US20020119910A1 - Compounds and compositions for delivering active agents - Google Patents

Compounds and compositions for delivering active agents Download PDF

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Publication number
US20020119910A1
US20020119910A1 US09/746,548 US74654800A US2002119910A1 US 20020119910 A1 US20020119910 A1 US 20020119910A1 US 74654800 A US74654800 A US 74654800A US 2002119910 A1 US2002119910 A1 US 2002119910A1
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US
United States
Prior art keywords
acid
aminophenyl
aminocaprylic
butyric
hydroxy
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
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US09/746,548
Inventor
Andrea Leone-Bay
Eric Wang
Donald Sarubbi
Harry Leipold
Koc-Kan Ho
David Gschneidner
Eugene Barantsevich
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Emisphere Technologies Inc
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Emisphere Technologies Inc
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Publication date
Application filed by Emisphere Technologies Inc filed Critical Emisphere Technologies Inc
Priority to US09/746,548 priority Critical patent/US20020119910A1/en
Assigned to EMISPHERE TECHNOLOGIES, INC. reassignment EMISPHERE TECHNOLOGIES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BARANSEVICH, EUGENE N., SARUBBI, DONALD J.
Publication of US20020119910A1 publication Critical patent/US20020119910A1/en
Priority to US10/395,685 priority patent/US7071214B2/en
Priority to US11/354,045 priority patent/US7553872B2/en
Priority to US12/482,320 priority patent/US8686154B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/23—Calcitonins
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH] (Somatotropin)
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone (parathormone); Parathyroid hormone-related peptides
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    • 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
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
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    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07C237/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
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    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
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    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C271/06—Esters of carbamic acids
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    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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    • C07C271/54—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/12—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 3 and unsubstituted in position 7
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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    • C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones

Definitions

  • the present invention relates to compounds for delivering active agents, and particularly biologically or chemically active agents. These compounds are used as carriers to facilitate the delivery of a cargo to a target.
  • the carrier compounds are well suited to form non-covalent mixtures with biologically-active agents for oral administration to animals. Methods for the preparation administration of such compositions are also disclosed.
  • barriers are imposed by the body.
  • physical barriers are the skin and various organ membranes that must be traversed before reaching a target.
  • Chemical barriers include, but are not limited to, pH variations, lipid bi-layers, and degrading enzymes.
  • RNA enzymatic inhibitors e.g., pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) and trasylol
  • Liposomes have also been described as drug delivery systems for insulin and heparin. See, for example, U.S. Pat. No. 4,239,754; Patel et al. (1976), FEBS Letters, Vol. 62, pg. 60; and Hashimoto et al. (1979), Endocrinology Japan, Vol. 26, pg. 337.
  • microspheres of artificial polymers of mixed amino acids have been used to deliver pharmaceuticals.
  • proteinoids mixed amino acids
  • U.S. Pat. No. 4,925,673 describes drug-containing proteinoid microsphere carriers as well as methods for their preparation and use. These proteinoid microspheres are useful for the delivery of a number of active agents.
  • compositions which are useful in the delivery of active agents are provided. These compositions include at least one active agent, preferably a biologically or chemically active agent, and at least one of the following compounds 1-193, or salts thereof.
  • compositions comprising the carrier compounds discussed above and active agents are effective in delivering active agents to selected biological systems.
  • compositions of the present invention include an active agent and a carrier. These compositions may be used to deliver various active agents through various biological, chemical, and physical barriers and are particularly suited for delivering active agents which are subject to environmental degradation.
  • the compositions of the subject invention are particularly useful for delivering or administering biologically or chemically active agents to any animals such as birds including, but not limited to, chickens; mammals, such as primates and particularly humans; and insects.
  • compositions and the formulation methods of the present invention are cost effective, simple to perform, and amenable to industrial scale up for commercial production.
  • Subcutaneous, sublingual, and intranasal coadministration of an active agent such as, for example, recombinant human growth hormone (rhGH); salmon calcitonin; heparin, including, but not limited to, low molecular weight heparin; parathyroid hormone; and compounds in compositions as described herein result in an increased bioavailability of the active agent compared to administration of the active agent alone.
  • an active agent such as, for example, recombinant human growth hormone (rhGH); salmon calcitonin; heparin, including, but not limited to, low molecular weight heparin; parathyroid hormone; and compounds in compositions as described herein result in an increased bioavailability of the active agent compared to administration of the active agent alone.
  • Active agents suitable for use in the present invention include biologically or chemically active agents, chemically active agents, including, but not limited to, fragrances, as well as other active agents such as, for example, cosmetics.
  • Bioly or chemically active agents include, but are not limited to, pesticides, pharmacological agents, and therapeutic agents.
  • biologically or chemically active agents suitable for use in the present invention include, but are not limited to, peptides, and particularly small peptides; hormones, and particularly hormones which by themselves do not or only a fraction of the administered dose passes through the gastro-intestinal mucosa and/or are susceptible to chemical cleavage by acids and enzymes in the gastro-intestinal tract; polysaccharides, and particularly mixtures of muco-polysaccharides; carbohydrates; lipids; or any combination thereof.
  • Further examples include, but are not limited to, human growth hormones; bovine growth hormones; growth releasing hormones; interferons; interleukin-1; insulin; heparin, and particularly low molecular weight heparin; calcitonin; erythropoietin; atrial naturetic factor; antigens; monoclonal antibodies; somatostatin; adrenocorticotropin, gonadotropin releasing hormone; oxytocin; vasopressin; cromolyn sodium (sodium or disodium chromoglycate); vancomycin; desferrioxamine (DFO); parathyroid hormone anti-microbials, including, but not limited to anti-fungal agents; or any combination thereof.
  • human growth hormones bovine growth hormones
  • growth releasing hormones interferons
  • interleukin-1 insulin
  • insulin heparin, and particularly low molecular weight heparin
  • calcitonin erythropoietin
  • carrier compounds or poly amino acids, and peptides, including acids may be used to deliver active agents including, but not limited to, biologically or chemically active agents such as for example, pharmacological and therapeutic agents.
  • An amino acid is any carboxylic acid having at least one free amine group and includes naturally occurring and synthetic amino acids.
  • Poly amino acids are either peptides or two or more amino acids linked by a bond formed by other groups which can be linked, e.g. an ester, anhydride, or an anhydride linkage.
  • Peptides are two or more amino acids joined by a peptide bond. Peptides can vary in length from dipeptides with two amino acids to poly peptides with several hundred amino acids. See Chambers Biological Dictionary, editor Peter M. B. Walker, Cambridge, England: Chambers Cambridge, 1989, page 215. Special mention is made of di-peptides, tri-peptides, tetra-peptides, and penta-peptides.
  • Salts such as, for example, sodium salt of these carrier compounds can be used as well.
  • amino acids including, but not limited to, aminocaprylic acid, butyrylhydroxaminic acid, aminophenylbutyric acid, aminophenylhexanoic acid, aminophenylpropionic acid, amino salicylic acid, aminophenylsuccinic acid, aminononanic acid, aminonicotinic acid, amino valenic acid, aminophenylacetic acid, aminocaproic acid, aminoundecanoic acid, aminoheptanoic acid, aminohydroxybenzoic acid, and aminodecanoic acid by methods within the skill of those in the art based upon the present disclosure and the methods described in U.S. patent application Ser. Nos. 60/017,902, filed Mar. 29, 1996; 08/414,654, filed Mar. 31, 1995; 08/335,148, filed Oct. 25, 1994; and 60/003,111, filed Sep. 1, 1995.
  • these compounds may be prepared by reacting the single acid with the appropriate agent which reacts with free amino moiety present in the amino acids to form amides.
  • Protecting groups may be used to avoid unwanted side reactions as would be known to those skilled in the art.
  • the carrier compound may be purified by recrystallization or by fractionation on solid column supports.
  • Suitable recrystallization solvent systems include acetonitrile, methanol and tetrahydrofuran. Fractionation may be performed on a suitable solid column supports such as alumina, using methanol/n-propanol mixtures as the mobile phase; reverse phase column supports using trifluoroacetic acid/acetonitrile mixtures as the mobile phase; and ion exchange chromatography using water as the mobile phase.
  • anion exchange chromatography preferably a subsequent 0-500 mM sodium chloride gradient is employed.
  • compositions of the present invention may include one or more active agents.
