 and pyridine (1.022 g) and then added to the triphosgene solution. The reaction was then slowly warmed to room temperature and stirred for 1 hr. The reaction mixture was then cooled back down to −78° C. and 1-(propan-3′-ol)-2,3,4,6-tetra-O-acetyl-β-
1-((2′,6′-Diisopropylphenoxy)carbonyloxy)propyl-2,3,4,6-tetra-O-acetyl-β-
1-(2′-Bromoethyl)-2,3,4,6-β-
1-(2′-Azidoethyl)-2,3,4,6-β-
Triphosgene (0.047 g) was dissolved in CH2Cl2 (0.5 mL) and cooled to −78° C. Propofol (0.085 g) and pyridine (0.225 g) were dissolved in 1 mL CH2Cl2 and added to the triphosgene mixture. The reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was then cooled back down to −78° C. and 1-(2′-amoniumethyl)-2,3,4,6-β-
1-((2′,6′-diisopropylphenoxy)carbonylamino)ethyl-2,3,4,6-tetra-O-acetyl-β-
1-Allyl hepta-O-acetyl-3-
1-(2-Oxyethyl)hepta-O-acetyl-β-
1-Allyl hepta-O-acetyl-β-
Triphosgene (0.465 g) was dissolved in 2 mL CH2Cl2 and cooled to −78° C. Propofol (0.838 g) was dissolved in pyridine (2.228 g) and CH2Cl2 (3 mL) and added to the triphosgene mixture. The reaction mixture was then slowly warmed to room temperature and stirred for 30 min. The reaction mixture was then cooled back down to −78° C. and 1-(ethan-2-ol) hepta-O-acetyl-β-
Triphosgene (0.205 g) was dissolved in 1 mL CH2Cl2 and cooled to −78° C. Propofol (0.369 g) and pyridine (0.982 g) was dissolved in 1 mL CH2Cl2 and added to the triphosgene solution. The reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was then cooled back down to −78° C. and 1-(propan-3-ol) hepta-O-acetyl-β-
1-((2′,6′-Diisopropylphenoxy)carbonyloxy)ethyl-hepta-O-acetyl-β-
1-((2′,6′-Diisopropylphenoxy)carbonyloxy)propyl-hepta-O-acetyl-β-
1-Allyl 2,3,4,6-tetra-O-acetyl-α-
1-(2′-Oxyethyl) 2,3,4,6-tetra-O-acetyl-α-
1-Allyl 2,3,4,6-tetra-O-acetyl-α-
Triphosgene (0.189 g) was dissolved in CH2Cl2 (0.5 mL) and cooled to −78° C. Propofol (0.341 g) and pyridine (0.503 g) were dissolved in CH2Cl2 (2 mL) and added to the triphosgene solution. The reaction mixture was warmed to room temperature and stirred for 15 min, then cooled back down to −78° C. 1-(Ethan-2′-ol)-2,3,4,6-tetra-O-acetyl-α-
Triphosgene (0.237 g) was dissolved in CH2Cl2 (0.5 mL) and cooled to −78° C. Propofol (0.428 g) and pyridine (0.632) were dissolved in CH2Cl2 (2 mL) and added to the triphosgen solution. The reaction mixture was then warmed to room temperature and stirred for 30 min before cooling it back down to −78° C. 1-(Propan-3′-ol)-2,3,4,6-tetra-O-acetyl-α-
1-((2′,6′-Diisopropylphenoxy)carbonyloxy)ethyl-2,3,4,6-tetra-O-acetyl-α-
1-((2′,6′-Diisopropylphenoxy)carbonyloxy)propyl-2,3,4,6-tetra-O-acetyl-α-
Triphosgene (0.076 g) was dissolved in 2 mL CH2Cl2 and cooled down to −78° C. and cholesterol (0.287 g) dissolved in 2 mL CH2Cl2 and 0.202 g pyridine added. The solution was warmed to room temperature stirred for 30 minutes, and then cooled back down to −78° C. 1-(Ethan-2′-ol)-2,3,4,6-tetra-O-acetyl-β-
Cholesteryl (2-(2′,3′,4′,6′-tetra-O-acetyl-β-
Triphosgene (0.048 g) was dissolved in 2 mL CH2Cl2 and cooled down to −78° C. and camptothecin (0.163 g) suspended in 4 mL CH2Cl2 and 0.128 g pyridine added, warmed to room temperature and stirred overnight. 1-(Ethan-2′-ol)-2,3,4,6-tetra-O-acetyl-β-
20-(2′-(2″,3″,4″,6″-tetra-O-acetyl-β-
Triphosgene (0.072 g) was dissolved in 2 mL CH2Cl2 and cooled down to −78° C. and 1-(ethan-2′-ol)-2,3,4,6-tetra-O-acetyl-β-
2-((Pyrrolidinyl)carbonyloxy)ethyl-2,3,4,6-tetra-O-acetyl-β-
Triphosgene (0.046 g) was dissolved in 2 mL CH2Cl2 and cooled down to −78° C. and 1-(ethan-2′-ol)-2,3,4,6-tetra-O-acetyl-β-
2-((4′-Hydroxyanilinyl)carbonyloxy)ethyl-2,3,4,6-tetra-O-acetyl-β-
Triphosgene (0.071 g) was dissolved in 2 mL CH2Cl2 and cooled down to −78° C. and 1-(ethan-2′-ol)-2,3,4,6-tetra-O-acetyl-β-
General Study Design.
