WO2012122422A2 - Active agent prodrugs with heterocyclic linkers - Google Patents
Active agent prodrugs with heterocyclic linkers Download PDFInfo
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- WO2012122422A2 WO2012122422A2 PCT/US2012/028367 US2012028367W WO2012122422A2 WO 2012122422 A2 WO2012122422 A2 WO 2012122422A2 US 2012028367 W US2012028367 W US 2012028367W WO 2012122422 A2 WO2012122422 A2 WO 2012122422A2
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- aryl
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- 0 C*(C(*)(*)C(C)(C)C(CC(C)(*)C(C1)C1C1)N1C(*)=O)NC(C(*)N(*)C(C(*)N(*)*)=O)=O Chemical compound C*(C(*)(*)C(C)(C)C(CC(C)(*)C(C1)C1C1)N1C(*)=O)NC(C(*)N(*)C(C(*)N(*)*)=O)=O 0.000 description 14
- QZTIDHGBHANOPD-TUSRLEQCSA-N CCOC(N(CC1)C[C@H](CNC([C@H](CCCNC(N)=N)NC(CNC(C)=O)=O)=O)N1C(OC1=CC[C@@H]([C@@H](C2)N(C)CC3)[C@]33c4c2ccc(OC)c4O[C@@H]13)=O)=O Chemical compound CCOC(N(CC1)C[C@H](CNC([C@H](CCCNC(N)=N)NC(CNC(C)=O)=O)=O)N1C(OC1=CC[C@@H]([C@@H](C2)N(C)CC3)[C@]33c4c2ccc(OC)c4O[C@@H]13)=O)=O QZTIDHGBHANOPD-TUSRLEQCSA-N 0.000 description 1
- XASIMHXSUQUHLV-UHFFFAOYSA-N CN(C)C(COC(Cc(cc1)ccc1OC(c(cc1)ccc1NC(N)=N)=O)=O)=O Chemical compound CN(C)C(COC(Cc(cc1)ccc1OC(c(cc1)ccc1NC(N)=N)=O)=O)=O XASIMHXSUQUHLV-UHFFFAOYSA-N 0.000 description 1
- LZODCTUOPSORQW-GHZFJQKZSA-N C[C@@H](C(N[C@@H](CCCNC(N)=N)C(NC[C@@H](CCCC1)N1C(OC1=CC[C@@H]([C@@H](C2)N(C)CC3)[C@]33c4c2ccc(OC)c4O[C@@H]13)=O)=O)=O)NC(CC(O)=O)=O Chemical compound C[C@@H](C(N[C@@H](CCCNC(N)=N)C(NC[C@@H](CCCC1)N1C(OC1=CC[C@@H]([C@@H](C2)N(C)CC3)[C@]33c4c2ccc(OC)c4O[C@@H]13)=O)=O)=O)NC(CC(O)=O)=O LZODCTUOPSORQW-GHZFJQKZSA-N 0.000 description 1
- ARNVWEGCBMVRMJ-FPKSHQFTSA-N C[C@H]1N(C)CC[C@]23c(c(C)ccc4OC)c4O[C@H]2C(OC(N2C(CNC([C@H](CCCNC(N)=N)NC(CNC(C)=O)=O)=O)CCCC2)=O)=CC[C@@]13O Chemical compound C[C@H]1N(C)CC[C@]23c(c(C)ccc4OC)c4O[C@H]2C(OC(N2C(CNC([C@H](CCCNC(N)=N)NC(CNC(C)=O)=O)=O)CCCC2)=O)=CC[C@@]13O ARNVWEGCBMVRMJ-FPKSHQFTSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06086—Dipeptides with the first amino acid being basic
- C07K5/06095—Arg-amino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- a number of drugs are susceptible to misuse, abuse, or overdose. Use of and access to these drugs therefore needs to be controlled.
- the control of access to the drugs is expensive to administer and can result in denial of treatment for patients that are not able to present themselves for dosing. For example, patients suffering from acute pain may be denied treatment with a drug unless they have been admitted to a hospital. Furthermore, control of use is often ineffective, leading to substantial morbidity and deleterious social consequences.
- This disclosure concerns a prodrug of an active agent that provides controlled release of the active agent.
- a prodrug comprises an active agent covalently attached to a promoiety.
- the promoiety comprises an enzyme-cleavable moiety and a cyclizable spacer leaving group such that the active agent prodrug provides controlled release of the active agent via enzyme cleavage followed by intramolecular cyclization.
- the enzyme-mediated release of the active agent can occur in the gastrointestinal tract upon oral administration of the corresponding prodrug.
- the present disclosure also provides a composition, such as a pharmaceutical composition, that comprises an active agent prodrug of the embodiments.
- a composition can optionally provide an inhibitor that interacts with the enzyme that mediates the controlled release of active agent from the prodrug so as to attenuate enzymatic cleavage of the prodrug.
- the disclosure provides for the enzyme being a gastrointestinal (GI) enzyme, such as trypsin.
- GI gastrointestinal
- methods of use such as a method of providing patients with controlled release of active agent using an active agent prodrug of the embodiments.
- the embodiments include an active agent prodrug that is a compound of formula I
- X is selected from a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X is selected from a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)- CH(R 6 )-N(R 3 )]b-R 7 ; and a residue of an amide-containing opioid, wherein
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- Certain embodiments provide controlled release of ketone-containing active agent. More particularly, the embodiments relate to a prodrug of a ketone-containing active agent that provides controlled release of the active agent.
- a prodrug comprises a ketone-containing active agent covalently attached to a promoiety through the enolic oxygen atom of the ketone- containing active agent.
- the promoiety comprises an enzyme-cleavable moiety and a cyclizable spacer leaving group such that the ketone-modified active agent prodrug provides controlled release of active agent via enzyme cleavage followed by intramolecular cyclization.
- Ketone- modified active agent prodrugs of the disclosure provide efficient delivery of active agent when ingested.
- the present disclosure also provides a composition, such as a pharmaceutical composition, that comprises a ketone-modified active agent prodrug of the embodiments. Also provided are methods of use, such as a method of providing patients with controlled release of ketone-containing active agent using a ketone-modified active agent prodrug of the
- X represents a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; the A ring is a heterocyclic 5 to 12-membered ring;
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- Certain embodiments provide controlled release of phenolic active agents. More particularly, the embodiments relate to a prodrug of a phenolic active agent that provides controlled release of the active agent.
- a prodrug comprises a phenolic active agent covalently attached to a promoiety through the phenolic oxygen atom of the phenolic active agent.
- the promoiety comprises an enzyme-cleavable moiety and a cyclizable spacer leaving group such that the phenolic active agent prodrug provides controlled release of active agent via enzyme cleavage followed by intramolecular cyclization.
- Phenolic active agent prodrugs of the disclosure provide efficient delivery of active agent when ingested.
- the present disclosure also provides a composition, such as a pharmaceutical composition, that comprises a phenolic active agent prodrug of the embodiments. Also provided are methods of use, such as a method of providing patients with controlled release of phenolic active agent using a phenolic active agent prodrug of the embodiments.
- X represents a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH- C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ;
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- Certain embodiments provide controlled release of amide-containing active agents. More particularly, the embodiments relate to a prodrug of an amide-containing active agent that provides controlled release of the active agent.
- a prodrug comprises an amide-containing active agent covalently attached to a promoiety through the enolic oxygen atom of the amide enol moiety or through the oxygen of the imine tautomer of the amide-containing active agent.
- the promoiety comprises an enzyme-cleavable moiety and a cyclizable spacer leaving group such that the amide-modified active agent prodrug provides controlled release of active agent via enzyme cleavage followed by intramolecular cyclization.
- Amide-modified active agent prodrugs of the disclosure provide efficient delivery of active agent when ingested.
- the present disclosure also provides a composition, such as a pharmaceutical composition, that comprises an amide- modified active agent prodrug of the embodiments. Also provided are methods of use, such as a method of providing patients with controlled release of amide-containing active agent using an amide-modified active agent prodrug of the embodiments.
- X represents a residue of an amide-containing active agent, wherein -C(0)-N[(A ring)- Y c ]-(CR 1 R 2 )a-NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )]b-R 7 is connected to the amide- containing active agent through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- Certain embodiments provide controlled release of acetaminophen. More particularly, the embodiments relate to a prodrug of acetaminophen that provides controlled release of acetaminophen.
- a prodrug comprises acetaminophen covalently attached to a promoiety through the phenolic oxygen atom of acetaminophen or through the oxygen of the amide group of acetaminophen.
- the promoiety comprises an enzyme-cleavable moiety and a cyclizable spacer leaving group such that the acetaminophen prodrug provides controlled release of acetaminophen via enzyme cleavage followed by intramolecular cyclization.
- Acetaminophen prodrugs of the disclosure provide efficient delivery of acetaminophen when ingested.
- the present disclosure also provides a composition, such as a pharmaceutical composition, that comprises acetaminophen prodrug of the embodiments.
- methods of use such as a method of providing patients with controlled release of acetaminophen using acetaminophen prodrug of the embodiments.
- X represents acetaminophen, wherein the hydrogen atom of the phenolic hydroxyl group of acetaminophen is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)- CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; or wherein -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)- CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is connected to acetaminophen through the oxygen of the amide group of acetaminophen, wherein the amide group is converted to an amide enol or an imine tautomer;
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- Figure 1 is a schematic representing the effect of increasing the level of a GI enzyme inhibitor ("inhibitor", X axis) on a PK parameter (e.g., drug Cmax) (Y axis) for a fixed dose of prodrug.
- a GI enzyme inhibitor e.g., drug Cmax
- Y axis e.g., drug Cmax
- the effect of inhibitor upon a prodrug PK parameter can range from undetectable, to moderate, to complete inhibition (i.e., no detectable drug release).
- Figure 2 provides schematics of drug concentration in plasma (Y axis) over time (X axis).
- Panel A is a schematic of a pharmacokinetic (PK) profile following ingestion of prodrug with a GI enzyme inhibitor (dashed line) where the drug Cmax is modified relative to that of prodrug without inhibitor (solid line).
- Panel B is a schematic of a PK profile following ingestion of prodrug with inhibitor (dashed line) where drug Cmax and drug Tmax are modified relative to that of prodrug without inhibitor (solid line).
- Panel C is a schematic of a PK profile following ingestion of prodrug with inhibitor (dashed line) where drug Tmax is modified relative to that of prodrug without inhibitor (solid line).
- Figure 3 provides schematics representing differential concentration-dose PK profiles that can result from the dosing of multiples of a dose unit (X axis) of the present disclosure.
- Different PK profiles (as exemplified herein for a representative PK parameter, drug Cmax (Y axis)) can be provided by adjusting the relative amount of prodrug and GI enzyme inhibitor contained in a single dose unit or by using a different prodrug or inhibitor in the dose unit.
- Figure 4 compares mean plasma concentrations over time of oxycodone release following PO administration to rats of several ketone-modified active agent prodrugs of the embodiments.
- Figure 5A compares mean plasma concentrations over time of oxycodone release following PO administration to dogs of several ketone-modified active agent prodrugs of the embodiments.
- Figure 5B compares mean plasma concentrations over time of oxycodone release following PO administration to dogs of ketone-modified active agent prodrug Compound KC-17 of the embodiments, oxycodone prodrug Compound KC-3, OxyContin ® tablets, or oxycodone HC1.
- Figure 6A compares mean plasma concentrations over time of oxycodone release following PO administration to rats of increasing doses of ketone-modified active agent prodrug Compound KC-12.
- Figure 6B compares mean plasma concentrations over time of oxycodone release following PO administration to rats of increasing doses of ketone-modified active agent prodrug Compound KC-17.
- Figure 7A compares mean plasma concentrations over time of oxycodone release following PO administration to rats of ketone-modified active agent prodrug Compound KC-12 co-dosed with increasing amounts of trypsin inhibitor Compound 109.
- Figure 7B and Figure 7C compare mean plasma concentrations over time of oxycodone release following PO
- Figure 8 compares mean plasma concentrations over time of tapentadol release following PO administration to rats of phenolic active agent prodrug Compound TP-5 in the absence or presence of a co-dose of trypsin inhibitor Compound 109.
- Figure 9 compares mean plasma concentrations over time of hydrocodone release following PO administration to rats of increasing doses of ketone-modified active agent prodrug Compound KC-31.
- Figure 10 compares mean plasma concentrations over time of hydrocodone release following PO administration to rats of hydrocodone and PO administration to rats of
- hydrocodone prodrugs Compound KC-32, Compound KC-35, Compound KC-36, and
- Figure 11 compares mean plasma concentrations over time of hydrocodone release following PO administration to rats of hydrocodone and PO administration to rats of
- hydrocodone prodrugs Compound KC-38 and Compound KC-39.
- Figure 12 compares mean plasma concentrations over time of hydrocodone release following PO administration to rats of hydrocodone and PO administration to rats of
- hydrocodone prodrugs Compound KC-40, Compound KC-47, and Compound KC-50.
- Figure 13A compares mean plasma concentrations over time of hydrocodone release following PO administration to rats of prodrug Compound KC-40 with increasing amounts of co- dosed trypsin inhibitor Compound 109.
- Figure 13B compares mean plasma concentrations over time of hydrocodone release following PO administration to rats of prodrug Compound KC-40 with increasing amounts of co-dosed trypsin inhibitor Compound 109 to hydrocodone values expected from a normalized hydrocodone dose.
- Figure 13C compares the mean plasma concentrations over time of hydrocodone release following PO administration to rats of prodrug Compound KC-50 with increasing amounts of co-dosed trypsin inhibitor Compound 109.
- Figure 13D compares mean plasma concentrations over time of hydrocodone release following PO administration to rats of prodrug Compound KC-50 with increasing amounts of co-dosed trypsin inhibitor Compound 109 to hydrocodone values expected from a normalized hydrocodone dose.
- Figure 14A compares mean plasma concentrations over time of hydrocodone following PO administration to dogs of hydrocodone and PO administration to dogs of increasing amounts of prodrug Compound KC-40.
- Figure 14B, Figure 14C and 14D each compares mean plasma concentrations over time of hydrocodone following PO administration to dogs of, respectively, 1, 4 or 10 dose units comprising prodrug Compound KC-40 and trypsin inhibitor Compound 109 to plasma concentrations of hydrocodone following PO administered to dogs of 1 dose equivalent of hydrocodone or predicted concentrations for 4 or 10 dose equivalents of hydrocodone, respectively.