  • compounds or salts of compounds 1-193 or poly amino acids or peptides that include at least one of these compounds or salts may be used directly as a delivery carrier by simply mixing one or more compound or salt, poly amino acid or peptide with the active agent prior to administration.
  • the administration mixtures are prepared by mixing an aqueous solution of the carrier with an aqueous solution of the active ingredient, just prior to administration.
  • the carrier and the biologically or chemically active ingredient can be admixed during the manufacturing process.
  • the solutions may optionally contain additives such as phosphate buffer salts, citric acid, acetic acid, gelatin, and gum acacia.
  • Stabilizing additives may be incorporated into the carrier solution. With some drugs, the presence of such additives promotes the stability and dispersibility of the agent in solution.
  • the stabilizing additives may be employed at a concentration ranging between about 0.1 and 5% (W/V), preferably about 0.5% (W/V).
  • Suitable, but non-limiting, examples of stabilizing additives include gum acacia, gelatin, methyl cellulose, polyethylene glycol, carboxylic acids and salts thereof, and polylysine.
  • the preferred stabilizing additives are gum acacia, gelatin and methyl cellulose.
  • the amount of active agent is an amount effective to accomplish the purpose of the particular active agent.
  • the amount in the composition typically is a pharmacologically, biologically, therapeutically, or chemically effective amount. However, the amount can be less than a pharmacologically, biologically, therapeutically, or chemically effective amount when the composition is used in a dosage unit form, such as a capsule, a tablet or a liquid, because the dosage unit form may contain a multiplicity of carrier/biologically or chemically active agent compositions or may contain a divided pharmacologically, biologically, therapeutically, or chemically effective amount.
  • the total effective amounts can then be administered in cumulative units containing, in total, pharmacologically, biologically, therapeutically or chemically active amounts of biologically or pharmacologically active agent.
  • the total amount of active agent, and particularly biologically or chemically active agent, to be used can be determined by those skilled in the art. However, it has surprisingly been found that with some biologically or chemically active agents, the use of the presently disclosed carriers provides extremely efficient delivery, particularly in oral, intranasal, sublingual, intraduodenal, or subcutaneous systems. Therefore, lower amounts of biologically or chemically active agent than those used in prior dosage unit forms or delivery systems can be administered to the subject, while still achieving the same blood levels and therapeutic effects.
  • the amount of carrier in the present composition is a delivery effective amount and can be determined for any particular carrier or biologically or chemically active agent by methods known to those skilled in the art.
  • Dosage unit forms can also include any of excipients; diluents; disintegrants; lubricants; plasticizers; colorants; and dosing vehicles, including, but not limited to water, 1,2-propane diol, ethanol, olive oil, or any combination thereof.
  • Administration of the present compositions or dosage unit forms preferably is oral or by intraduodenal injection.
  • the delivery compositions of the present invention may also include one or more enzyme inhibitors.
  • enzyme inhibitors include, but are not limited to, compounds such as actinonin or epiactinonin and derivatives thereof. These compounds have the formulas below:
  • R 5 is sulfoxymethyl or carboxyl or a substituted carboxy group selected from carboxamide, hydroxyaminocarbonyl and alkoxycarbonyl groups; and R 6 is hydroxyl, alkoxy, hydroxyamino or sulfoxyamino group.
  • Other enzyme inhibitors include, but are not limited to, aprotinin (Trasylol) and Bowman-Birk inhibitor.
  • the compounds and compositions of the subject invention are useful for administering biologically or chemically active agents to any animals such as birds; mammals, such as primates and particularly humans; and insects.
  • the system is particularly advantageous for delivering chemically or biologically or chemically active agents which would otherwise be destroyed or rendered less effective by conditions encountered before the active agent its target zone (i.e. the area in which the active agent of the delivery composition are to be released) and within the body of the animal to which they are administered.
  • the compounds and compositions of the present invention are useful in orally administering active agents, especially those which are not ordinarily orally deliverable.
  • a 2 L three-neck round bottom flask was fitted with a magnetic stirrer and two addition funnels under an argon atmosphere.
  • a suspension of 3-(4-aminophenyl)propionic acid (46.3 g, 0.28 moles, 1.17 equiv.) in ethyl acetate (700 mL) was added to the flask.
  • a solution of 2,3-dimethoxybenzoylchloride (48.0 g, 0.24 moles, 1.00 equiv.) in ethyl acetate (250 mL) was charged to one of the addition funnels and added dropwise over 1 h.
  • Triethylamine (28.20 g, 0.28 moles, 1.00 equiv.) was subsequently charged to the second funnel and added dropwise over 15 min. The reaction was stirred at ambient temperature for 3 h, and the solvent was evaporated in vacuo giving a residual brown oil. Water (600 mL) was added to the residue followed by sodium hydroxide (2 M, 500 mL), and the mixture was stirred at ambient temperature for 3 hours. The resultant brown solution was acidified with 2 M hydrochloric acid (ca 1 L). After cooling the mixture in an ice bath for 1 h, a yellow solid formed and was collected by filtration. The solid was washed with water (3 ⁇ 1.5 L) and recrystallized from 50% ethanol-water (v/v) to give compound 79 as a tan solid (59.2 g, 68%).
  • the reflux condenser was replaced with an addition funnel containing triethylamine (42.50 g, 0.42 moles, 1.50 equiv.). The triethylamine was added dropwise over 15 min, and a yellow solid formed during the addition.
  • the funnel was replaced by another addition funnel containing a solution of 2,3-dimethoxybenzoylchloride (48.0 g, 0.24 moles, 1.00 equiv. in dichloromethane (100 mL). The solution was added dropwise over 30 min. The reaction was stirred in the ice bath for another 30 min and at ambient temperature for 1 h. The dichloromethane was evaporated in vacuo to give a brown oil.
  • the brown oil was cooled in an ice bath, and an ice-cold solution of 2 M sodium hydroxide (700 mL) was added. The ice bath was removed, and the reaction was stirred for 2 h to afford a clear brown solution.
  • the solution was acidified with 2 M sulfuric acid (400 mL) and stored at ca 5° C. for 1 hour. A yellow solid formed and was collected by filtration. The solid was washed with water (3 ⁇ 100 mL) and recrystallized from 50% ethanol-water (v/v) to afford compound 79 as tan needles (64.7 g, 82%).
  • 1,4-benzodioxan-2-one (3.93 g, 0.0262 mol) was dissolved, with stirring, in acetonitrile (70 mls) in a 250 ml round bottomed flask fitted with a magnetic stir bar, argon purge and cold water condenser.
  • Triethylamine (2.64 g, 0.0262 mol) and 8-aminocaprylic acid (500 g, 0.0262 mol) were added and a tan slurry was formed. Heating was started, and the reaction mixture was allowed to reflux for approximately 3 hours.
  • Compound 150 was also prepared by this procedure.
  • a suspension of 2.11 g (10.1 mmol) ethyl carbamoylanthranilic acid and 5 mL of CH 2 Cl 2 was treated with 2.20 mL of oxalyl chloride. After stirring for 1 h the volatiles were stripped off. At that same time, a suspension of 1.60 g (10.1 mmol) of 8-aminocaprylic acid and 15 mL of CH 2 Cl 2 was treated with 2.60 mL (2.23 g, 20.5 mmol) of TMSCl. This mixture was heated to reflux for 90 min, cooled in an ice bath and treated with 4.30 mL (3.12 g, 30.9 mmol) of triethylamine.
  • Compound 103 is available from Aldrich Chemical Company, Inc., Milwaukee, Wis.
  • the dosing solutions are designated P- carrier number—DS.
  • An intracolonic dosing composition containing 100 mg/kg of a carrier having the formula
  • mice Male Sprague-Dawley rats weighing between 200-250 g were fasted for 24 hours and were administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to dosing. The rats were administered one of dosing solutions P-9-DS, P-33-DS, P-35-DS, P-77-DS, P-79-DS, and P-141-DS by oral gavage (“PO”) or intra-colonic instillation (“IC”). Blood samples were collected serially from the tail artery for serum determination of parathyroid hormone concentration. Serum parathyroid hormone concentrations were quantified by a parathyroid hormone immunoaccuracy test host.
  • Example 3 The procedure of Example 3 was followed substituting dosing solution P-9A-DS for dosing solution P-9-DS. Results are illustrated in Table 2, below.