Each of the analogs and 9, 12, 17, 24, 25, 32, and 33 and propofol were to be tested on three male Sprague Dawley rats each at identical doses per weight. If possible, each analog and propofol was to be formulated in water only. Each analog and propofol were to be formulated at identical molar concentrations based on a dose of 30 mg/Kg propofol and administered to the rats i.v. at identical rates of 1 mL/Kg/min for a period of 10 minutes. Blood samples were to be taken pre-dose, during dose and post dose at designated intervals, with the blood quickly processed and stored at −70° C. until analysis.
Animal Specifications.
The male Sprague Dawley rats were obtained from SLAC Laboratory Animal Co. Ltd., Shanghai, China. Following arrival at the testing facility (WuXi AppTec in Shanghai, China), the, rats were assessed as to their general health by a member of the veterinary staff. The rats were acclimated for at least 3 days upon arrival at WuXi AppTec before being placed on study.
Animal Husbandry.
The rats were group-housed during acclimation and individually housed during the study. The animal room environment was controlled (temperature 18 to 26° C., relative humidity 30 to 70%, 12 hours artificial light and 12 hours dark, monitored daily). All animals had access to Certified Rodent Diet (Catalog #M-01F, SLAC Laboratory Animal Co. Ltd., Shanghai, China) ad libitum with each lot number and specifications of each lot used archived. Water was autoclaved before provided to the animals ad libitum; periodic analysis of the water was performed and the results archived.
Dose Formulation.
Formulations were prepared on the morning of the dosing day and each was passed through a 0.22 μm filter prior to being administered to animals. A standard dose of 0.168 mmol/Kg per analog was administered to each of the rats. The formulation for analogs 9, 12, 24, 25, 32, and 33 and propofol was water; due to its poor solubility, the formulation for 17 was 10% tween 20 in water. Analog stability in the formulations was verified by preparing each formulation and harvesting 200 μL aliquots at 0, 1, 2 and 8 hr while standing at room temperature. After harvesting, each sample was immediately frozen in dry ice until analysis; concentrations of test compounds in the samples were examined by HPLC-UV. Dose formulations were assayed in duplicates for each dose with a calibration curve at least 5 points; it was verified that each analog was stable in its formulation.
Dose Administration.
The animals were surgically prepared with indwelling cannula, double cannulation in carotid artery and jugular vein for i.v. infusion. The anesthetic pentobarbital was used during the surgery, and the animals were allowed to recover 3-5 days after surgery before the formulation was dosed. The dose formulation was administered intravenously via the jugular vein cannula. The 16.8 μmol/mL formulation was administered i.v. at a rate of 1 mL/Kg/min for 10 min.
Blood Collection.
Approximately 0.20 mL blood was collected at each designated time point from carotid artery via a catheter. A total of 12 plasma samples were taken from each animal: 1 pre-dose; 2 during the dose (5 into the 10 min infusion and one just prior termination of the 10 min infusion) and 9 post-infusion at 2, 5, 15, 30 min and 1, 2, 3, 4, and 6 hr post-dose. All blood samples were transferred into plastic microcentrifuge tubes containing 5 μL of K2-EDTA (0.5M) as anti-coagulant and placed on ice until processed for plasma. Blood samples were processed for plasma by centrifugation at approximately 5° C. Plasma samples were then stored in 1.5 mL tubes, quick frozen over dry ice and kept at −70±10° C. until LC/MSMS analysis.
Analog and Propofol Concentration in Blood Evaluation:
The plasma concentrations of each of the analogs and propofol were quantified by LC/MS/MS with an internal standard. For each, a minimum of 6 standard point curve runs in duplicates, and minimum of 5 standards were back calculated to within ±20% of their nominal concentrations. The LLOQ of each test article in plasma was established and 6 QC samples were included in assay runs of samples to ensure assay performance. It was confirmed that the measured concentration of each QC sample was within ±20% of their nominal concentrations, and for each assay run at least 4 out of 6 QC samples were within the acceptable range.
Data Analysis.
Plasma concentration versus time data was analyzed by non-compartmental approaches using the WinNonlin software program (version 5.2, Pharsight, Mountain View, Calif.) and the pharmacokinetic parameters T½, CL, Vss, AUC(0-t), AUC(0-inf), MRT, and graphs of plasma concentration versus time calculated for each.
1Solubility determined by suspending the sample in several mLs of D2O and stirred vigorously for overnight. Each solution gave a soapy solution that was not filterable by a.2 μ syringe filter. A small amount of the solution was then separated and D2O added until the solution was clear (this solution first becomes opalescent). A weighed amount DSS was added (density measurements were also made and used to check the volume accuracy by using weight of the solution as a check). The resultant solution was then analyzed by 1H NMR and the relative concentration of analog versus DSS measured, allowing for the solubility determination.
2Reported solubility of 0.7 mM
3Saturated solution was filterable and provided a clear, non-opalescent solution and thus should probably be compared to propofol's reported solubility of 0.7 mM rather than the 1.1 mM value.
4Relative to propofol's reported solubility of 0.7 mM
| Number | Date | Country | |
|---|---|---|---|
| 61475035 | Apr 2011 | US |