- Figure 15A compares mean plasma concentrations over time of hydrocodone following PO administration to dogs of hydrocodone and PO administration to dogs of increasing amounts of prodrug Compound KC-50.
- Figure 15B and Figure 15C compare mean plasma concentrations over time of hydrocodone following PO administration to dogs of hydrocodone to plasma concentrations over time of hydrocodone following PO administration to dogs of the indicated doses of prodrug Compound KC-50 with or without trypsin inhibitor Compound 109.
- Figure 16 compares mean plasma concentrations over time of oxycodone release following PO administration to rats of oxycodone prodrug Compound KC-55 or oxycodone.
- Figure 17A provides oxycodone exposure results for rats orally administered prodrug Compound KC-55 alone or co-dosed with trypsin inhibitor Compound 109.
- Figure 17B provides oxycodone exposure results for rats orally administered prodrug Compound KC-55 alone or co- dosed with trypsin inhibitor Compound 109.
- Alkyl by itself or as part of another substituent refers to a saturated branched or straight-chain monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
- Typical alkyl groups include, but are not limited to, methyl; ethyl, propyls such as propan-l-yl or propan-2-yl; and butyls such as butan-l-yl, butan-2-yl, 2-methyl-propan-l-yl or 2-methyl-propan-2-yl.
- an alkyl group comprises from 1 to 20 carbon atoms.
- an alkyl group comprises from 1 to 10 carbon atoms.
- an alkyl group comprises from 1 to 6 carbon atoms, such as from 1 to 4 carbon atoms.
- alkanyl by itself or as part of another substituent refers to a saturated branched, straight-chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of an alkane.
- Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-l-yl, propan-2-yl (isopropyl), cyclopropan-l-yl, etc.; butanyls such as butan-l-yl, butan-2-yl (sec-butyl), 2-methyl-propan-l-yl (isobutyl), 2-methyl-propan-2- yl (t-butyl), cyclobutan-l-yl, etc.; and the like.
- Alkylene refers to a branched or unbranched saturated hydrocarbon chain, usually having from 1 to 40 carbon atoms, more usually 1 to 10 carbon atoms and even more usually 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH 2 -), ethylene
- Alkenyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of an alkene.
- the group may be in either the cis or trans conformation about the double bond(s).
- Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl, cycloprop-l-en-l-yl; cycloprop-2-en-l-yl; butenyls such as but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-1,3- dien-l-yl, buta-l,3-dien-2-yl, cyclobut-l-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-l,3-dien-l-yl, etc.; and the like.
- Alkynyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of an alkyne.
- Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-l-yn-l-yl, prop-2-yn-l-yl, etc.; butynyls such as but-l-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl, etc.; and the like.
- Acyl by itself or as part of another substituent refers to a radical -C(0)R 30 , where R 30 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,
- heteroarylalkyl as defined herein and substituted versions thereof.
- Representative examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, piperonyl, succinyl, and malonyl, and the like.
- Acylamino refers to the groups -NR 20 C(O)alkyl, -NR 20 C(O)substituted alkyl, N R 20 C(O)cycloalkyl, -NR 20 C(O)substituted cycloalkyl, -
- Amino refers to the group -NH 2 .
- Substituted amino refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl provided that at least one R is not hydrogen.
- Aminoacyl refers to the group -C(0)NR 21 R 22 , wherein R 21 and R 22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl
- Alkoxy by itself or as part of another substituent refers to a radical -OR 31 where R 31 represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.
- Alkoxycarbonyl by itself or as part of another substituent refers to a radical -C(0)OR 31 where R 31 represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
- Aryl by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of an aromatic ring system.
- Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
- Arylalkyl by itself or as part of another substituent refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with an aryl group.
- Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 2-phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2- naphthylethen-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like.
- an arylalkyl group is (C 7 -C 30 ) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C 1 -C 10 ) and the aryl moiety is (C6-C 20 ).
- an arylalkyl group is (C 7 -C 20 ) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (Ci-Cg) and the aryl moiety is (C 6 -Ci 2 ).
- Arylaryl by itself or as part of another substituent, refers to a monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a ring system in which two or more identical or non-identical aromatic ring systems are joined directly together by a single bond, where the number of such direct ring junctions is one less than the number of aromatic ring systems involved.
- Typical arylaryl groups include, but are not limited to, biphenyl, triphenyl, phenyl-napthyl, binaphthyl, biphenyl-napthyl, and the like. When the number of carbon atoms in an arylaryl group is specified, the numbers refer to the carbon atoms comprising each aromatic ring.
- arylaryl is an arylaryl group in which each aromatic ring comprises from 5 to 14 carbons, e.g., biphenyl, triphenyl, binaphthyl, phenylnapthyl, etc.
- each aromatic ring system of an arylaryl group is independently a (C 5 -C 14 ) aromatic.
- each aromatic ring system of an arylaryl group is
- each aromatic ring system is identical, e.g., biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.
- Carboxyl refers to -CO 2 H or salts thereof.
- Cycloalkyl by itself or as part of another substituent refers to a saturated or unsaturated cyclic alkyl radical. Where a specific level of saturation is intended, the nomenclature
- cycloalkanyl or “cycloalkenyl” is used.
- Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like.
- the cycloalkyl group is (C 3 -C 10 ) cycloalkyl.
- the cycloalkyl group is (C 3 -C 7 ) cycloalkyl.
- Cycloheteroalkyl or “heterocyclyl” by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom.
- Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Where a specific level of saturation is intended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used.
- Typical cycloheteroalkyl groups include, but are not limited to, groups derived from epoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine and the like.
- Heteroalkyl, Heteroalkanyl, Heteroalkenyl and Heteroalkynyl by themselves or as part of another substituent refer to alkyl, alkanyl, alkenyl and alkynyl groups, respectively, in which one or more of the carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatomic groups.
- Heteroaryl by itself or as part of another substituent, refers to a monovalent
- heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a heteroaromatic ring system.
- Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,
- the heteroaryl group is from 5-20 membered heteroaryl. In certain embodiments, the heteroaryl group is from 5-10 membered heteroaryl. In certain embodiments, heteroaryl groups are those derived from thiophene, pyrrole,
- benzothiophene benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
- Heteroarylalkyl by itself or as part of another substituent, refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylalkenyl and/or hetero arylalkynyl is used.
- the hetero arylalkyl group is a 6-30 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10 membered and the heteroaryl moiety is a 5-20-membered heteroaryl.
- the heteroarylalkyl group is 6-20 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8 membered and the heteroaryl moiety is a 5-12-membered heteroaryl.
- Heterocycle refers to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 15 ring atoms, including 1 to 4 hetero atoms. These hetero atoms are selected from the group consisting of nitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring.
- the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N- oxide, -S(O)-, or -S0 2 - moieties.
- aromatic ring system fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc.
- Typical aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as- indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta- 2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like.
- Heteroaromatic Ring System by itself or as part of another substituent, refers to an aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "heteroaromatic ring systems” are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, arsindole, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc.
- Typical heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, ⁇ - carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadia
- Substituted refers to a group in which one or more hydrogen atoms are independently replaced with the same or different substituent(s).
- R 64 and R 65 are independently hydrogen, alkyl, substituted alkyl, aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 64 and R 65 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted heteroaryl, or optionally R 64 and R 65 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted
- substituents include -M, -R 60 ,
- substituents include -M, -R 60 ,
- a substituted group may bear a methylenedioxy substituent or one, two, or three substituents selected from a halogen atom, a (l-4C)alkyl group and a (l-4C)alkoxy group.
- any of the groups disclosed herein which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
- the subject compounds include all stereochemical isomers arising from the substitution of these compounds.
- arylalkyloxycarbonyl refers to the group (aryl)-(alkyl)-0-C(0)-.
- Dose unit refers to a combination of a GI enzyme-cleavable prodrug (e.g., trypsin-cleavable prodrug) and a GI enzyme inhibitor (e.g., a trypsin inhibitor).
- a GI enzyme-cleavable prodrug e.g., trypsin-cleavable prodrug
- a GI enzyme inhibitor e.g., a trypsin inhibitor
- a “single dose unit” is a single unit of a combination of a GI enzyme-cleavable prodrug (e.g., trypsin- cleavable prodrug) and a GI enzyme inhibitor (e.g., trypsin inhibitor), where the single dose unit provide a therapeutically effective amount of drug (i.e., a sufficient amount of drug to effect a therapeutic effect, e.g., a dose within the respective drug's therapeutic window, or therapeutic range).
- a therapeutically effective amount of drug i.e., a sufficient amount of drug to effect a therapeutic effect, e.g., a dose within the respective drug's therapeutic window, or therapeutic range.
- Gastrointestinal enzyme or "GI enzyme” refers to an enzyme located in the central nervous system
- GI gastrointestinal
- Trypsin is an example of a GI enzyme.
- Gastrointestinal enzyme-cleavable moiety or “GI enzyme-cleavable moiety” refers to a group comprising a site susceptible to cleavage by a GI enzyme.
- a "trypsin- cleavable moiety” refers to a group comprising a site susceptible to cleavage by trypsin.
- Gastrointestinal enzyme inhibitor or "GI enzyme inhibitor” refers to any agent capable of inhibiting the action of a gastrointestinal enzyme on a substrate.
- the term also encompasses salts of gastrointestinal enzyme inhibitors.
- a "trypsin inhibitor” refers to any agent capable of inhibiting the action of trypsin on a substrate.
- Patient includes humans, and also other mammals, such as livestock, zoo animals, and companion animals, such as a cat, dog, or horse.
- “Pharmaceutical composition” refers to at least one compound and can further comprise a pharmaceutically acceptable carrier, with which the compound is administered to a patient.
- “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or vehicle with, or in which a compound is administered.
- “Pharmaceutically acceptable salt” refers to a salt of a compound, which possesses the desired pharmacological activity of the compound.
- Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-
- PD profile refers to a profile of the efficacy of a drug in a patient (or subject or user), which is characterized by PD parameters.
- PD parameters include “drug Emax” (the maximum drug efficacy), “drug EC50” (the concentration of drug at 50% of the Emax) and side effects.
- PK parameter refers to a measure of drug concentration in blood or plasma, such as: 1) “drug Cmax”, the maximum concentration of drug achieved in blood or plasma; 2) “drug Tmax”, the time elapsed following ingestion to achieve Cmax; and 3) “drug exposure”, the total concentration of drug present in blood or plasma over a selected period of time, which can be measured using the area under the curve (AUC) of a time course of drug release over a selected period of time (t). Modification of one or more PK parameters provides for a modified PK profile.
- PK profile refers to a profile of drug concentration in blood or plasma. Such a profile can be a relationship of drug concentration over time (i.e., a "concentration-time PK profile”) or a relationship of drug concentration versus number of doses ingested (i.e., a "concentration-dose PK profile”).
- a PK profile is characterized by PK parameters.
- Preventing or “prevention” or “prophylaxis” refers to a reduction in risk of occurrence of a condition, such as pain.
- Prodrug refers to a derivative of an active agent that requires a transformation within the body to release the active agent.
- the transformation is an enzymatic transformation.
- the transformation is a cyclization transformation.
- the transformation is a combination of an enzymatic transformation and a cyclization transformation. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent.
- Promoiety refers to a form of protecting group that when used to mask a functional group within an active agent converts the active agent into a prodrug. Typically, the promoiety will be attached to the drug via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.
- solute refers to a complex or aggregate formed by one or more molecules of a solute, e.g. a prodrug or a pharmaceutically acceptable salt thereof, and one or more molecules of a solvent.
- solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent.
- Representative solvents include by way of example, water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is water, the solvate formed is a hydrate.
- “Therapeutically effective amount” means the amount of a compound (e.g., prodrug) that, when administered to a patient for preventing or treating a condition such as pain, is sufficient to effect such treatment.
- the “therapeutically effective amount” will vary depending on the compound, the condition and its severity and the age, weight, etc., of the patient.
- Treating” or “treatment” of any condition refers, in certain embodiments, to ameliorating the condition (i.e., arresting or reducing the development of the condition). In certain embodiments “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the patient. In certain embodiments, “treating” or “treatment” refers to inhibiting the condition, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In certain embodiments, “treating” or “treatment” refers to delaying the onset of the condition.
- a entity or “an” entity refers to one or more of that entity.
- a compound refers to one or more compounds.
- the terms “a”, “an”, “one or more” and “at least one” can be used interchangeably.
- the terms “comprising”, “including” and “having” can be used interchangeably.
- chromatographic means such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography.
- HPLC high performance liquid chromatography
- Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. See, e.g., Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, ed. E. Stahl, Springer- Verlag, New York, 1969.
- any of the processes for preparation of the compounds of the present disclosure it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Fourth edition, Wiley, New York 2006.
- the protecting groups can be removed at a convenient subsequent stage using methods known from the art.
- the compounds described herein can contain one or more chiral centers and/or double bonds and therefore, can exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, all possible enantiomers and stereoisomers of the compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures are included in the description of the compounds herein. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.
- the compounds can also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.
- the compounds described also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include, but are not limited to, 2 H, 3 H, U C, 13 C, 14 C, 15 N, 18 0, 17 0, etc.
- Compounds can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, compounds can be hydrated or solvated. Certain compounds can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure.
- the disclosure provides a method of providing a patient with post administration- activated, controlled release of an active agent, which comprises administering to the patient a corresponding compound in which the active agent has a substituent which is a spacer leaving group bearing a nucleophilic nitrogen that is protected with an enzyme-cleavable moiety, the configuration of the spacer leaving group being such that, upon enzymatic cleavage of the cleavable moiety, the nucleophilic nitrogen is capable of forming a cyclic urea, liberating the compound from the spacer leaving group so as to provide the patient with controlled release of an active agent.
- the corresponding compound provides post administration-activated, controlled release of an active agent, because it requires enzymatic cleavage to initiate release of the compound, and because the rate of release of the active agent depends upon both the rate of enzymatic cleavage and the rate of cyclization.
- the prodrug is configured so that it will not provide excessively high plasma levels of the active agent if it is administered inappropriately, and cannot readily be decomposed to afford the active agent other than by enzymatic cleavage followed by controlled cyclization.