  • Example 3 The procedure of Example 3 was followed with a dosing solution (at a dose of 25 ⁇ g/kg of parathyroid hormone (intra-colonic) or 100 ⁇ g/kg of parathyroid hormone (oral)), P-A-DS, that omitted the carrier.
  • a dosing solution at a dose of 25 ⁇ g/kg of parathyroid hormone (intra-colonic) or 100 ⁇ g/kg of parathyroid hormone (oral)
  • P-A-DS that omitted the carrier.
  • Intracolonic dosing compositions containing 25 mg/kg of carrier and 1 mg/kg of rHGH in phosphate buffer or oral gavage dosing solutions containing 600 mg/kg of carrier and 3 mg/kg of rHGH in phosphate buffer were prepared with carriers 9, 35, 36, 47, 62, 64, 67, 77, 79, 90, 94, 107, 109, 136, and 141.
  • the dosing solutions are designated R- carrier number—DS.
  • mice Male Sprague-Dawley rats weighing 200-250 g were fasted for 24 hours and administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to dosing. The rats were administered one of the dosing solutions of Example 3 by either oral gavage or intracolonic instillation. Blood samples were collected serially from the tail artery for determination of serum rHGH concentrations. Serum rHGH concentrations were quantified by an rHGH immunoassay test kit.
  • Example 5 The procedure of Example 5 was followed, substituting the dosing solutions of Comparative Examples 3A-3C for the dosing solutions.
  • Example 5 The procedure of Example 5 was followed, with dosing solutions of active agent (at a dose of 1 mg of rHGH/kg (intracolonic) or 3 mg of rHGH/kg (oral) and no carrier. These dosing solutions are designated R-D-DS and R-E-DS, respectively. Results are illustrated in Table 3, below.
  • An intracolonic dosing composition containing 50 mg/kg of carrier 9 and 250 ⁇ g/kg of interferon in 50% propylene glycol was prepared. Rats were administered the dosing composition by intracolonic instillation. Delivery was evaluated by use of an ELISA assay for human interferon a from Biosource, Inc. Mean peak serum interferon concentration was 2611 ⁇ 695.
  • Rats were administered, orally and by intracolonic instillation, dosing solutions of 1 mg/kg of interferon and no carrier. Delivery was evaluated according to the procedure of Example 6. Mean peak serum interferon concentration was 1951 ⁇ 1857 (PO) and 79 ⁇ 100 (IC).
  • Intracolonic dosing compositions containing 50 mg/kg of carrier and 25 mg/kg of heparin in 25% aqueous propylene glycol or oral gavage dosing solutions containing 300 mg/kg of carrier and 100 mg/kg of heparin in 25% aqueous propylene glycol were prepared with carriers 9, 35, 47, 50, 58, 62, 64, 67, 76, 96, 102, 109, 110, 111, 117, 122, 123, 139, 141, 144, and 169.
  • the dosing solutions are designated H-carrier number-DS.
  • H-35A-DS H-35B-DS
  • H-109A-DS H-109A-DS
  • Example 7 The dosing solutions of Example 7 were administered to fasted rats either by oral gavage or intracolonic instillation.
  • An intracolonic dosing solution of 25 mg/kg of heparin and an oral gavage dosing solution of 100 mg/kg of heparin were administered to fasted rats. These dosage solutions were designated H-A-DS and H-B-DS, respectively.

Abstract

Carrier compounds and compositions therewith which are useful in the delivery of active agents are provided. Methods of administration and preparation are provided as well.

Description

    FIELD OF THE INVENTION
  • The present invention relates to compounds for delivering active agents, and particularly biologically or chemically active agents. These compounds are used as carriers to facilitate the delivery of a cargo to a target. The carrier compounds are well suited to form non-covalent mixtures with biologically-active agents for oral administration to animals. Methods for the preparation administration of such compositions are also disclosed. [0001]
    • BACKGROUND OF THE INVENTION
  • Conventional means for delivering active agents are often severely limited by biological, chemical, and physical barriers. Typically, these barriers are imposed by the environment through which delivery occurs, the environment of the target for delivery, or the target itself. Biologically or chemically active agents are particularly vulnerable to such barriers. [0002]
  • For example in the delivery to animals of biologically active or chemically active pharmacological and therapeutic agents, barriers are imposed by the body. Examples of physical barriers are the skin and various organ membranes that must be traversed before reaching a target. Chemical barriers include, but are not limited to, pH variations, lipid bi-layers, and degrading enzymes. [0003]
  • These barriers are of particular significance in the design of oral delivery systems. Oral delivery of many biologically or chemically active agents would be the route of choice for administration to animals if not for biological, chemical, and physical barriers such as varying pH in the gastro-intestinal (GI) tract, powerful digestive enzymes, and active agent impermeable gastro-intestinal membranes. Among the numerous agents which are not typically amenable to oral administration are biologically or chemically active peptides, such as calcitonin and insulin; polysaccharides, and in particular mucopolysaccharides including, but not limited to, heparin; heparinoids; antibiotics; and other organic substances. These agents are rapidly rendered ineffective or are destroyed in the gastrointestinal tract by acid hydrolysis, enzymes, or the like. [0004]
  • Earlier methods for orally administering vulnerable pharmacological agents have relied on the co-administration of adjuvants (e.g., resorcinols and non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) to increase artificially the permeability of the intestinal walls, as well as the co-administration of enzymatic inhibitors (e.g., pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymatic degradation. [0005]
  • Liposomes have also been described as drug delivery systems for insulin and heparin. See, for example, U.S. Pat. No. 4,239,754; Patel et al. (1976), [0006] FEBS Letters, Vol. 62, pg. 60; and Hashimoto et al. (1979), Endocrinology Japan, Vol. 26, pg. 337.
  • However, broad spectrum use of such drug delivery systems is precluded because: (1) the systems require toxic amounts of adjuvants or inhibitors; (2) suitable low molecular weight cargos, i.e. active agents, are not available; (3) the systems exhibit poor stability and inadequate shelf life; (4) the systems are difficult to manufacture; (5) the systems fail to protect the active agent (cargo); (6) the systems adversely alter the active agent; or (7) the systems fail to allow or promote absorption of the active agent. [0007]
  • More recently, microspheres of artificial polymers of mixed amino acids (proteinoids) have been used to deliver pharmaceuticals. For example, U.S. Pat. No. 4,925,673 describes drug-containing proteinoid microsphere carriers as well as methods for their preparation and use. These proteinoid microspheres are useful for the delivery of a number of active agents. [0008]
  • There is still a need in the art for simple, inexpensive delivery systems which are easily prepared and which can deliver a broad range of active agents. [0009]
    • SUMMARY OF THE INVENTION
  • Compounds and compositions which are useful in the delivery of active agents are provided. These compositions include at least one active agent, preferably a biologically or chemically active agent, and at least one of the following compounds 1-193, or salts thereof. [0010]
    Figure US20020119910A1-20020829-C00001
  • Compositions comprising the carrier compounds discussed above and active agents are effective in delivering active agents to selected biological systems.[0011]
    • DETAILED DESCRIPTION OF THE INVENTION
  • The specific compositions of the present invention include an active agent and a carrier. These compositions may be used to deliver various active agents through various biological, chemical, and physical barriers and are particularly suited for delivering active agents which are subject to environmental degradation. The compositions of the subject invention are particularly useful for delivering or administering biologically or chemically active agents to any animals such as birds including, but not limited to, chickens; mammals, such as primates and particularly humans; and insects. [0012]
  • Other advantages of the present invention include the use of easy to prepare, inexpensive raw materials. The compositions and the formulation methods of the present invention are cost effective, simple to perform, and amenable to industrial scale up for commercial production. [0013]
  • Subcutaneous, sublingual, and intranasal coadministration of an active agent, such as, for example, recombinant human growth hormone (rhGH); salmon calcitonin; heparin, including, but not limited to, low molecular weight heparin; parathyroid hormone; and compounds in compositions as described herein result in an increased bioavailability of the active agent compared to administration of the active agent alone. [0014]
  • Active Agents [0015]
  • Active agents suitable for use in the present invention include biologically or chemically active agents, chemically active agents, including, but not limited to, fragrances, as well as other active agents such as, for example, cosmetics. [0016]
  • Biologically or chemically active agents include, but are not limited to, pesticides, pharmacological agents, and therapeutic agents. For example, biologically or chemically active agents suitable for use in the present invention include, but are not limited to, peptides, and particularly small peptides; hormones, and particularly hormones which by themselves do not or only a fraction of the administered dose passes through the gastro-intestinal mucosa and/or are susceptible to chemical cleavage by acids and enzymes in the gastro-intestinal tract; polysaccharides, and particularly mixtures of muco-polysaccharides; carbohydrates; lipids; or any combination thereof. Further examples include, but are not limited to, human growth hormones; bovine growth hormones; growth releasing hormones; interferons; interleukin-1; insulin; heparin, and particularly low molecular weight heparin; calcitonin; erythropoietin; atrial naturetic factor; antigens; monoclonal antibodies; somatostatin; adrenocorticotropin, gonadotropin releasing hormone; oxytocin; vasopressin; cromolyn sodium (sodium or disodium chromoglycate); vancomycin; desferrioxamine (DFO); parathyroid hormone anti-microbials, including, but not limited to anti-fungal agents; or any combination thereof. [0017]
  • Carriers [0018]
  • Although compounds 1-193 above have been found to act as carriers for the oral delivery of biologically or chemically active agents, special mention is made of compounds 9, 35, 64, 67, 79,102, 109, 111, 117,122, 136, and 141, above. [0019]
  • Properties of compounds 1-193 are listed in Table 1, below. [0020]
    TABLE 1
    Carrier Properties
    Anal. Calculated For Found Melting
    Compound C H N S C H N S Point (° C.)