- the enzyme capable of cleaving the enzyme-cleavable moiety can be a peptidase, also referred to as a protease - the enzyme-cleavable moiety being linked to the nucleophilic nitrogen through an amide (e.g. a peptide: -NHCO-) bond.
- the enzyme is a digestive enzyme, such as a digestive enzyme of a protein.
- the enzyme-cleavable moiety linked to the nucleophilic nitrogen through an amide bond can be, for example, a residue of an amino acid or a peptide, a variant of a residue of an amino acid or a peptide, a derivative of a residue of an amino acid or a peptide, or a derivative of a residue of an amino acid variant or a peptide variant.
- an amino acid variant refers to an amino acid other than any of the 20 common naturally occurring L-amino acids that is hydrolyzable by a protease in a manner similar to the ability of a protease to hydrolyze a naturally occurring L-amino acid.
- a derivative refers to a substance that has been altered from another substance by modification, partial substitution, homologation, truncation, or a change in oxidation state.
- an N-acyl derivative of an amino acid is an example of a derivative of an amino acid.
- the enzyme-cleavable moiety can be an (alpha) N-acyl derivative of an amino acid or peptide or an (alpha) N-acyl derivative of an amino acid variant or peptide variant.
- the peptide can contain, for example, up to about 100 amino acid residues.
- Each amino acid can advantageously be a naturally occurring amino acid, such as an L-amino acid.
- Examples of naturally occurring amino acids are alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
- examples of enzyme-cleavable moieties include residues of the L-amino acids listed herein and N-acyl derivatives thereof, and peptides formed from at least two of the L-amino acids listed herein and the N-acyl derivatives thereof.
- Additional examples include residues of amino acid variants and N-acyl derivatives thereof, and peptides formed from at least two of the L-amino acids listed above and/or variants thereof, and N-acyl derivatives thereof. Also included are derivatives of such amino acids or amino acid variants and peptides thereof.
- the embodiments provide a prodrug with a substituent which is a spacer leaving group bearing a nucleophilic nitrogen that is protected with an enzyme-cleavable moiety. Upon enzymatic cleavage of the cleavable moiety, the nucleophilic nitrogen is capable of forming a cyclic urea.
- a representative scheme of a cyclization of a spacer group is shown below, wherein X is an active agent.
- the rate of cyclization of the cyclic urea can be adjusted by incorporation of a heterocyclic ring within the spacer group.
- incorporation of a heterocyclic ring within the spacer group results in formation of a fused ring cyclic urea and in a faster cyclization reaction.
- cyclic urea is generally very stable and have low toxicity.
- the embodiments include pharmaceutical compositions, which comprise a GI enzyme-cleavable active agent prodrug and an optional GI enzyme inhibitor.
- GI enzyme-cleavable active agent prodrug and an optional GI enzyme inhibitor. Examples of active agent prodrugs and enzyme inhibitors are described below.
- active agent refers to a chemical substance that exerts a pharmacological action.
- active agents include, but are not limited to, active agents that are susceptible to misuse, abuse, or overdose.
- active agents include, but are not limited to, opioids, NSAIDs, other analgesics, GABA agonists, GABA antagonists, and psychostimulants.
- the disclosure provides a prodrug which provides enzymatically-controlled release of an active agent.
- the disclosure provides a promoiety that is attached to an active agent through any suitable structural moiety on the drug, where the structural moiety has a reactive group.
- reactive groups on an active agent include, but are not limited to, ketone, phenol, and amide.
- compositions of the present disclosure include compounds of formula I shown below.
- compositions of the present disclosure also include compounds of formula I shown below.
- compositions and methods of the present disclosure also contemplate compounds of formula I.
- X is selected from a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-
- N(R )]b-R a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)- CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; and a residue of an amide-containing active agent, wherein -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is connected to the amide-containing active agent through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- opioid refers to a chemical substance that exerts its pharmacological action by interaction at an opioid receptor.
- An opioid can be a natural product, a synthetic compound or a semi-synthetic compound.
- an opioid is a compound with a
- the disclosure provides an opioid prodrug that provides controlled release of an opioid.
- the disclosure provides a promoiety that is attached to an opioid through any structural moiety on the opioid, where the structural moiety has a reactive group.
- reactive groups on an opioid include, but are not limited to ketone, phenol, and amide.
- opioids bearing at least some of the functionalities described herein will be developed; such opioids are included as part of the scope of this disclosure.
- Compounds of the present disclosure include compounds of formula II shown below.
- Compositions of the present disclosure also include compounds of formula II shown below.
- Pharmaceutical compositions and methods of the present disclosure also contemplate compounds of formula II.
- X is selected from a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)- CH(R 6 )-N(R 3 )]b-R 7 ; and a residue of an amide-containing opioid, wherein
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X can be selected from a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)- CH(R 6 )-N(R 3 )] b -R 7 ; a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)- CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; and a residue of an amide-
- X is a ketone-containing opioid, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 .
- X is a ketone-containing opioid, wherein the opioid is selected from acetylmorphone, hydrocodone, hydromorphone, ketobemidone, methadone, naloxone, naltrexone, N-methylnaloxone, N-methylnaltrexone, oxycodone, oxymorphone, and
- X is a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH- C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 .
- X is a phenolic opioid, wherein the opioid is selected from buprenorphine, dihydroetorphine, diprenorphine, etorphine, hydromorphone, levorphanol, morphine, nalbuphine, nalmefene, nalorphine, naloxone, naltrexone, N-methyldiprenorphine, N- methylnaloxone, N-methylnaltrexone, oripavine, oxymorphone, butorphanol, dezocine, ketobemidone, meptazinol, o-desmethyltramadol, pentazocine, phenazocine, and tapentadol.
- the opioid is selected from buprenorphine, dihydroetorphine, diprenorphine, etorphine, hydromorphone, levorphanol, morphine, nalbuphine, nalmefene, nalorphin
- X is a residue of an amide-containing opioid, wherein -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer.
- X is an amide-containing opioid, wherein the opioid is selected from alfentanil, carfentanil, fentanyl, lofentanil, loperamide, olmefentanyl, remifentanil, and sufentanil.
- the disclosure provides a ketone-modified active agent prodrug that provides controlled release of a ketone-containing active agent.
- a promoiety is attached to the ketone-containing active agent through the enolic oxygen atom of the ketone moiety.
- the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone-containing active agent is replaced by a covalent bond to a promoiety.
- an enzyme-cleavable ketone-modified active agent prodrug is a ketone-modified active agent prodrug that comprises a promoiety comprising an enzyme- cleavable moiety, i.e., a moiety having a site susceptible to cleavage by an enzyme.
- the cleavable moiety is a GI enzyme-cleavable moiety, such as a trypsin-cleavable moiety.
- Such a prodrug comprises a ketone-containing active agent covalently bound to a promoiety comprising an enzyme-cleavable moiety, wherein cleavage of the enzyme-cleavable moiety by an enzyme mediates release of the drug.
- Compounds of the present disclosure include compounds of formulae III- VI shown below.
- Compositions of the present disclosure also include compounds of formulae III- VI shown below.
- Pharmaceutical compositions and methods of the present disclosure also contemplate compounds of formulae III- VI.
- Reference to the formula number is meant to include compounds of both the “a” and "b” versions of the formula number.
- X represents a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; the A ring is a heterocyclic 5 to 12-membered ring;
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; the A ring is a heterocyclic 5 to 12-membered ring;
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- R a is hydrogen or hydroxyl
- R b is hydrogen or alkyl
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X represents a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; the A ring is a heterocyclic 5 to 12-membered ring;
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is a side chain of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states;
- each R 6 is a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; the A ring is a heterocyclic 5 to 12-membered ring;
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is a side chain of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states;
- each R 6 is a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X represents a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )- N(R 3 )] b -R 7 ;
- the A ring is a heterocyclic 5 to 12-membered ring; each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 represents a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant that effects -C(0)-CH(R 5 )-N(R 3 )- to be a GI enzyme-cleavable moiety;
- each R 6 represents a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; or a salt, hydrate or solvate thereof.
- X represents a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; the A ring is a heterocyclic 5 to 12-membered ring;
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 represents a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant that effects -C(0)-CH(R 5 )-N(R 3 )- to be a GI enzyme-cleavable moiety;
- each R 6 represents a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X can be a residue of a ketone-containing active agent or a ketone-containing opioid.
- the ketone-containing active agent is a ketone-containing opioid.
- a "ketone-containing opioid” refers to a subset of the opioids that contain a ketone group.
- a ketone-containing opioid is an opioid containing an enolizable ketone group.
- a ketone-containing opioid is a compound with a pharmacophore that presents to the opioid receptor an aromatic group and an aliphatic amine group in an architecturally discrete way. See, for example, Foye's Principles of Medicinal Chemistry, Sixth Edition, ed. T.L. Lemke and D.A. Williams, Lippincott Williams & Wilkins, 2008, particularly Chapter 24, pages 653-678.
- ketone-containing opioids include, but are not limited to, acetylmorphone, hydrocodone, hydromorphone, ketobemidone, methadone, naloxone, naltrexone, N- methylnaloxone, N-methylnaltrexone, oxycodone, oxymorphone, and pentamorphone.
- the ketone-containing opioid is hydrocodone, hydromorphone, oxycodone, or oxymorphone.
- the ketone-containing opioid is naloxone, naltrexone, N- methylnaloxone, or N-methylnaltrexone. In certain embodiments, the ketone-containing opioid is hydrocodone or oxycodone. In certain embodiments, the ketone-containing opioid is hydrocodone. In certain embodiments, the ketone-containing opioid is oxycodone.
- opioids bearing at least some of the functionalities described herein will be developed; such opioids are included as part of the scope of this disclosure.
- R a can be hydrogen or hydroxyl. In certain instances, R a is hydrogen. In other instances, R a is hydroxyl.
- R b is hydrogen or alkyl. In certain instances, R b is hydrogen. In other instances, R b is alkyl.
- Com ound KC-32 Particular compounds of interest, and salts or solvates or stereoisomers thereof, include: Com ound KC-32:
- the disclosure provides a phenolic active agent prodrug that provides controlled release of a phenolic active agent.
- a promoiety is attached to the phenolic active agent through the phenolic oxygen atom.
- the oxygen atom of the phenol group of the phenolic active agent is replaced by a covalent bond to a promoiety.
- an enzyme-cleavable phenolic active agent prodrug is a phenolic active agent prodrug that comprises a promoiety comprising an enzyme-cleavable moiety, i.e., a moiety having a site susceptible to cleavage by an enzyme.
- the cleavable moiety is a GI enzyme-cleavable moiety, such as a trypsin-cleavable moiety.
- Such a prodrug comprises a phenolic active agent covalently bound to a promoiety comprising an enzyme- cleavable moiety, wherein cleavage of the enzyme-cleavable moiety by an enzyme mediates release of the drug.
- compositions of the present disclosure include compounds of formulae VII-X shown below.
- compositions of the present disclosure also include compounds of formulae VII-X shown below.
- Pharmaceutical compositions and methods of the present disclosure also contemplate compounds of formulae VII- X.
- Reference to the formula number is meant to include compounds of both the “a” and "b” versions of the formula number.
- X represents a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH- C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ;
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)- CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ;
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- R a is hydrogen or hydroxyl
- R b is hydrogen or alkyl
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, acylamino, substituted acylamino, substituted aminoacyl, amino, substituted amino, acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X represents a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH- C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ;
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is a side chain of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states;
- each R 6 is a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)- CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ;
- the A ring is a heterocyclic 5 to 12-membered ring; each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is a side chain of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states;
- each R 6 is a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X represents a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH- C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ;
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 represents a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant that effects -C(0)-CH(R 5 )-N(R 3 )- to be a GI enzyme-cleavable moiety;
- each R 6 represents a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X represents a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)- CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ;
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 represents a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant that effects -C(0)-CH(R 5 )-N(R 3 )- to be a GI enzyme-cleavable moiety;
- each R 6 represents a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X can be a residue of a phenolic active agent or a phenolic opioid.
- the phenolic active agent is a phenolic opioid.
- a "phenolic opioid” refers to a subset of the opioids that contain a phenol group.
- a phenolic opioid is a compound with a pharmacophore that presents to the opioid receptor an aromatic group and an aliphatic amine group in an architecturally discrete way. See, for example, Foye's Principles of Medicinal Chemistry, Sixth Edition, ed. T.L. Lemke and D.A. Williams, Lippincott Williams & Wilkins, 2008, particularly Chapter 24, pages 653-678.
- the following opioids contain a phenol group that can be a point of attachment to a promoiety: buprenorphine, dihydroetorphine, diprenorphine, etorphine, hydromorphone, levorphanol, morphine, nalbuphine, nalmefene, nalorphine, naloxone, naltrexone, N-methyldiprenorphine, N-methylnaloxone, N-methylnaltrexone, oripavine, oxymorphone, butorphanol, dezocine, ketobemidone, meptazinol, o-desmethyltramadol, pentazocine, phenazocine, and tapentadol.
- the phenolic opioid is hydromorphone, morphine, oxymorphone, or tapentadol.
- the phenolic opioid is naloxone, naltrexone, N-methylnaloxone, or N-methylnaltrexone. In certain embodiments, the phenolic opioid is diprenorphine or N- methyldiprenorphine .
- the phenolic opioid is hydromorphone. In certain embodiments, the phenolic opioid is morphine. In certain embodiments, the phenolic opioid is oxymorphone. In certain embodiments, the phenolic opioid is tapentadol.
- opioids bearing at least some of the functionalities described herein will be developed; such opioids are included as part of the scope of this disclosure.
- R a can be hydrogen or hydroxyl. In certain instances, R a is hydrogen. In other instances, R a is hydroxyl.
- R b is hydrogen or alkyl. In certain instances, R b is hydrogen. In other instances, R b is alkyl.
- the disclosure provides an amide-modified active agent prodrug that provides controlled release of an amide-containing active agent.
- a promoiety is attached to the amide-containing active agent through the enolic oxygen atom of the amide enol moiety or through the oxygen of the imine tautomer.
- the hydrogen atom of the corresponding enolic group of the amide enol or of the imine tautomer of the amide-containing active agent is replaced by a covalent bond to a promoiety.