     1 48.8 4.70 4.40 48.81 4.64 4.39
     2 64.73 7.97 10.06 64.54 7.81 10.19
     3 55.33 5.80 4.03 55.40 5.79 3.96 69-71
     4 62.64 6.06 5.62 62.75 6.08 5.51 151-154
     5 65.16 6.11 13.40 65.29 6.03 13.29 144-145
     6 54.70 3.24 3.75 54.29 3.24 3.54 165-169
     7 69.00 6.11 4.47 69.09 6.24 4.43 126-129
     8 65.51 7.90 4.78 65.60 8.25 4.83 89-90
     9 68.99 6.11 4.47 69.01 6.08 4.47 104-107
    10 52.74 4.42 7.69 52.91 4.45 7.49 142-145
    11 48.83 5.85 8.14 48.95 5.89 8.02 120-122
    12 69.71 6.47 4.28 69.56 6.47 4.38 144-146
    13 65.51 7.90 4.77 65.23 7.88 4.72 72.5-74.5
    14 60.17 5.36 4.39 10.04 60.09 5.36 4.35 9.99 155-156
    15 52.38 4.79 11.11 52.45 4.94 11.08 220-222
    16 67.60 5.95 3.94 67.34 6.01 3.91 219-222
    17 68.09 6.53 3.78 67.77 6.24 3.81 130-133
    18 54.13 5.30 10.52 54.12 5.24 10.54 192.5-
    195.5
    19 55.26 4.21 7.16 54.48 4.32 6.86 >280  
    dec
    20 65.51 7.90 4.77 65.52 7.90 4.77 75-80
    21 58.85 7.21 15.84 58.86 7.16 15.69 120-122
    22 63.15 5.30 14.73 63.30 5.43 14.18 197-201
    23 64.04 5.66 7.86 64.17 5.67 7.75 188-190
    24 69.91 6.88 8.46 69.98 6.79 8.58 131-134
    25 58.36 4.56 12.76 58.20 4.63 12.61 138-141
    26 56.98 3.94 7.82 56.39 3.92 7.74 221-223
    27 55.33 5.80 4.03 55.47 6.10 4.04 70-72
    28
    29 65.74 7.58 4.79 65.51 7.89 4.78 52-55
    30 64.50 7.57 5.02 64.07 7.81 5.40 70-74
    31 54.70 5.17 3.99 54.50 4.99 3.95 173-174
    32 58.63 5.94 9.12 58.73 6.20 10.34 125-129
    33 69.00 6.10 4.47 69.18 6.08 4.54 100-102
    34 63.99 5.37 9.33 63.46 5.35 9.06  218-221c
    35 65.5 7.90 4.78 65.37 8.00 4.66   96-97C
    36 68.22 5.72 4.68 67.88 5.65 4.55 134-137
    37 63.14 7.23 6.69 63.15 7.29 6.58 53.5-56  
    38 60.00 7.14 10.00 59.78 7.31 9.94 135-138
    39 61.67 4.41 10.29 61.69 4.41 10.12 >225
    40 55.39 4.65 7.18 55.52 4.77 7.30 162.5-
    166
    41 56.10 6.52 20.14 55.66 6.71 19.69 129-131
    42 65.24 6.39 4.23 65.42 6.16 3.78 130-
    133.5
    43 70.59 7.96 4.84 70.35 8.13 4.79 111-113
    44 68.37 4.88 3.99 68.61 4.89 3.79 120-123
    45 70.59 7.96 4.84 70.48 7.97 4.71 108-110
    46 60.75 6.37 5.90 60.97 6.18 5.80 100.5-
    103
    47 64.50 7.57 5.02 64.42 7.58 5.01  97-100
    48 64.86 5.98 7.56 64.50 6.01 7.52 165-169
    49 72.18 3.76 0.00 72.13 3.84 0.00 >225
    50 72.51 8.76 4.23 72.39 8.84 4.12 120-122
    51 64.50 7.58 5.01 64.75 7.65 4.69 200.5-
    204
    52 7.74 4.33 7.82 4.30 88-89
    53 65.24 6.39 4.23 65.15 6.46 4.23 93-97
    54 60.49 6.77 4.70 60.54 6.76 4.65 114-116
    55 64.04 7.17 4.98 63.90 7.11 4.93 105-106
    56 61.00 7.17 4.74 60.49 6.92 4.65 146-148
    57 63.14 7.79 4.33 63.22 7.82 4.36 59-61
    58 63.14 7.79 4.33 63.17 7.86 4.26 102-104
    59 63.14 7.79 4.33 63.35 7.68 4.20 89-90
    60 60.15 6.64 3.69 59.84 6.66 3.64 112-113
    61 65.53 8.85 6.65 65.34 8.73 6.67 89-92
    62 61.00 7.17 4.74 60.94 7.12 4.49 104-108
    63 66.43 8.20 4.56 66.29 8.23 4.36 77-78
    64 65.51 7.90 4.77 65.52 8.06 4.54 97-98
    65 69.59 9.28 4.77 69.64 9.35 4.86 62-65
    66 68.41 8.04 5.32 68.41 8.06 5.28 88-89
    67 62.12 7.49 4.53 61.94 7.45 4.43 98-99
    68 64.04 7.17 4.98 64.07 7.16 4.95 106-107
    69 52.64 5.89 4.09 52.63 5.85 4.03 109-110
    70 63.15 7.74 4.33 63.26 7.90 4.14  97-100
    71 52.64 5.89 4.09 52.67 5.99 3.97 114-115
    72 46.31 5.18 3.61 46.25 4.86 3.52 143-144
    73 49.89 3.94 3.42 49.92 3.85 3.39 170-171
    74 72.19 5.48 4.01 71.51 5.33 3.75 180
    75 66.46 6.16 4.08 66.47 6.26 4.06 168.5-
    171
    76 67.37 5.26 4.91 67.31 5.25 5.07 130-133
    77 65.65 5.78 4.26 65.49 6.04 4.26 179-183
    78 49.89 3.94 3.42 49.8 3.71 3.29 237-238
    79 65.65 5.78 4.26 65.21 6.05 4.24 156-158
    80 56.38 4.45 3.87 56.4 4.21 3.91 130-131
    81 56.38 4.45 3.87 56.46 4.5 3.84 197-198
    82 56.6 7.49 4.4 56.3 7.49 4.14 58-62
    83 57.03 8.2 3.91 57.17 7.8 3.7 138-140
    84 57.58 7.11 3.95 57.52 7.7 3.94
    85 56.38 4.45 3.87 56.31 4.25 3.64 230-231
    86 57.42 6.42 4.46 57.14 6.45 4.2 116-117
    87 61 7.17 4.74 61.18 7.05 4.65 108-109
    88 62.12 7.49 4.53 62.34 7.21 4.39 107-109
    89 58.63 6.76 4.27 58.53 6.81 4.2 117-118
    90 66.46 6.16 4.08 66.18 6.15 3.84 100-104
    91 62.16 5.21 4.03 61.93 4.97 3.86 183-185
    92 62.16 5.21 4.03 62.2 5.14 3.98 167-170
    93 58.63 6.76 4.27 58.64 6.83 4.19 106-108
    94 65.65 5.81 4.25 65.56 5.64 4.2 153-156
    95 49.89 3.94 3.42 49.9 3.81 3.18 216-217
    96 69.82 7.64 5.09 69.91 7.66 5.02 129-131
    97 46.31 5.18 3.61 46.54 4.95 3.64 122-123
    98 56.8 6.55 8.28 56.69 6.67 8.1
    99 56.8 6.55 8.28 57.37 6.57 8.33 117-118
    100  60.33 5.06 7.82 59.98 4.97 7.67 207-209
    101  66.46 6.16 4.08 66.37 6.32 3.96 126-128
    102  50.29 5.63 3.91 50.14 5.7 3.76 129-131
    103  70.93 5.95 6.89 70.94 6.44 6.89
    104  65.84 6.14 8.53 65.94 6.19 8.54 228-231
    105  64.96 5.77 8.91 64.89 5.82 8.82
    106  66.65 6.48 8.18 66.39 6.49 8.05 140-142
    107  66.47 6.12 4.07 66.5 6.26 4.08 140-142
    108  60.33 5.06 7.82 60.32 4.99 7.78 150-151
    109  57.41 6.42 4.46 57.07 6.44 4.39 121-123
    110  44.46 4.97 3.46 133-135
    111  69.28 7.03 4.25 68.86 7.07 4.11 147-149
    112  55.55 6.22 8.64 55.27 5.99 8.5 120-121
    113  53.99 4.26 3.7 53.98 4.25 3.63 210
    decom
    114  57.49 7.39 4.74 57.72 7.57 4.43 80-83
    115  65.5 7.9 4.77 64.97 7.79 4.75 90-92
    116  65.5 7.9 4.77 65.11 8.03 4.71 125-127
    117  71.26 8.3 4.2 70.6 7.89 4.83 94-96
    118  56.29 4.17 7.72 56.23 4.01 7.6 173-175
    119  47.89 3.81 3.29 47.52 3.71 3.16 236-237
    120  55.7 6.55 13 55.71 6.58 13.05 123-5 
    121  57.98 5.81 7.95 57.9 7.11 7.82 131-133
    122  51.74 5.5 4.02 51.41 5.43 3.61 118-
    119.5
    123  41.22 4.38 3.2 41.45 4.36 2.94 143-
    144.5
    124  57.06 6.06 4.44 57.02 6.12 4.35 57-58
    125  61.18 4.83 4.2 60.71 4.76 3.89 214
    decom
    126  55.55 6.22 8.64 55.4 6.24 8.53 150-151
    127  65.17 4.83 4.47 65.27 4.87 4.48 208-209
    128  73.03 8.99 4.06 72.92 9.36 4.1  99-101
    129  72.25 5.44 4 72.14 5.24 4.01 216-217
    130  52.56 5.58 8.17 52.66 5.44 8.21  96-100
    131  56.28 6.41 9.38 56.32 6.42 9.28  98-100
    132  52.56 5.58 8.17 52.46 5.65 7.86 150-153
    133  69.89 4.89 4.53 69.64 5 4.54 136-9 
    134  71.68 5.2 4.2 71.24 5.1 4.13 251-253
    135  65.64 5.78 4.25 65.3 5.91 4.04 79-83
    136  33.92 3.61 2.64 34.48 3.84 2.48 164-165
    137  57.06 6.06 4.44 57.09 6.17 4.45 88-89
    138  69.79 7.69 5.09 69.68 7.78 5.08 102-3
    139  69.28 7.04 4.25 68.99 7 4.1 107-108
    140  66.42 6.62 4.84 66.2 6.49 4.81 88-9 
    141  58.62 6.76 4.27 58.66 6.93 4.18 134-135
    142  63.38 7.21 5.28 63.22 7.28 5.24 71-73
    143  56.29 4.17 7.72 56.19 4.04 7.65 156-160
    144  71.13 7.88 3.77 70.39 7.91 3.64 95-97
    145  58.44 6.06 8.02 58.25 6.38 7.84 165-8 
    146  54.22 5.79 5.75 54.26 5.65 5.69   77-78.5
    147  54.22 5.79 5.75 54.21 5.85 5.61 80-81
    148  58.78 4.93 40.3 58.64 4.89 3.97 172-173
    149  56.19 4.72 3.85 56.31 4.67 3.86 177
    150  66.46 4.65 4.31 66.41 4.56 4.23 158-160
    151  58.61 7.24 5.69 58.79 7.35 5.66
    152  54.22 5.79 5.75 54.21 5.72 5.62 54-55
    153  60.85 4.25 7.89 60.27 4.37 7.89 >260  
    154  62.5 7.3 10.14 64.77 7.27 9.9 187-190
    155  55.4 6.5 3.6 55.56 6.51 3.5 114-116
    156  45.85 4.9 4.86 46.06 4.78 4.71 67-68
    156  48.8 4.7 4.4 48.81 4.64 4.39 144-146
    157  50.3 5.1 4.2 50.25 5.12 3.99 141-143
    158  55.5 4.1 3.8 55.55 3.88 3.75 190-192
    159  64.97 6.9 5.05 64.7 6.82 5.02 171-174
    160  54.3 3.7 4 54.31 3.58 3.83 222-224
    161  56.4 6.7 3.5 56.69 6.98 3.11 76-78
    162  63.63 6.47 5.3 64.76 6.84 4.74 188-191
    163  48.91 4.48 5.19 48.89 4.31 5.10 88.5-90  
    164  66.66 10.04 5.18 66.69 10.77 5.16 67.5-70.5
    165  39.42 4.21 4.18 39.19 4.35 3.88 oil
    166  53.05 5.19 5.16 53.06 5.03 4.86 151-152
    167  65.53 7.85 4.78 65.4 7.84 4.57 85-89
    168  68.99 6.11 4.47 68.62 5.87 4.49 162-6 
    169  69.71 6.47 4.28 69.67 6.58 4.50 132.5-
    135
    170  61.21 7.53 9.52 61.21 7.68 9.46 134-135
    171  62.14 7.44 4.53 61.96 7.52 4.57 101-104
    172  58.63 6.71 6.22 58.15 6.83 6.04
    173  52.96 3.26 4.12 52.96 3.28 4.02 225-227
    174  57.42 6.42 4.46 57.3 6.38 4.39 119-120
    175  68.99 6.11 4.47 68.84 6.08 4.51 131-4 
    176  66.43 8.2 4.56 66.42 8.16 4.51 109-110
    177  62.14 6.82 5.57 61.96 6.66 5.52 127-128
    178  51.00 4.56 3.97 51.09 4.61 3.93
    179  67.36 5.30 4.90 67.26 5.24 4.91 185-186
    180  66.43 8.20 4.56 66.32 8.60 5.12 51.5-55  
    181  69.92 6.79 8.58 67.02 6.93 8.20 81-84
    182  66.46 8.14 4.56 66.43 8.34 4.47 82-84
    183  62.13 4.89 22.64 62.05 4.88 22.45 271-272
    184  68.16 7.32 6.36 67.73 7.44 6.70 114-117
    185  71.30 5.98 5.73 71.10 5.97 5.74 146-149
    186  68.16 7.32 6.36 67.94 7.31 6.41 105-108
    187  65.51 7.90 4.77 65.35 7.63 4.59 102-103
    188  64.50 7.58 5.01 64.19 7.69 4.83 133-134
    189  64.5 7.58 5.01 64.5 7.57 4.90 116-118
    190  61.15 7.71 3.97 61.27 7.79 4.08 124-127
    191  65.5 7.9 4.77 65.32 7.94 4.7 114-115
    192  56.77 6.51 8.28 56.83 6.76 8.21 141-143
    193  60.29 4.74 8.79 60.17 4.58 8.74 202-205
    194  48.8 4.7 4.4 48.81 4.64 4.39 144-146
  • These carrier compounds or poly amino acids, and peptides, including acids, may be used to deliver active agents including, but not limited to, biologically or chemically active agents such as for example, pharmacological and therapeutic agents. [0021]
  • An amino acid is any carboxylic acid having at least one free amine group and includes naturally occurring and synthetic amino acids. [0022]
  • Poly amino acids are either peptides or two or more amino acids linked by a bond formed by other groups which can be linked, e.g. an ester, anhydride, or an anhydride linkage. [0023]
  • Peptides are two or more amino acids joined by a peptide bond. Peptides can vary in length from dipeptides with two amino acids to poly peptides with several hundred amino acids. See [0024] Chambers Biological Dictionary, editor Peter M. B. Walker, Cambridge, England: Chambers Cambridge, 1989, page 215. Special mention is made of di-peptides, tri-peptides, tetra-peptides, and penta-peptides.