- the promoiety that replaces the hydrogen atom of the corresponding enolic group of the amide enol or the imine tautomer of the amide- containing active agent contains an acyl group as the point of connection.
- R and R' are collectively the rest of the amide-containing where R, R', and R" are collectively the rest of the amide-containing opioid or one of R and R' is hydrogen and the other is the opioid or at least one of R, R', and R" is hydrogen and the rest of rest is the amide-containing opioid R, R', and R" are collectively the rest of the amide-containing opioid
- an enzyme-cleavable amide-modified active agent prodrug is an amide-modified active agent prodrug that comprises a promoiety comprising an enzyme- cleavable moiety, i.e., a moiety having a site susceptible to cleavage by an enzyme. Release of the active agent is mediated by enzymatic cleavage of the promoiety from the amide-containing active agent.
- the cleavable moiety is a GI enzyme-cleavable moiety, such as a trypsin-cleavable moiety.
- compositions of the present disclosure include compounds of formulae XI-XIII shown below.
- compositions of the present disclosure also include compounds of formulae XI-XIII shown below.
- Pharmaceutical compositions and methods of the present disclosure also contemplate compounds of formulae XI-XIII.
- Reference to the formula number is meant to include compounds of both the “a” and "b” versions of the formula number.
- X represents a residue of an amide-containing active agent, wherein -C(0)-N[(A ring)- Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is connected to the amide- containing active agent through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X represents a residue of an amide-containing opioid, wherein -C(0)-N[(A ring)-Y c ]- (CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is connected to the amide- containing active agent through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
- the A ring is a heterocyclic 5 to 12-membered ring; each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X represents a residue of an amide-containing active agent, wherein -C(0)-N[(A ring)- Y c ]-(CR 1 R 2 )a-NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )]b-R 7 is connected to the amide- containing active agent through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is a side chain of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states;
- each R 6 is a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X represents a residue of an amide-containing opioid, wherein -C(0)-N[(A ring)-Y c ]- (CR 1 R 2 )a-NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is connected to the amide- containing active agent through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is a side chain of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states;
- each R 6 is a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X represents a residue of an amide-containing active agent, wherein -C(0)-N[(A ring)- Y c ]-(CR 1 R 2 )a-NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )]b-R 7 is connected to the amide- containing active agent through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
- the A ring is a heterocyclic 5 to 12-membered ring
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 represents a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant that effects -C(0)-CH(R 5 )-N(R 3 )- to be a GI enzyme-cleavable moiety;
- each R 6 represents a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X represents a residue of an amide-containing opioid, wherein -C(0)-N[(A ring)-Y c ]- (CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is connected to the amide- containing active agent through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
- the A ring is a heterocyclic 5 to 12-membered ring; each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 represents a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant that effects -C(0)-CH(R 5 )-N(R 3 )- to be a GI enzyme-cleavable moiety;
- each R 6 represents a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; or a salt, hydrate or solvate thereof.
- X can be a residue of an amide-containing active agent, where the amide-containing active agent is connected through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer of an amide-containing opioid, where the amide-containing active agent is connected through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer.
- the amide-containing active agent is an amide-containing opioid.
- An "amide-containing opioid” refers to a subset of the opioids that contain an amide group.
- an amide-containing opioid is an opioid containing an enolizable amide group.
- An amide-containing opioid is a compound with a pharmacophore that presents to the opioid receptor an aromatic group and an aliphatic amine group in an architecturally discrete way. See, for example, Foye's Principles of Medicinal Chemistry, Sixth Edition, ed. T.L. Lemke and D.A. Williams, Lippincott Williams & Wilkins, 2008, particularly Chapter 24, pages 653-678.
- opioids contain an amide group that can be a point of attachment to a promoiety: alfentanil, carfentanil, fentanyl, lofentanil, loperamide, olmefentanyl, remifentanil, and sufentanil.
- opioids bearing at least some of the functionalities described herein will be developed; such opioids are included as part of the scope of this disclosure.
- Acetaminophen refers to a chemical substance that exerts its pharmacological action by inhibiting cyclooxygenase (COX), such as COX-2.
- COX cyclooxygenase
- Acetaminophen can be a synthetic compound or a semi-synthetic compound.
- acetaminophen is a compound with a pharmacophore that inhibits COX (e.g., COX-2) and has analgesic and antipyretic effects. See, for example, Foye's Principles of Medicinal Chemistry, Sixth Edition, ed. T.L. Lemke and D.A. Williams, Lippincott Williams & Wilkins, 2008, particularly Chapter 36, pages 959-965.
- the disclosure provides for an acetaminophen prodrug, wherein the acetaminophen has an optionally substituted acetaminophen structure:
- the disclosure provides an acetaminophen prodrug that provides controlled release of acetaminophen.
- a promoiety is attached to acetaminophen through the phenolic oxygen atom wherein the hydrogen atom of the phenolic hydroxyl group of acetaminophen is replaced by a covalent bond to the promoiety or through the oxygen of the amide group of acetaminophen, wherein the amide group is converted to an amide enol or an imine tautomer.
- compositions of the present disclosure include compounds of formula XIV shown below.
- compositions of the present disclosure also include compounds of formula XIV shown below.
- Pharmaceutical compositions and methods of the present disclosure also contemplate compounds of formula XIV.
- X represents acetaminophen, wherein the hydrogen atom of the phenolic hydroxyl group of acetaminophen is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)- CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; or wherein -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)- CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is connected to acetaminophen through the oxygen of the amide group of acetaminophen, wherein the amide group is converted to an amide enol or an imine tautomer;
- the A ring is a heterocyclic 5 to 12-membered ring; each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- c is a number from zero to 3;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X represents acetaminophen, wherein the hydrogen atom of the phenolic hydroxyl group of acetaminophen is replaced by a covalent bond to -C(0)-N[(A ring)-Y c ]- (CR ⁇ a -NH-CCO-CHCR ⁇ -NCR ⁇ -tCCO-CHCR ⁇ -NCR ⁇ l b -R 7 ; or wherein -C(0)-N[(A ring)-Y c ]- (CR 1 R 2 )a-NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is connected to acetaminophen through the oxygen of the amide group of acetaminophen, wherein the amide group is converted to an amide enol or an imine tautomer.
- X represents acetaminophen, wherein the hydrogen atom of the phenolic hydroxyl group of acetaminophen is replaced by a covalent bond to -C(0)-N[(A ring)- Ycl-CCR ⁇ a-NH-CCO-CHCR ⁇ -NCR ⁇ -tCCO-CHCR ⁇ -NCR ⁇ lb-R 7 .
- X represents acetaminophen, wherein -C(0)-N[(A ring)-Y c ]- (CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is connected to acetaminophen through the oxygen of the amide group of acetaminophen, wherein the amide group is converted to an amide enol or an imine tautomer.
- X represents acetaminophen, wherein -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is connected to acetaminophen through the oxygen of the amide group of acetaminophen, wherein the amide group is converted to an amide enol.
- X represents acetaminophen, wherein -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is connected to acetaminophen through the oxygen of the amide group of acetaminophen, wherein the amide group is converted to
- acetaminophen wherein -C(0)-N[(A ring)-Y c ]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)- CH(R 6 )-N(R 3 )] b -R 7 is connected to acetaminophen through the oxygen of the amide group of acetaminophen, wherein the amide group is converted to an imine tautomer.
- compositions of the present disclosure include compounds of formulae XV-XVII shown below.
- compositions of the present disclosure also include compounds of formulae XV-XVII shown below.
- Pharmaceutical compositions and methods of the present disclosure also contemplate compounds of formulae XV-XVII.
- X is selected from a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-
- N(R )] b -R a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)- CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; and a residue of an amide-containing active agent, wherein -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
- a 1 , A 2 , A 4 , and A 5 are independently selected from carbon, nitrogen, oxygen, and sulfur;
- A is carbon or nitrogen
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X is selected from a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)- CH(R 6 )-N(R 3 )] b -R 7 ; and a residue of an amide-containing opioid, wherein -C(0)-
- a 1 , A 2 , A 4 , and A 5 are independently selected from carbon, nitrogen, oxygen, and sulfur;
- A is carbon or nitrogen
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;
- b is a number from zero to 100
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl; or a salt, hydrate or solvate thereof.
- X is selected from a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-
- N(R )] b -R a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)- CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; and a residue of an amide-containing active agent, wherein -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
- a 1 , A 2 , A 4 , and A 5 are independently selected from carbon, nitrogen, oxygen, and sulfur;
- A is carbon or nitrogen
- Y is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is a side chain of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states;
- each R 6 is a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X is selected from a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)- CH(R 6 )-N(R 3 )]b-R 7 ; and a residue of an amide-containing opioid, wherein -C(0)-N[
- a 1 , A 2 , A 4 , and A 5 are independently selected from carbon, nitrogen, oxygen, and sulfur;
- A is carbon or nitrogen
- Y is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 is a side chain of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states;
- each R 6 is a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X is selected from a residue of a ketone-containing active agent, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-
- N(R )]b-R a residue of a phenolic active agent, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)- CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; and a residue of an amide-containing active agent, wherein -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer;
- a 1 , A 2 , A 4 , and A 5 are independently selected from carbon, nitrogen, oxygen, and sulfur;
- A is carbon or nitrogen;
- Y is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 represents a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant that effects -C(0)-CH(R 5 )-N(R 3 )- to be a GI enzyme-cleavable moiety;
- each R 6 represents a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X is selected from a residue of a ketone-containing opioid, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)- CH(R 6 )-N(R 3 )]b-R 7 ; and a residue of an amide-containing opioid, wherein -C(0)-N[
- a 1 , A 2 , A 4 , and A 5 are independently selected from carbon, nitrogen, oxygen, and sulfur;
- A is carbon or nitrogen
- Y is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano;
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano; or R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group; a is an integer from one to 8;
- each R is independently hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
- R 5 represents a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant that effects -C(0)-CH(R 5 )-N(R 3 )- to be a GI enzyme-cleavable moiety;
- each R 6 represents a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine;
- b is a number from zero to 100;
- R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl,
- alkoxycarbonyl substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl;
- X can be selected from a residue of a ketone-containing active agent or opioid, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH- C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; a residue of a phenolic active agent or opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to - C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 ; and
- X is a ketone-containing opioid, wherein the hydrogen atom of the corresponding hydroxyl group of the enolic tautomer of the ketone is replaced by a covalent bond to -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 .
- X is a ketone-containing opioid, wherein the opioid is selected from acetylmorphone, hydrocodone, hydromorphone, ketobemidone, methadone, naloxone, naltrexone, N-methylnaloxone, N-methylnaltrexone, oxycodone, oxymorphone, and
- X is a residue of a phenolic opioid, wherein the hydrogen atom of the phenolic hydroxyl group is replaced by a covalent bond to -C(0)-N[(A ring)-Y]-(CR 1 R 2 ) a -NH- C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 .
- X is a phenolic opioid, wherein the opioid is selected from buprenorphine, dihydroetorphine, diprenorphine, etorphine, hydromorphone, levorphanol, morphine, nalbuphine, nalmefene, nalorphine, naloxone, naltrexone, N-methyldiprenorphine, N- methylnaloxone, N-methylnaltrexone, oripavine, oxymorphone, butorphanol, dezocine, ketobemidone, meptazinol, o-desmethyltramadol, pentazocine, phenazocine, and tapentadol.
- the opioid is selected from buprenorphine, dihydroetorphine, diprenorphine, etorphine, hydromorphone, levorphanol, morphine, nalbuphine, nalmefene, nalorphin
- X is a residue of an amide-containing opioid, wherein -C(0)-N[(A ring)-Y]-(CR 1 R 2 )a-NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )]b-R 7 is connected to the amide-containing opioid through the oxygen of the amide group, wherein the amide group is converted to an amide enol or an imine tautomer.
- X is an amide-containing opioid, wherein the opioid is selected from alfentanil, carfentanil, fentanyl, lofentanil, loperamide, olmefentanyl, remifentanil, and sufentanil.
- a 1 , A 2 , A 4 , and A 5 are independently selected from carbon, nitrogen, oxygen, and sulfur. In certain instances, A 1 , A 2 , A 4 , and A 5 are independently selected from carbon and nitrogen. In certain instances, A 1 , A 2 , A 4 , and A 5 are independently selected from carbon and oxygen. In certain instances, A 1 , A 2 , A 4 , and A 5 are independently selected from carbon and sulfur. In certain instances, A 1 , A 2 , A 4 , and A 5 are carbon.
- a 3 is carbon or nitrogen. In certain instances, A 3 is carbon. In certain instances, A is nitrogen.
- -(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b -R 7 is attached to A 1 .
- -(CR 1 R 2 ) a -NH-C(0)-CH(R 5 )-N(R 3 )-[C(0)-CH(R 6 )-N(R 3 )] b - R 7 is attached to A 2 .
- the A ring can be a heterocyclic 5 to 12-membered ring.
- the A ring is a heterocyclic 5 to 11-membered ring. In certain instances, the A ring is a heterocyclic 5 to 10-membered ring. In certain instances, the A ring is a heterocyclic 5 to 9-membered ring. In certain instances, the A ring is a heterocyclic 5 to 8- membered ring. In certain instances, the A ring is a heterocyclic 5 to 7-membered ring. In certain instances, the A ring is a heterocyclic 5 or 6-membered ring. In certain instances, the A ring is a heterocyclic 5-membered ring.
- the A ring is a heterocyclic 6 to 12-membered ring. In certain instances, the A ring is a heterocyclic 6 to 11-membered ring. In certain instances, the A ring is a heterocyclic 6 to 10-membered ring. In certain instances, the A ring is a heterocyclic 6 to 9- membered ring. In certain instances, the A ring is a heterocyclic 6 to 8-membered ring. In certain instances, the A ring is a heterocyclic 6 or 7-membered ring. In certain instances, the A ring is a heterocyclic 6-membered ring. In certain instances, the A ring is a heterocyclic 7- membered ring. In certain instances, the A ring is a heterocyclic 8-membered ring.
- c can be a number from zero to 3. In certain instances, c is zero. In certain instances, c is 1. In certain instances, c is 2. In certain instances, c is 3.
- each Y is independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano.
- Y can be carboxyl or amino. In certain instances, Y is carboxyl. In certain instances, Y is amino.