  • Salts such as, for example, sodium salt of these carrier compounds can be used as well. [0025]
  • Many of the compounds described herein are derived from amino acids. [0026]
  • Many of the compounds of the present invention can be readily prepared from amino acids including, but not limited to, aminocaprylic acid, butyrylhydroxaminic acid, aminophenylbutyric acid, aminophenylhexanoic acid, aminophenylpropionic acid, amino salicylic acid, aminophenylsuccinic acid, aminononanic acid, aminonicotinic acid, amino valenic acid, aminophenylacetic acid, aminocaproic acid, aminoundecanoic acid, aminoheptanoic acid, aminohydroxybenzoic acid, and aminodecanoic acid by methods within the skill of those in the art based upon the present disclosure and the methods described in U.S. patent application Ser. Nos. 60/017,902, filed Mar. 29, 1996; 08/414,654, filed Mar. 31, 1995; 08/335,148, filed Oct. 25, 1994; and 60/003,111, filed Sep. 1, 1995. [0027]
  • For example, these compounds may be prepared by reacting the single acid with the appropriate agent which reacts with free amino moiety present in the amino acids to form amides. Protecting groups may be used to avoid unwanted side reactions as would be known to those skilled in the art. [0028]
  • The carrier compound may be purified by recrystallization or by fractionation on solid column supports. Suitable recrystallization solvent systems include acetonitrile, methanol and tetrahydrofuran. Fractionation may be performed on a suitable solid column supports such as alumina, using methanol/n-propanol mixtures as the mobile phase; reverse phase column supports using trifluoroacetic acid/acetonitrile mixtures as the mobile phase; and ion exchange chromatography using water as the mobile phase. When anion exchange chromatography is performed, preferably a subsequent 0-500 mM sodium chloride gradient is employed. [0029]
  • Delivery Systems [0030]
  • The compositions of the present invention may include one or more active agents. [0031]
  • In one embodiment, compounds or salts of compounds 1-193 or poly amino acids or peptides that include at least one of these compounds or salts may be used directly as a delivery carrier by simply mixing one or more compound or salt, poly amino acid or peptide with the active agent prior to administration. [0032]
  • The administration mixtures are prepared by mixing an aqueous solution of the carrier with an aqueous solution of the active ingredient, just prior to administration. Alternatively, the carrier and the biologically or chemically active ingredient can be admixed during the manufacturing process. The solutions may optionally contain additives such as phosphate buffer salts, citric acid, acetic acid, gelatin, and gum acacia. [0033]
  • Stabilizing additives may be incorporated into the carrier solution. With some drugs, the presence of such additives promotes the stability and dispersibility of the agent in solution. [0034]
  • The stabilizing additives may be employed at a concentration ranging between about 0.1 and 5% (W/V), preferably about 0.5% (W/V). Suitable, but non-limiting, examples of stabilizing additives include gum acacia, gelatin, methyl cellulose, polyethylene glycol, carboxylic acids and salts thereof, and polylysine. The preferred stabilizing additives are gum acacia, gelatin and methyl cellulose. [0035]
  • The amount of active agent is an amount effective to accomplish the purpose of the particular active agent. The amount in the composition typically is a pharmacologically, biologically, therapeutically, or chemically effective amount. However, the amount can be less than a pharmacologically, biologically, therapeutically, or chemically effective amount when the composition is used in a dosage unit form, such as a capsule, a tablet or a liquid, because the dosage unit form may contain a multiplicity of carrier/biologically or chemically active agent compositions or may contain a divided pharmacologically, biologically, therapeutically, or chemically effective amount. The total effective amounts can then be administered in cumulative units containing, in total, pharmacologically, biologically, therapeutically or chemically active amounts of biologically or pharmacologically active agent. [0036]
  • The total amount of active agent, and particularly biologically or chemically active agent, to be used can be determined by those skilled in the art. However, it has surprisingly been found that with some biologically or chemically active agents, the use of the presently disclosed carriers provides extremely efficient delivery, particularly in oral, intranasal, sublingual, intraduodenal, or subcutaneous systems. Therefore, lower amounts of biologically or chemically active agent than those used in prior dosage unit forms or delivery systems can be administered to the subject, while still achieving the same blood levels and therapeutic effects. [0037]
  • The amount of carrier in the present composition is a delivery effective amount and can be determined for any particular carrier or biologically or chemically active agent by methods known to those skilled in the art. [0038]
  • Dosage unit forms can also include any of excipients; diluents; disintegrants; lubricants; plasticizers; colorants; and dosing vehicles, including, but not limited to water, 1,2-propane diol, ethanol, olive oil, or any combination thereof. [0039]
  • Administration of the present compositions or dosage unit forms preferably is oral or by intraduodenal injection. [0040]
  • The delivery compositions of the present invention may also include one or more enzyme inhibitors. Such enzyme inhibitors include, but are not limited to, compounds such as actinonin or epiactinonin and derivatives thereof. These compounds have the formulas below: [0041]
    Figure US20020119910A1-20020829-C00002
  • Derivatives of these compounds are disclosed in U.S. Pat. No. 5,206,384. Actinonin derivatives have the formula: [0042]
    Figure US20020119910A1-20020829-C00003
  • wherein R[0043] 5 is sulfoxymethyl or carboxyl or a substituted carboxy group selected from carboxamide, hydroxyaminocarbonyl and alkoxycarbonyl groups; and R6 is hydroxyl, alkoxy, hydroxyamino or sulfoxyamino group. Other enzyme inhibitors include, but are not limited to, aprotinin (Trasylol) and Bowman-Birk inhibitor.