- Y is alkyl or substituted alkyl. In certain instances, Y is alkyl. In certain instances, Y is substituted alkyl. In certain instances, Y is alkenyl or substituted alkenyl. In certain instances, Y is alkenyl. In certain instances, Y is substituted alkenyl. In certain instances, Y is alkynyl or substituted alkynyl. In certain instances, Y is alkynyl. In certain instances, Y is substituted alkynyl. In certain instances, Y is aryl or substituted aryl. In certain instances, Y is aryl. In certain instances, Y is substituted aryl.
- Y is acyl or substituted acyl. In certain instances, Y is acyl. In certain instances, Y is substituted acyl. In certain instances, Y is carboxyl. In certain instances, Y is alkoxycarbonyl or substituted alkoxycarbonyl. In certain instances, Y is alkoxycarbonyl. In certain instances, Y is substituted alkoxycarbonyl. In certain instances, Y is aminoacyl or substituted aminoacyl. In certain instances, Y is aminoacyl. In certain instances, Y is substituted aminoacyl. In certain instances, Y is amino or substituted amino. In certain instances, Y is amino. In certain instances, Y is substituted amino. In certain instances, Y is acylamino or substituted acylamino. In certain instances, Y is acylamino. In certain instances, Y is substituted acylamino. In certain instances, Y is cyano.
- Y is substituted alkyl.
- Y is an alkyl group substituted with a carboxylic group such as a carboxylic acid, alkoxycarbonyl or aminoacyl.
- Y is -(CH 2 ) q (C 6 H4)-COOH, -(CH 2 ) q (C 6 H 4 )-COOCH 3 , or -(CH 2 ) q (C 6 H 4 )- COOCH 2 CH 3 , where q is an integer from one to 10.
- Y is aminoacyl.
- Y is an alkyl group substituted with an amino group, substituted amino, or acylamino.
- Y is aminoacyl or substituted aminoacyl.
- Y is aminoacyl comprising phenylenediamine. In certain instances,
- Y is ; wherein each R is independently selected from hydrogen, alkyl, substituted alkyl, and acyl and R 11 is alkyl or substituted alkyl. In certain instances, at least one of R 10 is acyl. In certain instances, at least one of R 10 is alkyl or substituted alkyl. In certain instances, at least one of R 10 is hydrogen. In certain instances, both of R 10 are hydrogen.
- Y is ; wherein R , 1 1 0 U is hydrogen, alkyl, substituted alkyl, or acyl. In certain instances, R 10 is acyl. In certain instances, R 10 is alkyl or substituted alkyl. In certain instances, R 10 is hydrogen. O R 10
- Y is ; wherein each R is independently hydrogen, alkyl, substituted alkyl, or acyl and b is a number from one to 5. In certain instances, O R 10
- Y is R 10 O ; wherein each R 10 is independently hydrogen, alkyl, substituted alkyl, or
- Y is R O . w h erem R lua i s alkyl and each R 1U is independently hydrogen, alkyl, substituted alk l, or acyl.
- Y is . wne rein R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl and b is a number from one to 5. In certain instances, Y is ; wherein R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl.
- Y is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein each R 10a and R 10b is independently selected from hydrogen, alkyl, substituted alkyl, and acyl.
- Y is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is an alkyl and R 10b is substituted alkyl.
- Y is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is an alkyl and R 10b is alkyl substituted with a carboxylic acid or alkoxycarbonyl.
- Y is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is methyl and R 10b is alkyl substituted with a carboxylic acid or alkoxycarbonyl.
- Y is carboxyl
- Y is acyl or substituted acyl.
- Y is alkoxycarbonyl or substituted alkoxycarbonyl.
- Y is amino or substituted amino.
- Y is acylamino or substituted acylamino.
- a can be an integer from one to 8. In certain instances, a is one. In certain instances, a is 2. In certain instances, a is 3. In certain instances, a is 4. In certain instances, a is 5. In certain instances, a is 6. In certain instances, a is 7. In certain instances, a is 8.
- each R 1 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano.
- R 1 is hydrogen. In certain instances, R 1 is alkyl or substituted alkyl. In certain instances, R 1 is alkyl. In certain instances, R 1 is substituted alkyl. In certain instances, R 1 is alkenyl or substituted alkenyl. In certain instances, R 1 is alkenyl. In certain instances, R 1 is substituted alkenyl. In certain instances, R 1 is alkynyl or substituted alkynyl. In certain instances, R 1 is alkynyl. In certain instances, R 1 is substituted alkynyl. In certain instances, R 1 is aryl or substituted aryl. In certain instances, R 1 is aryl. In certain instances, R 1 is substituted aryl.
- R 1 is acyl or substituted acyl. In certain instances, R 1 is acyl. In certain instances, R 1 is substituted acyl. In certain instances, R 1 is carboxyl. In certain instances, R 1 is alkoxycarbonyl or substituted alkoxycarbonyl. In certain instances, R 1 is alkoxycarbonyl. In certain instances, R 1 is substituted alkoxycarbonyl. In certain instances, R 1 is aminoacyl or substituted aminoacyl. In certain instances, R 1 is aminoacyl. In certain instances, R 1 is substituted aminoacyl. In certain instances, R 1 is amino or substituted amino. In certain instances, R 1 is amino. In certain instances, R 1 is substituted amino. In certain instances, R 1 is acylamino or substituted acylamino. In certain instances, R 1 is acylamino. In certain instances, R 1 is substituted acylamino. In certain instances, R 1 is cyano.
- each R is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, acyl, substituted acyl, carboxyl, alkoxycarbonyl, substituted alkoxycarbonyl, aminoacyl, substituted aminoacyl, amino, substituted amino, acylamino, substituted acylamino, and cyano.
- R 2 is hydrogen. In certain instances, R 2 is alkyl or substituted alkyl.
- R 2 is alkyl. In certain instances, R 2 is substituted alkyl. In certain instances,
- R 2 is alkenyl or substituted alkenyl. In certain instances, R 2 is alkenyl. In certain instances, R 2 is
- R is alkynyl or substituted alkynyl.
- R 2 is alkynyl. In certain instances, R 2 is substituted alkynyl. In certain instances, R 2 is aryl or substituted aryl. In certain instances, R 2 is aryl. In certain instances, R 2 is substituted aryl.
- R 2 is acyl or substituted acyl. In certain instances, R 2 is acyl. In certain instances, R 2 is substituted acyl. In certain instances, R 2 is carboxyl. In certain instances, R 2 is alkoxycarbonyl or substituted alkoxycarbonyl. In certain instances, R is alkoxycarbonyl. In certain instances, R 2 is substituted alkoxycarbonyl. In certain instances, R 2 is aminoacyl or substituted aminoacyl. In certain instances, R 2 is aminoacyl. In certain instances, R 2 is substituted aminoacyl. In certain instances, R is amino or substituted amino. In certain instances, R 2 is amino. In certain instances, R 2 is amino. In certain instances, R 2 is substituted amino. In certain instances, R 2 is acylamino or substituted acylamino. In certain instances, R is acylamino. In certain instances, R is acylamino. In certain instances,
- R 2 is substituted acylamino. In certain instances, R 2 is cyano.
- one of R 1 and R2 is hydrogen. In certain instances, one of R 1 and R2 is alkyl. In certain instances, one of R 1 and R 2 is substituted alkyl. In certain instances, one of
- R 1 and R2 is alkenyl or substituted alkenyl. In certain instances, one of R 1 and R2 is alkynyl or substituted alkynyl. In certain instances, one of R I and R 2 is aryl or substituted aryl. In certain instances, one of R 1 and R2 is acyl or substituted acyl. In certain instances, one of R 1 and R2 is carboxyl. In certain instances, one of R 1 and R 2 is alkoxycarbonyl or substituted alkoxycarbonyl.
- one of R 1 and R 2 is aminoacyl or substituted aminoacyl. In certain instances, one of R 1 and R2 is amino or substituted amino. In certain instances, one of R 1 and R2 is acylamino or substituted acylamino. In certain instances, one of R 1 and R 2" is cyano.
- R 1 and R2 are hydrogen. In certain instances, R 1 and R2 on the same carbon are both alkyl. In certain instances, R 1 and R 2 on the same carbon are methyl. In certain instances, R 1 and R 2 on the same carbon are ethyl.
- R 1 and R1 which are vicinal are both alkyl and R 2 and R 2 which are vicinal are both hydrogen.
- R I and RI which are vicinal are both ethyl and R 2 and R 2 which are vicinal are both hydrogen.
- R 1 and R1 which are vicinal are both methyl and R 2 and R 2 which are vicinal are both hydrogen.
- R 1 and R 2 is -(CH 2 ) q (C 6 H4)-COOH, -(CH2) q (C 6 H 4 )-COOCH 3 , or -(CH2) q (C 6 H 4 )-COOCH 2 CH 3 , where q is an integer from one to 10. In certain instances, one or both of R 1 and R 2 is aminoacyl.
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl or substituted cycloalkyl group, or two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached, can form a cycloalkyl or substituted cycloalkyl group.
- R 1 and R 2 together with the carbon to which they are attached can form a cycloalkyl group.
- R 1 and R 2 on the same carbon form a spirocycle.
- R 1 and R 2 together with the carbon to which they are attached can form a substituted cycloalkyl group.
- two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached can form a cycloalkyl group.
- two R 1 or R 2 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached can form a substituted cycloalkyl group.
- one of R 1 and R 2 is aminoacyl.
- one of R 1 and R 2 is aminoacyl comprising phenylenediamine.
- R 1 and R 2 is wherein each R 10 is independently selected from hydrogen, alkyl, substituted alkyl, and acyl and R 11 is alkyl or substituted alkyl. In certain instances, at least one of R 10 is acyl. In certain instances, at least one of R 10 is alkyl or substituted alkyl. In certain instances, at least one of R 10 is hydrogen. In certain instances, both of R 10 are hydrogen.
- R 1 and R 2 is R 10 ; wherein R 10 is hydrogen, alkyl, substituted alkyl, or acyl. In certain instances, R 10 is acyl. In certain instances, R 10 is alkyl or substituted alkyl. In certain instances, R 10 is hydrogen. In certain instances, one of R 1 and R 2 is ; wherein each R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl and b is a number from one to 5. In
- R 10 certain instances, one of R 1 and R 2 is R 10 O ; wherein each R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl. In certain instances, one of R 1 and R 2" is . w herein R 10a is alkyl and each R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl.
- one of R 1 and R 2 is ; wherein R is independently hydrogen, alkyl, substituted alkyl, or acyl and b is a number from one to 5. In certain instances,
- R is independently hydrogen, alkyl, substituted alkyl, or acyl.
- one of R 1 and R 2 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein each R 10a and R 10b is independently selected from hydrogen, alkyl, substituted alkyl, and acyl.
- one of R 1 and R 2 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is an alkyl and R 10b is substituted alkyl.
- one of R 1 and R 2 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is an alkyl and R 10b is alkyl substituted with a carboxylic acid or alkoxycarbonyl.
- one of R 1 and R 2 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is methyl and R 10b is alkyl substituted with a carboxylic acid or alkoxycarbonyl.
- one of R 1 and R 2" are carboxyl.
- one of R 1 and R 2 is acyl or substituted acyl.
- one of R 1 and R 2 is alkoxycarbonyl or substituted alkoxycarbonyl. In certain instances, one of R 1 and R 2" is amino or substituted amino.
- one of R 1 and R 2 is acylamino or substituted acylamino.
- R 1 or R2 can modulate a rate of intramolecular cyclization.
- R 1 or R2 can speed up a rate of intramolecular cyclization, when compared to the corresponding molecule where R 1 and R2 are both hydrogen.
- R 1 or R2 comprise an electron- withdrawing group or an electron-donating group.
- R 1 or R 2 comprise an electron-withdrawing group.
- R 1 or R 2 comprise an electron-donating group.
- Atoms and groups capable of functioning as electron-withdrawing substituents are well known in the field of organic chemistry. They include electronegative atoms and groups containing electronegative atoms. Such groups function to lower the basicity or protonation state of a nucleophilic nitrogen in the beta position via inductive withdrawal of electron density. Such groups can also be positioned on other positions along the alkylene chain.
- halogen atoms for example, a fluorine atom
- acyl groups for example an alkanoyl group, an aroyl group, a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group or an aminocarbonyl group (such as a carbamoyl, alkylaminocarbonyl, dialkylaminocarbonyl or arylaminocarbonyl group)
- ether groups for example an alkoxy group
- each of the electron withdrawing substituents can be selected independently from these.
- -[C(R 1 )(R 2 )] a - is selected from -CH(CH 2 F)CH(CH 2 F)- ; -CH(CHF 2 )CH(CHF 2 )-; -CH(CF 3 )CH(CF 3 )-; -CH 2 CH(CF 3 )-; -CH 2 CH(CHF 2 )- ; -CH 2 CH(CH 2 F)-; -CH 2 CH(F)CH 2 -; -CH 2 C(F 2 )CH 2 -; -CH 2 CH(C(O)NR 20 R 21 )- ; -CH 2 CH(C(0)OR 22 )-; -CH 2 CH(C(0)OH)-; -CH(CH 2 F)CH 2 CH(CH 2 F)-
- R 20 , R 21 , R 22 and R 23 each independently represents hydrogen or (l-6C)alkyl, and R 24 and R 25 each independently represents (l-6C)alkyl.
- the A ring when a is one, the A ring is a heterocyclic 6 to 12-membered ring; and when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 8. In certain instances, when a is one, the A ring is a heterocyclic 6 to 11-membered ring. In certain instances, when a is one, the A ring is a heterocyclic 6 to 10-membered ring. In certain instances, when a is one, the A ring is a heterocyclic 6 to 9-membered ring. In certain instances, when a is one, the A ring is a heterocyclic 6 to 8-membered ring. In certain instances, when a is one, the A ring is a heterocyclic 6 to 7-membered ring. In certain instances, when a is one, the A ring is a heterocyclic 6-membered ring.
- a is an integer from 2 to 7. In certain instances, when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 6. In certain instances, when the A ring is a heterocyclic 5- membered ring, then a is an integer from 2 to 5. In certain instances, when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 4. In certain instances, when the A ring is a heterocyclic 5-membered ring, then a is an integer from 2 to 3. In certain instances, when the A ring is a heterocyclic 5-membered ring, then a is 2.
- the A ring is a heterocyclic 7-membered or 8-membered ring and a is 1 or 2. In certain instances, the A ring is a heterocyclic 7-membered ring and a is 1. In certain instances, the A ring is a heterocyclic 7-membered ring and a is 2. In certain instances, the A ring is a heterocyclic 8-membered ring and a is 1. In certain instances, the A ring is a
- heterocyclic 8-membered ring and a is 2.
- a certain group of compounds are compounds of formulae I-XIV, wherein A ring is a 5-membered ring and a is 2.
- a certain group of compounds are compounds of formulae I-XIV, wherein A ring is a 6-membered ring and a is one.
- each R can independently be hydrogen, alkyl, substituted alkyl, aryl or substituted aryl.
- At least one R 3 is hydrogen. In certain instances, at least one R 3 is alkyl. In certain instances, at least one R is substituted alkyl. In certain instances, at least one
- R 3 is aryl. In certain instances, at least one R 3 is substituted aryl.
- each of the R 3 is hydrogen or alkyl. In certain instances, all R 3 are hydrogen. In certain instances, all R 3 are alkyl. In certain instances, the R 3 of N-R 3 that is adjacent to C-R 5 is hydrogen or alkyl. In certain instances, the R 3 of N-R 3 that is adjacent to C-R 5 is hydrogen or alkyl. In certain instances, the R 3 of N-R 3 that is adjacent to C-
- R 5 is hydrogen.
- the R 3 of N-R 3 that is adjacent to C-R 5 is alkyl.
- R 5 can be selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.
- R 5 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.
- R 5 is selected from hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, and substituted heteroarylalkyl.
- R 5 is hydrogen.
- R 5 is alkyl.
- R 5 is substituted alkyl.
- R 5 is arylalkyl or substituted arylalkyl.
- R 5 is heteroarylalkyl or substituted heteroarylalkyl.
- R 5 is a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant.
- R 5 can be a side chain of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states.
- R 5 can be a side chain of an amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
- R 5 is a side chain of an L-amino acid selected from L-alanine, L- arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L- histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, L-valine, L-homoarginine, L-homolysine, L-ornithine, L- arginine mimic, L-arginine homologue, L-arginine truncate, L-arginine with varying oxidation states, L-lysine mimic, L-lysine homologue, L-lysine truncate, and L-lysine with varying oxidation states.
- R 5 is a side chain of an L-amino acid selected from L-alanine, L- arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L- histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine.
- L-amino acid selected from L-alanine, L- arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L- histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L
- R 5 is a side chain of an amino acid selected from arginine, lysine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states.
- arginine and lysine mimics include
- R 5 is a side chain of an amino acid selected from arginine, lysine, homoarginine, homolysine, and ornithine. In certain instances, R 5 is a side chain of an amino acid selected from arginine or lysine. In certain instances, R 5 is a side chain of arginine. In certain instances, R 5 is a side chain of lysine.
- R 5 is a side chain of an L-amino acid selected from L-arginine, L- lysine, L-homoarginine, L-homolysine, L-ornithine, L-arginine mimic, L-arginine homologue, L- arginine truncate, L-arginine with varying oxidation states, L-lysine mimic, L-lysine homologue, L-lysine truncate, and L-lysine with varying oxidation states.
- L-amino acid selected from L-arginine, L- lysine, L-homoarginine, L-homolysine, L-ornithine, L-arginine mimic, L-arginine homologue, L- arginine truncate, L-arginine with varying oxidation states, L-lysine mimic, L-lysine homologue, L-lysine truncate, and L-lysine with varying oxid
- R 5 is a side chain of an L-amino acid selected from L-arginine, L-lysine, L-homoarginine, L-homolysine, and L-ornithine. In certain instances, R 5 is a side chain of an L-amino acid selected from L- arginine or L-lysine. In certain instances, R 5 is a side chain of L-arginine. In certain instances, R 5 is a side chain of L-lysine.
- R 5 can be a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant that effects -C(0)-C(R 5 )-N(R 3 )- to be a GI enzyme-cleavable moiety, such as a trypsin-cleavable moiety.
- a GI enzyme-cleavable moiety is a structural moiety that is capable of being cleaved by a GI enzyme.
- a trypsin-cleavable moiety is a structural moiety that is capable of being cleaved by trypsin.
- a GI enzyme-cleavable moiety comprises a charged moiety that can fit into an active site of a GI enzyme and is able to orient the prodrug for cleavage at a scissile bond.
- a trypsin-cleavable moiety comprises a charged moiety that can fit into an active site of trypsin and is able to orient the prodrug for cleavage at a scissile bond.
- the charged moiety of a GI enzyme- cleavable moiety such as a trypsin-cleavable moiety, can be a basic moiety that exists as a charged moiety at physiological pH.
- a derivative of an amino acid or of an amino acid variant refers to a substance that has been altered from another substance by modification, partial substitution, homologation, truncation, or a change in oxidation state, while retaining the ability to be cleaved by a GI enzyme.
- R 5 can include, but is not limited to, a side chain of lysine (such as L-lysine), arginine (such as L-arginine), homolysine, homoarginine, and ornithine.
- Other values for R 5 include, but are not limited to, a side chain of an arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states (for instance, metabolites), lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states (for instance, metabolites).
- arginine and lysine mimics include arylguanidines, arylamidines (substituted benzamidines), benzylamines, (bicyclo[2.2.2]octan-l- yl)methanamine, citrulline, homocitrulline and derivatives thereof.
- R is a side chain of an amino acid that effects -C(0)-C(R N(R to be a GI enzyme-cleavable moiety, such as a trypsin-cleavable moiety.
- R 5 is a side chain of an amino acid variant that effects -C(0)-C(R 5 )-N(R 3 )- to be a GI enzyme- cleavable moiety, such as a trypsin-cleavable moiety.
- R 5 is a derivative of a side chain of an amino acid that effects -C(0)-C(R 5 )-N(R 3 )- to be a GI enzyme-cleavable moiety, such as a trypsin-cleavable moiety.
- R 5 is a derivative of a side chain of an amino acid variant that effects -C(0)-C(R 5 )-N(R 3 )- to be a GI enzyme-cleavable moiety, such as a trypsin-cleavable moiety.
- R 5 is a side chain of an amino acid selected from arginine, lysine, homoarginine, homolysine, ornithine, arginine mimic, arginine homologue, arginine truncate, arginine with varying oxidation states, lysine mimic, lysine homologue, lysine truncate, and lysine with varying oxidation states.
- R 5 is a side chain of an amino acid selected from arginine, lysine, homoarginine, homolysine, and ornithine.
- R 5 is a side chain of an amino acid selected from arginine or lysine.
- R 5 is a side chain of arginine.
- R 5 is a side chain of lysine.
- R 5 is a side chain of an L-amino acid selected from L-arginine, L- lysine, L-homoarginine, L-homolysine, L-ornithine, L-arginine mimic, L-arginine homologue, L- arginine truncate, L-arginine with varying oxidation states, L-lysine mimic, L-lysine homologue, L-lysine truncate, and L-lysine with varying oxidation states.
- L-amino acid selected from L-arginine, L- lysine, L-homoarginine, L-homolysine, L-ornithine, L-arginine mimic, L-arginine homologue, L- arginine truncate, L-arginine with varying oxidation states, L-lysine mimic, L-lysine homologue, L-lysine truncate, and L-lysine with varying oxid
- R 5 is a side chain of an L-amino acid selected from L-arginine, L-lysine, L-homoarginine, L-homolysine, and L-ornithine. In certain instances, R 5 is a side chain of an L-amino acid selected from L- arginine and L-lysine. In certain instances, R 5 is a side chain of L-arginine. In certain instances, R 5 is a side chain of L-lysine.
- b is a number from zero to 100. In certain instances, b is zero to 50. In certain instances, b is zero to 90, 80, 70, 60, 50, 40, 30, 20, or 10. In certain instances, b is 100. In certain instances, b is 75. In certain instances, b is 50. In certain instances, b is 25. In certain instances, b is 20. In certain instances, b is 15. In certain instances, b is 10. In certain instances, b is 9. In certain instances, b is 8. In certain instances, b is 7. In certain instances, b is 6. In certain instances, b is 5. In certain instances, b is 4. In certain instances, b is 3. In certain instances, b is 2. In certain instances, b is one. In certain instances, b is zero. In certain instances, b is zero or one. In certain instances, b is zero or two.
- each R 6 can be independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.
- each R 6 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.
- R 6 is hydrogen.
- R 6 is alkyl.
- R 6 is substituted alkyl.
- R 6 is arylalkyl or substituted arylalkyl.
- R 6 is heteroarylalkyl or substituted heteroarylalkyl.
- R 6 is a side chain of an amino acid, a side chain of an amino acid variant, a derivative of a side chain of an amino acid, or a derivative of a side chain of an amino acid variant. In certain instances, R 6 is a side chain of an amino acid. In certain instances, R 6 is a side chain of an amino acid variant. In certain instances, R 6 is a derivative of a side chain of an amino acid. In certain instances, R 6 is a derivative of a side chain of an amino acid variant.
- each R 6 is a side chain of an amino acid independently selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
- R 6 is a side chain of an L-amino acid selected from L-alanine, L- arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L- histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine.
- L-amino acid selected from L-alanine, L- arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, glycine, L- histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L
- R 6 that is immediately adjacent to R 5 represents -H or -CH 3 , the configuration of the carbon atom to which R 6 is attached corresponding with that in an L-amino acid. In certain instances, R 6 that is immediately adjacent to R 5 represents -H. In certain instances, R 6 that is immediately adjacent to R 5 represents -CH 3 , the configuration of the carbon atom to which R 6 is attached corresponding with that in an L-amino acid.
- R 6 that is immediately adjacent to R 5 is a side chain of an amino acid selected from L-alanine and glycine. In certain instances, R 6 that is immediately adjacent to R 5 is a side chain of L-alanine. In certain instances, R 6 that is immediately adjacent to R 5 is a side chain of glycine.
- R can be selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl.
- R is hydrogen, alkyl, acyl, or substituted acyl. In certain instances,
- R is hydrogen, acyl, or substituted acyl. In certain instances, R is hydrogen. In certain
- R is alkyl. In certain instances, R is acyl or substituted acyl. In certain instances, R
- R is acyl. In certain instances, R is substituted acyl. In certain instances, R can be acetyl, 7
- R can benzoyl, malonyl, piperonyl or succinyl.
- R can be acetyl.
- R can be malonyl.
- a certain group of compounds are compounds of formulae I- XVII, wherein R 5 is a side chain of an amino acid selected from arginine and lysine and b is one. In certain instances, a certain group of compounds are compounds of formulae I- XVII, wherein R 5 is a side chain of an amino acid selected from arginine and lysine; R 6 is a side chain of an amino acid selected from alanine and glycine; and b is one. In certain instances, a certain group of compounds are compounds of formulae I- XVII, wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine and b is one.
- a certain group of compounds are compounds of formulae I- XVII, wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of an amino acid selected from L- alanine and glycine; and b is one.
- a certain group of compounds are compounds of formulae I- XVII, wherein R 5 is a side chain of L-arginine; R 6 is a side chain of an amino acid selected from L-alanine and glycine; and b is one.
- a certain group of compounds are compounds of formulae I- XVII, wherein R 5 is a side chain of L-lysine; R 6 is a side chain of an amino acid selected from L-alanine and glycine; and b is one.
- a certain group of compounds are compounds of formulae I- XVII, wherein R 6 is a side chain of glycine and b is one. In certain instances, a certain group of compounds are compounds of formulae I- XVII, wherein R 5 is a side chain of an amino acid selected from arginine and lysine; R 6 is a side chain of glycine; and b is one. In certain instances, a certain group of compounds are compounds of formulae I- XVII, wherein R 5 is a side chain of an amino acid selected from L-arginine and L-lysine; R 6 is a side chain of glycine; and b is one.
- a certain group of compounds are compounds of formulae I- XVII, wherein R 6 is a side chain of alanine and b is one. In certain instances, a certain group of compounds are compounds of formulae I- XVII, wherein R 6 is a side chain of L-alanine and b is one. In certain instances, a certain group of compounds are compounds of formulae I- XVII, wherein R 5 is a side chain of an amino acid selected from arginine and lysine; R 6 is a side chain of alanine; and b is one.
- a certain group of compounds are compounds of formulae I- XVII, wherein R 5 is a side chain of an amino acid selected from L-arginine and L- lysine; R 6 is a side chain of L-alanine; and b is one.
- a certain group of compounds are compounds of formulae I- XVII, wherein R 5 is a side chain of L-arginine; R 6 is a side chain of L-alanine; and b is one.
- a certain group of compounds are compounds of formulae I- XVII, wherein R 5 is a side chain of L-arginine; R 6 is a side chain of glycine; and b is one.
- a certain group of compounds are compounds of formulae I- XVII, wherein R 5 is a side chain of L-lysine; R 6 is a side chain of L-alanine; and b is one. In certain instances, a certain group of compounds are compounds of formulae I- XVII, wherein R 5 is a side chain of L-lysine; R 6 is a side chain of glycine; and b is one.
- amino acid means a building block of a polypeptide.
- amino acid includes the 20 common naturally occurring L- amino acids and all amino acids variants.
- an amino acid is a cleavable substrate for a gastrointestinal enzyme.
- “Naturally occurring amino acids” means the 20 common naturally occurring L- amino acids, that is, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
- Amino acid variants means an amino acid other than any of the 20 common naturally occurring L-amino acids that is hydrolyzable by a protease in a manner similar to the ability of a protease to hydrolyze a naturally occurring L-amino acid.
- Amino acid variants thus, include amino acids or analogs of amino acids other than the 20 naturally-occurring amino acids.
- Amino acid variants include synthetic amino acids.
- the embodiments also include derivatives of amino acids and of amino acid variants.
- a derivative of an amino acid or of an amino acid variant refers to a substance that has been altered from another substance by modification, partial substitution, homologation, truncation, or a change in oxidation state, while retaining the ability to be cleaved by a GI enzyme.