  • The compounds and compositions of the subject invention are useful for administering biologically or chemically active agents to any animals such as birds; mammals, such as primates and particularly humans; and insects. The system is particularly advantageous for delivering chemically or biologically or chemically active agents which would otherwise be destroyed or rendered less effective by conditions encountered before the active agent its target zone (i.e. the area in which the active agent of the delivery composition are to be released) and within the body of the animal to which they are administered. Particularly, the compounds and compositions of the present invention are useful in orally administering active agents, especially those which are not ordinarily orally deliverable. [0044]
    • DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • The following examples illustrate the invention without limitation. All parts are given by weight unless otherwise indicated. [0045]
    • EXAMPLE 1
  • Carrier Preparation [0046]
  • General Preparations of Carriers. [0047]
  • The following procedures were used to prepare the compounds described herein. Many of the compounds were prepared by reaction of the appropriate amino acid with the appropriate acid chloride. The preparation of compound 79 is given as a representative example of the compounds prepared in this manner. [0048]
  • Preparation of Compound 79. Method A. [0049]
  • A 1 L round bottom flask fitted with a magnetic stirrer was charged with 3-(4-aminophenyl)propionic acid (46.3 g, 0.28 moles, 1.17 equiv.) and 2 M aqueous sodium hydroxide (300 mL). 2,3-dimethoxybenzoylchloride (48.0 g, 0.24 moles, 1.00 equiv.) was added portionwise over 1 h to the stirred solution. After the addition, the reaction was stirred for 2.5 h at ambient temperature, and the pH of the solution was kept at ca 10 by the addition of 10 M sodium hydroxide. The solution was then acidified with 1 M hydrochloric acid (3×100 mL), water (100 mL), and air dried. It was redissolved in boiling acetone (ca 500 mL), decolorized with activated charcoal (3 g), and filtered. Water (1.5 L) was added to the filtrate to induce the formation of a brown oil. The brown oil solidified upon stirring at room temperature for 10 min. The crude solid was collected by filtration and recrystallized from 70% methanol-water (v/v) to afford compound 79 as a tan solid (39.5) g, 50%). [0050]
  • Compounds 1, 5, 30, 31, 33, 36, 53-66, 68, 69, 71-74, 78, 80-88, 95, 97-99, 102, 108-110, 112-115, 119, 121-126, 136, 137, 139, 141, 144, 146, 147, 151, 152, 155-158, 160, 161, 163, 165, 166, 170, 172-174, 176, 177, 184-186, 188, 189, 191 and 192 were also-prepared by this process. [0051]
  • Preparation of Compound 79. Method B. [0052]
  • A 2 L three-neck round bottom flask was fitted with a magnetic stirrer and two addition funnels under an argon atmosphere. A suspension of 3-(4-aminophenyl)propionic acid (46.3 g, 0.28 moles, 1.17 equiv.) in ethyl acetate (700 mL) was added to the flask. A solution of 2,3-dimethoxybenzoylchloride (48.0 g, 0.24 moles, 1.00 equiv.) in ethyl acetate (250 mL) was charged to one of the addition funnels and added dropwise over 1 h. Triethylamine (28.20 g, 0.28 moles, 1.00 equiv.) was subsequently charged to the second funnel and added dropwise over 15 min. The reaction was stirred at ambient temperature for 3 h, and the solvent was evaporated in vacuo giving a residual brown oil. Water (600 mL) was added to the residue followed by sodium hydroxide (2 M, 500 mL), and the mixture was stirred at ambient temperature for 3 hours. The resultant brown solution was acidified with 2 M hydrochloric acid (ca 1 L). After cooling the mixture in an ice bath for 1 h, a yellow solid formed and was collected by filtration. The solid was washed with water (3×1.5 L) and recrystallized from 50% ethanol-water (v/v) to give compound 79 as a tan solid (59.2 g, 68%). [0053]
  • Compounds 18, 32, 37, 41, 168, 175, and 183 were also prepared by this process. [0054]
  • Preparation of Compound 79. Method C. [0055]
  • A 2 L round bottom flask equipped with a magnetic stirrer and a reflux condenser was charged with a suspension of 3-(4-aminophenyl)propionic acid (46.3 g, 0.28 moles, 1.17 equiv.) in dichloromethane (560 mL). Chlorotrimethylsilane (62.36 g, 0.57 moles, 2.05 equiv.) was added in one portion, and the mixture was heated to reflux for 1 h under argon. The reaction was allowed to cool to room temperature and was placed in an ice bath (internal temperature <10° C.). The reflux condenser was replaced with an addition funnel containing triethylamine (42.50 g, 0.42 moles, 1.50 equiv.). The triethylamine was added dropwise over 15 min, and a yellow solid formed during the addition. The funnel was replaced by another addition funnel containing a solution of 2,3-dimethoxybenzoylchloride (48.0 g, 0.24 moles, 1.00 equiv. in dichloromethane (100 mL). The solution was added dropwise over 30 min. The reaction was stirred in the ice bath for another 30 min and at ambient temperature for 1 h. The dichloromethane was evaporated in vacuo to give a brown oil. The brown oil was cooled in an ice bath, and an ice-cold solution of 2 M sodium hydroxide (700 mL) was added. The ice bath was removed, and the reaction was stirred for 2 h to afford a clear brown solution. The solution was acidified with 2 M sulfuric acid (400 mL) and stored at ca 5° C. for 1 hour. A yellow solid formed and was collected by filtration. The solid was washed with water (3×100 mL) and recrystallized from 50% ethanol-water (v/v) to afford compound 79 as tan needles (64.7 g, 82%). [0056]
  • Compounds 2-4, 6-17, 19-29, 34, 38-40, 42-48, 50-52, 67, 70, 75-77, 89-94, 96, 100, 101, 107, 111, 116-118, 127-132, 134, 135, 193, 142, 143, 148, 149, 159, 162, 164, 169, 178-182, 187, and 190 were also prepared by this process. [0057]
  • Preparation of Compound 35. [0058]
  • A solution of O-acetylsalicyloyl chloride (24.68 g, 124 mmol, 1 equiv) in tetrahydrofuran (300 mL) was cooled in an ice bath. Triethylamine (25 g, 249 mmol, 2 equiv) was added dropwise via an additional funnel. The methyl 9-aminononanoate hydrochloride was dissolved in DMF (190 mL, slightly warm to dissolve), charged to an addition funnel and added dropwise to the above mixture. The reaction was stirred in the ice-bath for 20 min and at room temperature for 2 h. Evaporation of the THF under reduced pressure gave a pink DMF solution. The pink solution was cooled in an ice-bath, and 2 M aqueous sodium hydroxide (300 mL) was added. After being stirred at room temperature for 12 h, the mixture was acidified with 2 M hydrochloric acid (500 mL). The solution was cooled in an ice-bath, and a solid formed. The solid was collected by filtration and was recrystallized from 50% ethanol/water to give compound 35 (32 g, 87%) as an off-white solid. [0059]
  • Preparation of Compound 49. [0060]
  • 1-(2-hydroxyphenyl)-3-(4-methyl benzoate)-1,3-propane dione (3.00 g, 0.0101 mil.) is placed in a 100 ml round bottomed flask fitted with argon purge, magnetic stir bar and cold water condenser. Glacial acetic acid (20 mls) and concentrated sulfuric acid (5 mls) were added, and heating of the reaction mixture was initiated. The reaction mixture was allowed to heat at reflux for 6 h before heating was discontinued. The reaction mixture was allowed to come to room temperature, and then was poured into 100 mls of ice/water. This was stirred for approximately ½ h before the mixture was filtered, and a brown solid was isolated. The brown solid was recrystallized twice from acetic acid, yielding compound 49 as a tan solid (1.44 g, 53.8%). [0061]
  • Preparation of Compound 167. [0062]
  • 2-coumaranone (4.21 g, 0.0314 mol) was dissolved, with stirring, in acetonitrile (75 mls) in a 250 ml round bottomed flask fitted with a magnetic stir bar, argon purge and cold water condenser. Triethylamine (3.18 g, 0.0314 mol) and 8-aminocaprylic acid (5.00 g, 0.0314 mol) were added, and a tan slurry was formed. Heating was started, and the reaction mixture was allowed to reflux overnight. After heating overnight, thin layer chromatography of the reaction mixture (50% ethyl acetate/50% hexane) indicated that the reaction had gone to completion. Heating was stopped, the reaction mixture was allowed to cool to room temperature, and was concentrated in vacuo. The resulting residue was taken up in methylene chloride, and was washed with two, 100 ml portions of 1N hydrochloric acid solution. The methylene chloride layer was dried with sodium sulfate and was concentrated in vacuo. The resulting tan solid was allowed to dry in vacuo overnight, yielding compound 167 as a tan solid (8.35 g, 70.4%). [0063]
  • Preparation of Compound 171. [0064]
  • 1,4-benzodioxan-2-one (3.93 g, 0.0262 mol) was dissolved, with stirring, in acetonitrile (70 mls) in a 250 ml round bottomed flask fitted with a magnetic stir bar, argon purge and cold water condenser. Triethylamine (2.64 g, 0.0262 mol) and 8-aminocaprylic acid (500 g, 0.0262 mol) were added and a tan slurry was formed. Heating was started, and the reaction mixture was allowed to reflux for approximately 3 hours. At this time, thin layer chromatography of the reaction mixture (50% ethyl acetate/50% hexane) indicated that the reaction had gone to completion. Heating was discontinued, and the reaction mixture was allowed to cool to room temperature and was concentrated in vacuo. The resulting residue was taken up in methylene chloride and was washed with a 100 ml portion of 1N hydrochloric acid solution. At this time, a tan solid was noted to precipitate, and it was isolated by filtration. This tan solid was washed further with an additional 100 ml portion of 1 N hydrochloric acid solution, and then with 100 ml of water. The resulting tan solid was allowed to dry in vacuo overnight yielding Compound 171 as a tan solid (7.73 g, 95.6%). [0065]
  • Preparation of Compound 120. [0066]
  • A solution of 3.00 g (18.3 mmol) of 2-nitrophenylisocyanate and 5 mL of tetrahydrofuran was dropwise over 10 min to an ice bath-cooled solution of 2.08 g (13.1 mmol) of 8-aminocaprylic acid, 1.40 mL of 10 N NaOH and 40 mL of water. The reaction mixture was stirred an additional 30 min, warmed to 25° C. and treated with 3% HCl solution until the pH was 5. The yellow precipitate was filtered off and rinsed with 100 ml of water. The yellow solid was recrystallized in 2-propanol and water to give 3.7 g of compound 120 as pale yellow crystals. [0067]
  • Compounds 104-106 were also prepared by this procedure. [0068]
  • Preparation of Compound 133. [0069]
  • A suspension of 2.40 g (16.3 mmol) and 2.80 g (15.6 mmol) of 4-(4aminophenyl)butyric acid in 20 mL of propylene glycol, 2.40 mL (1.74 g, 17.3 mmol) of triethylamine and 10 mg (0.08 mmol) of dimethylaminopyridine was heated to 140° C. The mixture became a clear solution after 5 min at 140° C. After stirring for 330 min, the reaction mixture was cooled to 25° C. and diluted with 20 mL of water. The solid phthalimide which had formed was filtered off. The filtrate was acidified with 3% HCl solution. The resulting solid was filtered off and was recrystallized from 2-propanol and water to give 0.62 g of compound 133 as a tan solid. [0070]
  • Preparation of Compound 138. [0071]
  • A solution of 1.73 g (12.9 mmol) of phthalic dialdehyde, 2.04 g 8-aminocaprylic acid and 20 mL of acetic acid was heated to reflux for 10 min. The reaction mixture was cooled to 40° C., diluted with water and extracted with CH[0072] 2Cl2 (2×20 mL). The organic phase was washed with water and brine, dried over Na2SO4 and evaporated. The residue was dissolved in ether and extracted with 2N NaOH. The layers were separated. The aqueous layer was made acidic with 3% HCl and extracted with CH2Cl2. The organic phase was dried over Na2SO4 and evaporated. The yellow residue was crystallized from acetonitrile and water to give 1.25 g of compound 138 as a yellow solid.