- amino acid variants include, but are not limited to: 2-aminoindane-2- carboxylic acid, 2-aminoisobutyric acid, 4-amino-phenylalanine, 5-hydroxylysine,
- dipropylglycine homoarginine, homocitrulline, homophenylalanine, homoproline, homoserine, homotyrosine, hydroxyproline, lanthionine, naphthylalanine, norleucine, ornithine,
- amino acid variants include, but are not limited to, N-methyl amino acids.
- N-methyl-alanine, N-methyl aspartic acid, N-methyl-glutamic acid, N- methyl-glycine (sarcosine) are N-methyl amino acids.
- amino acid variants include, but are not limited to: dehydroalanine, ethionine, hypusine, lanthionine, pyrrolysine, a-aminoisobutyric acid, selenomethionine and derivatives thereof.
- amino acid variants include, but are not limited to: (3, 2-amino benzoic acid, 2-amino methyl benzoic acid, 2-amino-3-guanidinopropionic acid, 2-amino-3- methoxy benzoic acid, 2-amino-3-ureidopropionic acid, 3-amino benzoic acid, 4-amino benzoic acid, 4-amino methyl benzoic acid, 4-nitroanthranillic acid, 5-acetamido-2-aminobenzoic acid, butanoic acid (HMB), glutathione, homocysteine, statine, taurine, ⁇ -alanine, 2-hydroxy-4- (methylthio), (3,4)-diamino benzoic acid, (3,5)-diamino benzoic acid and derivatives thereof.
- 3-amino benzoic acid 4-amino benzoic acid, 4-amino methyl benzoic acid, 4-nitroanthranillic acid, 5-acetamido-2-a
- amino acid variants include, but are not limited to: (2 amino ethyl) cysteine, 2-amino-3-ethyoxybutanoic acid, buthionine, cystathion, cysteic acid, ethionine, ethoxytheorine, methylserine, ⁇ - ⁇ - ⁇ -dimethyl-lysine, ⁇ - ⁇ -nitro-arginine, saccharopine, isoserine derivatives thereof, and combinations thereof.
- amino acid variants include, but are not limited to: /-carnitine, selenocysteine, /-sarcosine, /-lysinol, benzoic acid, citric acid, choline, EDTA or succinic acid and derivatives thereof.
- amino acid variants are amino alcohols.
- amino alcohols include, but are not limited to: alaninol, indano, norephedrine, asparaginol, aspartimol, glutamol, leucinol, methioninol, phenylalaninol, prolinol, tryptophanol, valinol, isoleucinol, argininol, serinol, tyrosinol, threoninol, cysteinol, lysinol, histidinol and derivatives thereof.
- Scheme 1 A representative synthesis for Compound Sl-104 is shown in Scheme 1.
- X, A ring, Y, and c are defined herein.
- PG 1 is an amino protecting group.
- Compound Sl-102 is an active agent where the active agent comprises a functional group that is connected to -C(0)-LG.
- active agent X comprises a functional group, such as a ketone, an alcohol of a phenol, or an amide, that reacts with a reagent to form a connection to -C(0)-LG.
- LG of Compound Sl-102 is a leaving group.
- LG is a leaving group, such as 4-nitrophenolate .
- Compound Sl-102 reacts with Compound SI- 103 to form Compound Sl-104.
- Compound Sl-103 is a commercially available starting material.
- Compound Sl-103 can be synthesized via a variety of different synthetic routes using commercially available starting materials and/or starting materials prepared by conventional synthetic methods.
- a representative synthesis for Compound SI -203 is shown in Scheme 2.
- a ring, Y, c, and R 5 are defined herein.
- PG 1 and PG2 are amino protecting groups.
- the protecting group PG 1 is removed from Compound Sl-104 to form Compound S 1-201. Conditions to remove amino groups can be found in Greene and Wuts.
- PG 1 is a Boc group
- the protecting group can be removed with acidic conditions, such as treatment with hydrochloric acid or trifluoroacetic acid.
- R 5 is a side chain of an amino acid and is optionally protected.
- Protecting groups for the side chain of amino acids are known to those skilled in art and can be found in Greene and Wuts.
- the protecting group for the side chain of arginine is a sulfonyl-type protecting group, such as 2,2,4,6,7-pentamethyldihydrobenzofurane (Pbf).
- Other protecting groups include 2,2,5,7,8- pentamethylchroman (Pmc) and l,2-dimethylindole-3-sulfonyl (MIS).
- a peptide coupling reaction typically employs a conventional peptide coupling reagent and is conducted under conventional coupling reaction conditions, typically in the presence of a trialkylamine, such as triethylamine or diisopropylethylamine (DIEA).
- Suitable coupling reagents for use include, by way of example, carbodiimides, such as ethyl-3-(3- dimethylamino)propylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC),
- DIC diisopropylcarbodiimide
- other well-known coupling reagents such as ⁇ , ⁇ '-carbonyldiimidazole, 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline (EEDQ), benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 0-(7- azabenzotriazol-l-yl)-N,N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and the like.
- ⁇ , ⁇ '-carbonyldiimidazole 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline
- EEDQ 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline
- BOP benzotriazol-l-yloxy-
- coupling promoters such as N-hydroxysuccinimide, 1- hydroxybenzotriazole (HOBT), l-hydroxy-7-azabenzotriazole (HO AT), N,N- dimethylaminopyridine (DMAP) and the like, can be employed in this reaction.
- this coupling reaction is conducted at a temperature ranging from about 0 °C to about 60 °C for about 1 to about 72 hours in an inert diluent, such as THF or DMF.
- Compound S 1-201 reacts with Compound S 1-202 to form Compound S 1-203 in the presence of HATU.
- the protecting group PG is removed from Compound S 1-203 to form Compound S 1-301.
- Conditions to remove amino groups can be found in Greene and Wuts.
- PG is a Boc group
- the protecting group can be removed with acidic conditions, such as treatment with hydrochloric acid or trifluoroacetic acid.
- a peptide coupling reaction typically employs a conventional peptide coupling reagent and is conducted under conventional coupling reaction conditions, typically in the presence of a trialkylamine, such as triethylamine or
- DIEA diisopropylethylamine
- Suitable coupling reagents for use include, by way of example, carbodiimides, such as ethyl-3-(3-dimethylamino)propylcarbodiimide (EDC),
- EDC ethyl-3-(3-dimethylamino)propylcarbodiimide
- DCC dicyclohexylcarbodiimide
- DIC diisopropylcarbodiimide
- other well-known coupling reagents such as ⁇ , ⁇ '-carbonyldiimidazole, 2-ethoxy-l-ethoxycarbonyl-l,2- dihydroquinoline (EEDQ), benzotriazol- 1 -yloxy-tris(dimethylamino)phosphonium
- hexafluorophosphate BOP
- HATU 0-(7-azabenzotriazol-l-yl)-N,N,N,N',N'-tetramethyluronium hexafluorophosphate
- well-known coupling promoters such as N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBT), l-hydroxy-7-azabenzotriazole
- HOAT ⁇ , ⁇ -dimethylaminopyridine
- DMAP ⁇ , ⁇ -dimethylaminopyridine
- this coupling reaction is conducted at a temperature ranging from about 0 °C to about 60 °C for about 1 to about 72 hours in an inert diluent, such as THF or DMF.
- Compound S 1-301 reacts with Compound S 1-302 to form Compound S 1-303 in the presence of HATU.
- Reaction using mono-tert- butyl malonate can be aided with use of activation reagents, such as symmetric anhydrides, O- (benzotriazol- 1 -yl) -N, N, N', N'-tetramethyluronium hexafluoropho sphate (HBTU) ,
- activation reagents such as symmetric anhydrides, O- (benzotriazol- 1 -yl) -N, N, N', N'-tetramethyluronium hexafluoropho sphate (HBTU) ,
- an alkanoyl group such as an acetyl group, can be attached via a reaction with alkanoyl anhydride or alkanoyl halide.
- Additional amino acids can be added to the compound through standard peptide coupling reactions as discussed herein. Removal of other protecting groups can be performed if other protecting groups were used, such as protecting groups present on the R 5 or R 6 moiety.
- Conditions for removal of other protecting groups depend on the identity of the protecting group and are known to those skilled in the art. The conditions can also be found in Greene and Wuts.
- Compound S2-100 can be semi- synthetically derived from natural materials or synthesized via a variety of different synthetic routes using commercially available starting materials and/or starting materials prepared by conventional synthetic methods.
- hexamethyldisilazide KHMDS
- the enolate of Compound S2-100 is then reacted with an activation agent, such as Compound S2-101, to form intermediate Compound S2-102.
- Suitable activation agents include carbonate-forming reagents, such as chloroformates.
- the activation agent Compound S2-101 is 4-nitrophenyl chloroformate.
- Other suitable activation agents can be used prior to reaction with Compound S2-103.
- Compound S2-102 reacts with Compound S2-103 to form Compound S2-104.
- Compound S2-103 is a commercially available starting material.
- Compound S2-103 can be synthesized via a variety of different synthetic routes using commercially available starting materials and/or starting materials prepared by conventional synthetic methods.
- a representative synthesis for Compound S2-203 is shown in Scheme 5.
- R a , A ring, Y, c, and R 5 are defined herein.
- PG 1 and PG 2 are amino protecting groups.
- the protecting group PG 1 is removed from Compound S2-104 to form Compound S2-201. Conditions to remove amino groups can be found in Greene and Wuts.
- PG 1 is a Boc group
- the protecting group can be removed with acidic conditions, such as treatment with hydrochloric acid or trifluoroacetic acid.
- R 5 is a side chain of an amino acid and is optionally protected.
- Protecting groups for the side chain of amino acids are known to those skilled in art and can be found in Greene and Wuts.
- the protecting group for the side chain of arginine is a sulfonyl-type protecting group, such as 2,2,4,6,7-pentamethyldihydrobenzofurane (Pbf).
- Other protecting groups include 2,2,5,7,8- pentamethylchroman (Pmc) and l,2-dimethylindole-3-sulfonyl (MIS).
- a peptide coupling reaction typically employs a conventional peptide coupling reagent and is conducted under conventional coupling reaction conditions, typically in the presence of a trialkylamine, such as triethylamine or diisopropylethylamine (DIEA).
- Suitable coupling reagents for use include, by way of example, carbodiimides, such as ethyl-3-(3- dimethylamino)propylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC),
- DIC diisopropylcarbodiimide
- other well-known coupling reagents such as ⁇ , ⁇ '-carbonyldiimidazole, 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline (EEDQ), benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 0-(7- azabenzotriazol-l-yl)-N,N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and the like.
- ⁇ , ⁇ '-carbonyldiimidazole 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline
- EEDQ 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline
- BOP benzotriazol-l-yloxy-
- coupling promoters such as N-hydroxysuccinimide, 1- hydroxybenzotriazole (HOBT), l-hydroxy-7-azabenzotriazole (HOAT), N,N- dimethylaminopyridine (DMAP) and the like, can be employed in this reaction.
- this coupling reaction is conducted at a temperature ranging from about 0 °C to about 60 °C for about 1 to about 72 hours in an inert diluent, such as THF or DMF.
- Compound S2-201 reacts with Compound S2-202 to form Compound S2-203 in the presence of HATU.
- the protecting group PG is removed from Compound S2-203 to form Compound S2-301.
- Conditions to remove amino groups can be found in Greene and Wuts.
- PG is a Boc group
- the protecting group can be removed with acidic conditions, such as treatment with hydrochloric acid or trifluoroacetic acid.
- Compound S2-301 reacts with Compound S2-302 to form Compound S2-303 in a peptide coupling reaction.
- a peptide coupling reaction typically employs a conventional peptide coupling reagent and is conducted under conventional coupling reaction conditions, typically in the presence of a trialkylamine, such as triethylamine or
- DIEA diisopropylethylamine
- Suitable coupling reagents for use include, by way of example, carbodiimides, such as ethyl-3-(3-dimethylamino)propylcarbodiimide (EDC),
- EDC ethyl-3-(3-dimethylamino)propylcarbodiimide
- DCC dicyclohexylcarbodiimide
- DIC diisopropylcarbodiimide
- other well-known coupling reagents such as ⁇ , ⁇ '-carbonyldiimidazole, 2-ethoxy-l-ethoxycarbonyl-l,2- dihydroquinoline (EEDQ), benzotriazol- 1 -yloxy-tris(dimethylamino)phosphonium
- hexafluorophosphate BOP
- HATU 0-(7-azabenzotriazol-l-yl)-N,N,N,N',N'-tetramethyluronium hexafluorophosphate
- well-known coupling promoters such as N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBT), l-hydroxy-7-azabenzotriazole
- HO AT ⁇ , ⁇ -dimethylaminopyridine
- DMAP ⁇ , ⁇ -dimethylaminopyridine
- this coupling reaction is conducted at a temperature ranging from about 0 °C to about 60 °C for about 1 to about 72 hours in an inert diluent, such as THF or DMF.
- Compound S2-301 reacts with Compound S2-302 to form Compound S2-303 in the presence of HATU.
- Reaction using mono-tert- butyl malonate can be aided with use of activation reagents, such as symmetric anhydrides, O- (benzotriazol- 1 -yl) -N, N, N', N'-tetramethyluronium hexafluoropho sphate (HBTU) ,
- activation reagents such as symmetric anhydrides, O- (benzotriazol- 1 -yl) -N, N, N', N'-tetramethyluronium hexafluoropho sphate (HBTU) ,
- an alkanoyl group such as an acetyl group, can be attached via a reaction with alkanoyl anhydride or alkanoyl halide.
- Additional amino acids can be added to the compound through standard peptide coupling reactions as discussed herein. Removal of other protecting groups can be performed if other protecting groups were used, such as protecting groups present on the R 5 or R 6 moiety.
- Conditions for removal of other protecting groups depend on the identity of the protecting group and are known to those skilled in the art. The conditions can also be found in Greene and Wuts.
- Scheme 7 Representative synthesis for Compound S-404 is shown in Scheme 7.
- a ring, Y, c, and R 5 are defined herein.
- PG 1 and PG2 are amino protecting groups. Although the schemes herein show R 1 and R2 as being hydrogen and a being one, the entire scope of 2 R", and a as applicable to Formula I-XVII is contemplated.
- Compound S-401 can be semi-synthetically derived from natural materials or synthesized via a variety of different synthetic routes using commercially available starting materials and/or starting materials prepared by conventional synthetic methods.
- Conditions to remove amino groups can be found in Greene and Wuts.
- PG 1 is a Boc group
- the protecting group can be removed with acidic conditions, such as treatment with hydrochloric acid or trifluoroacetic acid.
- R 5 is a side chain of an amino acid and is optionally protected.
- Protecting groups for the side chain of amino acids are known to those skilled in art and can be found in Greene and Wuts.
- the protecting group for the side chain of arginine is a sulfonyl-type protecting group, such as 2,2,4,6,7-pentamethyldihydrobenzofurane (Pbf).
- Other protecting groups include 2,2,5,7,8- pentamethylchroman (Pmc) and l,2-dimethylindole-3-sulfonyl (MIS).
- a peptide coupling reaction typically employs a conventional peptide coupling reagent and is conducted under conventional coupling reaction conditions, typically in the presence of a trialkylamine, such as triethylamine or diisopropylethylamine (DIEA).
- Suitable coupling reagents for use include, by way of example, carbodiimides, such as ethyl-3-(3- dimethylamino)propylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC),
- DIC diisopropylcarbodiimide
- other well-known coupling reagents such as ⁇ , ⁇ '-carbonyldiimidazole, 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline (EEDQ), benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 0-(7- azabenzotriazol-l-yl)-N,N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and the like.
- ⁇ , ⁇ '-carbonyldiimidazole 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline
- EEDQ 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline
- BOP benzotriazol-l-yloxy-
- coupling promoters such as N-hydroxysuccinimide, 1- hydroxybenzotriazole (HOBT), l-hydroxy-7-azabenzotriazole (HOAT), N,N- dimethylaminopyridine (DMAP) and the like, can be employed in this reaction.
- this coupling reaction is conducted at a temperature ranging from about 0 °C to about 60 °C for about 1 to about 72 hours in an inert diluent, such as THF or DMF.
- Compound S- 402 reacts with Compound S-403 to form Compound S-404 in the presence of HATU.
- Compound S-501 is a commercially available starting material.
- Compound S-501 can be synthesized via a variety of different synthetic routes using commercially available starting materials and/or starting materials prepared by conventional synthetic methods.
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IL228215A IL228215B (en) | 2011-03-09 | 2013-09-01 | Active agent prodrugs with heterocyclic linkers |
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US11851422B2 (en) | 2021-07-09 | 2023-12-26 | Aligos Therapeutics, Inc. | Anti-viral compounds |
US12011427B2 (en) | 2019-12-11 | 2024-06-18 | Inspirna, Inc. | Methods of treating cancer |
US12065428B2 (en) | 2021-09-17 | 2024-08-20 | Aligos Therapeutics, Inc. | Anti-viral compounds |
Families Citing this family (16)
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US20110262355A1 (en) | 2010-04-21 | 2011-10-27 | Jenkins Thomas E | Compositions comprising enzyme-cleavable opioid prodrugs and inhibitors thereof |
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US10717712B2 (en) | 2018-07-27 | 2020-07-21 | Concentric Analgesics, Inc. | Pegylated prodrugs of phenolic TRPV1 agonists |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010045599A1 (en) | 2008-10-17 | 2010-04-22 | Pharmacofore, Inc. | Pharmaceutical compositions with attenuated release of phenolic opioids |
WO2011007247A1 (en) | 2009-07-17 | 2011-01-20 | Llc Shire | Novel carbamate amino acid and peptide prodrugs of opioids and uses thereof |
Family Cites Families (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU527371B2 (en) | 1980-09-16 | 1983-03-03 | Torii & Co., Ltd. | Amidine |
US5109118A (en) | 1989-07-06 | 1992-04-28 | Yutaka Mizushima | Modified biologically active proteins |
US5217987A (en) | 1989-10-30 | 1993-06-08 | Berger Stephen P | Dopamine uptake inhibitors in reducing substance abuse and/or craving |
CA2032420A1 (en) | 1989-12-22 | 1991-06-23 | Akira Okuyama | Guanidinobenzene derivatives |
US6692766B1 (en) | 1994-06-15 | 2004-02-17 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Controlled release oral drug delivery system |
US6388122B1 (en) | 1996-04-10 | 2002-05-14 | Ono Pharmaceutical Co., Ltd. | Tryptase inhibitor and novel guanidino derivatives |
ES2194536T3 (en) | 1998-11-13 | 2003-11-16 | Lilly Co Eli | COMBINATION OF DULOXETINE WITH NON-STEROID ANTI-INFLAMMATORY DRUGS. |
EP1151090B1 (en) | 1998-12-15 | 2009-09-02 | Applera Corporation | Multiple enzyme assays |
US6849263B2 (en) | 1998-12-21 | 2005-02-01 | Generex Pharmaceutical Incorporated | Pharmaceutical compositions for buccal delivery of pain relief medications |
EP1161226B1 (en) | 1999-02-18 | 2004-05-26 | SuperGen, Inc. | Phosphocholine linked prodrug derivatives |
US7060708B2 (en) | 1999-03-10 | 2006-06-13 | New River Pharmaceuticals Inc. | Active agent delivery systems and methods for protecting and administering active agents |
US20030180352A1 (en) | 1999-11-23 | 2003-09-25 | Patel Mahesh V. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US6673574B2 (en) | 2000-11-30 | 2004-01-06 | Unigene Laboratories Inc. | Oral delivery of peptides using enzyme-cleavable membrane translocators |
ATE504315T1 (en) | 2001-06-11 | 2011-04-15 | Medarex Inc | METHOD FOR EVALUATION OF CD10-ACTIVATED PRODRUG COMPOUNDS |
US7169752B2 (en) | 2003-09-30 | 2007-01-30 | New River Pharmaceuticals Inc. | Compounds and compositions for prevention of overdose of oxycodone |
CA2477004C (en) | 2002-02-22 | 2011-05-10 | Thomas Piccariello | Novel sustained release pharmaceutical compounds to prevent abuse of controlled substances |
US20100092562A1 (en) | 2002-11-26 | 2010-04-15 | Hollenbeck R Gary | Sustained-release drug delivery compositions and methods |
WO2004082620A2 (en) | 2003-03-13 | 2004-09-30 | Controlled Chemicals, Inc. | Oxycodone conjugates with lower the abuse potential and extended duration of action |
EP1782834A3 (en) | 2003-03-13 | 2007-08-01 | Controlled Chemicals, Inc. | Oxycodone conjugates with lower abuse potential and extended duration of action |
JP4898445B2 (en) | 2003-05-29 | 2012-03-14 | シャイア エルエルシー | Abuse-resistant amphetamine compounds |
NZ546226A (en) | 2003-09-30 | 2009-03-31 | Shire Llc | Oxycodone conjugates for prevention of overdose or abuse |
US8163701B2 (en) * | 2005-08-19 | 2012-04-24 | Signature Therapeutics, Inc. | Prodrugs of active agents |
US20070093420A1 (en) | 2005-08-26 | 2007-04-26 | Yeomans David C | Therapy procedure for drug delivery for trigeminal pain |
CN101309917B (en) | 2005-10-06 | 2013-09-11 | 奥斯拜客斯制药有限公司 | Inhibitors of the gastric h+, k+-atpase with enhanced therapeutic properties |
DK1959948T3 (en) | 2005-12-05 | 2012-08-20 | Xenoport Inc | LEVODOPA PRODRUG MESYLATE, COMPOSITIONS THEREOF AND APPLICATIONS THEREOF |
JP2009533443A (en) | 2006-04-10 | 2009-09-17 | シャイア エルエルシー | Mono- and disubstituted oxycodone compounds and compositions |
JP2009533459A (en) | 2006-04-14 | 2009-09-17 | シャイア エルエルシー | Compositions and methods for enhancing analgesic action of covalently bound compounds, attenuating harmful side effects and preventing abuse of said compounds |
EP2402037B8 (en) | 2006-05-26 | 2019-12-04 | Signature Therapeutics, Inc. | Controlled release of phenolic opioids |
TWI401237B (en) | 2006-07-24 | 2013-07-11 | Preparation of 3-[(1r, 2r)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol monohydrochloride | |
KR20090055616A (en) | 2006-09-14 | 2009-06-02 | 스타파이어 시스템즈, 인크. | Synthetic process for cyclic organosilanes |
US20120142718A1 (en) | 2007-02-16 | 2012-06-07 | Jenkins Thomas E | N-17-Alkylated Prodrugs of Opioids |
US20110105381A2 (en) | 2007-02-16 | 2011-05-05 | Pharmacofore, Inc. | Prodrugs of Peripheral Phenolic Opioid Antagonists |
KR101607112B1 (en) | 2007-11-23 | 2016-03-29 | 그뤼넨탈 게엠베하 | Tapentadol compositions |
US9023860B2 (en) | 2007-11-26 | 2015-05-05 | Signature Therapeutics, Inc. | Pro-drugs for controlled release of biologically active compounds |
ES2671897T3 (en) | 2008-02-14 | 2018-06-11 | Alkermes, Inc. | Selective opioid compounds |
WO2010100477A2 (en) | 2009-03-03 | 2010-09-10 | Shire Llc | Amino acid and peptide carbamate prodrugs of tapentadol and uses thereof |
WO2010112942A1 (en) | 2009-04-02 | 2010-10-07 | Shire Llc | Novel dicarboxylic acid linked amino acid and peptide prodrugs of opioids and uses thereof |
MX348262B (en) | 2009-09-08 | 2017-06-05 | Signature Therapeutics Inc * | Compositions comprising enzyme-cleavable ketone-modified opioid prodrugs and optional inhibitors thereof. |
ES2710617T3 (en) | 2010-04-21 | 2019-04-26 | Signature Therapeutics Inc | Compositions comprising enzymatically cleavable amphetamine prodrugs and inhibitors thereof |
US20110262355A1 (en) | 2010-04-21 | 2011-10-27 | Jenkins Thomas E | Compositions comprising enzyme-cleavable opioid prodrugs and inhibitors thereof |
US9238020B2 (en) | 2010-04-21 | 2016-01-19 | Signature Therapeutics, Inc. | Compositions comprising enzyme-cleavable phenol-modified tapentadol prodrug |
WO2011133346A1 (en) | 2010-04-21 | 2011-10-27 | Pharmacofore, Inc. | Peripheral opioid agonists and peripheral opioid antagonists |
US20110262360A1 (en) | 2010-04-21 | 2011-10-27 | Jenkins Thomas E | Compositions Comprising Enzyme-Cleavable Phenol-Modified Opioid Prodrugs and Inhibitors Thereof |
US20110262359A1 (en) | 2010-04-21 | 2011-10-27 | Jenkins Thomas E | Compositions comprising enzyme-cleavable prodrugs of active agents and inhibitors thereof |
DE102010042013A1 (en) * | 2010-10-06 | 2012-04-12 | Robert Bosch Gmbh | Method for adjusting a temperature of a sensor element |
WO2012096887A2 (en) | 2011-01-11 | 2012-07-19 | Signature Therapeutics, Inc. | Compositions comprising enzyme-cleavable oxycodone prodrug |
WO2012096886A1 (en) | 2011-01-11 | 2012-07-19 | Signature Therapeutics, Inc. | Compositions comprising enzyme-cleavable oxycodone prodrug |
US8685916B2 (en) * | 2011-03-09 | 2014-04-01 | Signature Therapeutics, Inc. | Opioid prodrugs with heterocyclic linkers |
RU2608305C2 (en) | 2011-03-09 | 2017-01-17 | Сигничер Терапьютикс, Инк. | Prodrugs of active substances with heterocyclic linkers |
-
2012
- 2012-03-08 RU RU2013144368A patent/RU2608305C2/en active
- 2012-03-08 AU AU2012225337A patent/AU2012225337B2/en active Active
- 2012-03-08 WO PCT/US2012/028367 patent/WO2012122422A2/en active Application Filing
- 2012-03-08 BR BR112013022946A patent/BR112013022946A2/en not_active Application Discontinuation
- 2012-03-08 CN CN201280011870.8A patent/CN103813800B/en active Active
- 2012-03-08 JP JP2013557882A patent/JP6148182B2/en active Active
- 2012-03-08 EP EP12754373.4A patent/EP2683394B1/en active Active
- 2012-03-08 CA CA2827662A patent/CA2827662C/en active Active
- 2012-03-08 US US14/000,594 patent/US9139612B2/en active Active
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2013
- 2013-09-01 IL IL228215A patent/IL228215B/en active IP Right Grant
-
2015
- 2015-08-13 US US14/825,880 patent/US20160002291A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010045599A1 (en) | 2008-10-17 | 2010-04-22 | Pharmacofore, Inc. | Pharmaceutical compositions with attenuated release of phenolic opioids |
WO2011007247A1 (en) | 2009-07-17 | 2011-01-20 | Llc Shire | Novel carbamate amino acid and peptide prodrugs of opioids and uses thereof |
Non-Patent Citations (3)
Title |
---|
"Foye's Principles of Medicinal Chemistry", vol. 24, 2008, LIPPINCOTT WILLIAMS & WILKINS, pages: 653 - 678 |
"Foye's Principles of Medicinal Chemistry", vol. 36, 2008, LIPPINCOTT WILLIAMS & WILKINS, pages: 959 - 965 |
See also references of EP2683394A4 |
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Also Published As
Publication number | Publication date |
---|---|
WO2012122422A3 (en) | 2014-04-24 |
AU2012225337A1 (en) | 2013-05-09 |
US20140121152A1 (en) | 2014-05-01 |
EP2683394B1 (en) | 2021-01-06 |
RU2608305C2 (en) | 2017-01-17 |
CN103813800A (en) | 2014-05-21 |
US9139612B2 (en) | 2015-09-22 |
BR112013022946A2 (en) | 2017-07-18 |
EP2683394A2 (en) | 2014-01-15 |
IL228215B (en) | 2019-01-31 |
RU2013144368A (en) | 2015-04-10 |
CA2827662A1 (en) | 2012-09-13 |
CA2827662C (en) | 2020-07-14 |
CN103813800B (en) | 2017-12-19 |
JP6148182B2 (en) | 2017-06-14 |
EP2683394A4 (en) | 2015-06-03 |
JP2014518546A (en) | 2014-07-31 |
US20160002291A1 (en) | 2016-01-07 |
AU2012225337B2 (en) | 2016-04-28 |
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