  • Preparation of Compound 140. [0073]
  • A mixture of 1.40 g (9.48 mmol) of phthalic anhydride and 1.51 g (9.48 mmol) of 8-aminocaprylic acid was heated to 150° C. for 5 min. Upon cooling, 2.61 g of solid compound 140 was received. [0074]
  • Compound 150 was also prepared by this procedure. [0075]
  • Preparation of Compound 145. [0076]
  • A suspension of 2.11 g (10.1 mmol) ethyl carbamoylanthranilic acid and 5 mL of CH[0077] 2Cl2 was treated with 2.20 mL of oxalyl chloride. After stirring for 1 h the volatiles were stripped off. At that same time, a suspension of 1.60 g (10.1 mmol) of 8-aminocaprylic acid and 15 mL of CH2Cl2 was treated with 2.60 mL (2.23 g, 20.5 mmol) of TMSCl. This mixture was heated to reflux for 90 min, cooled in an ice bath and treated with 4.30 mL (3.12 g, 30.9 mmol) of triethylamine. Five min later, a slurry of the residue from the oxalyl chloride reaction in 20 mL of CH2Cl2 was added. The reaction mixture was warmed to 25° C. and stirred overnight. Upon acidification of the mixture with 3% HCl, a white solid formed. The solid was filtered off and recrystallized from EtOH and water to give 1.88 g of compound 145.
  • Compound 153 was also prepared by this procedure. [0078]
  • Preparation of Compound 154. A suspension of 4.02 g(25.6 mmol) of trans-4-aminomethylcyclohexane-carboxylic acid, 4.18 g (25.6 mmol) of isatoic anhydride, 20 mL of CH[0079] 2Cl2, 20 mL of dioxane, and 4 mL of water was heated to reflux for 12 h. The solution was cooled to 25° C. and extracted with ether (4×20 mL). The organic layer was dried over Na2SO4 and concentrated. The resulting solid was recrystallized from EtOH and water to give 4.95 g of compound 154.
  • Compound 103 is available from Aldrich Chemical Company, Inc., Milwaukee, Wis. [0080]
    • EXAMPLE 2
  • Parathyroid Hormone Dosing Solutions [0081]
  • Intracolonic (“IC”) dosing compositions containing 100 mg/kg of carrier and 25 μg/kg of parathyroid hormone in 25% aqueous propylene glycol or oral gavage “PO”) dosing solution containing 400 mg/kg of carrier and 100 μg/kg of parathyroid hormone in water, were prepared with carriers 9, 33, 35, 77, 79, 109, 110, 123, 136, 141, and 169. The dosing solutions are designated P- carrier number—DS. [0082]
    • Comparative Example 2A
  • Parathyroid Hormone Dosing Solutions [0083]
  • An intracolonic dosing composition containing 100 mg/kg of a carrier having the formula [0084]
    Figure US20020119910A1-20020829-C00004
  • and 25 ug/kg of parathyroid hormone in 25% aqueous propylene glycol was prepared. The dosing solution is identified as P-9A-DS. [0085]
    • EXAMPLES 3
  • In vivo Parathyroid Hormone Delivery [0086]
  • Male Sprague-Dawley rats weighing between 200-250 g were fasted for 24 hours and were administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to dosing. The rats were administered one of dosing solutions P-9-DS, P-33-DS, P-35-DS, P-77-DS, P-79-DS, and P-141-DS by oral gavage (“PO”) or intra-colonic instillation (“IC”). Blood samples were collected serially from the tail artery for serum determination of parathyroid hormone concentration. Serum parathyroid hormone concentrations were quantified by a parathyroid hormone immunoaccuracy test host. [0087]
  • Results are illustrated in Table 2, below. [0088]
    • Comparative Example 3A
  • In vivo Parathyroid Hormone Delivery [0089]
  • The procedure of Example 3 was followed substituting dosing solution P-9A-DS for dosing solution P-9-DS. Results are illustrated in Table 2, below. [0090]
    • Comparative Example 3B
  • In vivo Parathyroid Hormone Delivery [0091]
  • The procedure of Example 3 was followed with a dosing solution (at a dose of 25 μg/kg of parathyroid hormone (intra-colonic) or 100 μg/kg of parathyroid hormone (oral)), P-A-DS, that omitted the carrier. [0092]
  • Results are illustrated in Table 2, below. [0093]
    TABLE 2
    In vivo Parathyroid Hormone Delivery
    Mean Peak Serum [PTH] ±
    Dosing Solution Standard Deviation (pg/ml)
    P-9-DS 155 ± 105 (IC)
    P-33-DS 58 ± 18 (IC)
    P-35-DS 50 ± 27 (IC)
    P-77-DS 358 ± 274 (PO)
    P-79-DS 521 ± 128 (PO)
    P-109-DS 128 ± 25 (IC)
    P-110-DS 35 ± 11 (IC)
    P-123-DS 49 ± 22 (IC)
    P-136-DS 106 ± 72 (IC)
    P-141-DS 120 ± 120 (PO)
    P-169-DS 19 ± 33 (IC)
    P-9A-DS 116 ± 48 (IC)
    P-ØA-DS 11 ± 2 (PO), 27 ± 27 (IC)
    • EXAMPLES 4
  • Recombinant Human Growth Hormone Dosing Solutions [0094]
  • Intracolonic dosing compositions containing 25 mg/kg of carrier and 1 mg/kg of rHGH in phosphate buffer or oral gavage dosing solutions containing 600 mg/kg of carrier and 3 mg/kg of rHGH in phosphate buffer were prepared with carriers 9, 35, 36, 47, 62, 64, 67, 77, 79, 90, 94, 107, 109, 136, and 141. [0095]
  • The dosing solutions are designated R- carrier number—DS. [0096]
    • Comparative Example 4A
  • Recombinant Human Growth Hormone Dosing Solutions [0097]
  • An intracolonic dosing solution was prepared according to the procedure of Example 4, substituting a carrier having the formula [0098]
    Figure US20020119910A1-20020829-C00005
  • for the carrier. This dosing solution is designated as R-35A-DS. [0099]
    • Comparative Example 4B
  • Recombinant Human Growth Hormone Dosing Solutions [0100]
  • An intracolonic dosing solution was prepared according to the procedure of Example 4, substituting a carrier having the formula [0101]
    Figure US20020119910A1-20020829-C00006
  • for the carrier. This dosing solution is designated as R-35B-DS. [0102]
    • Comparative Example 4C
  • Recombinant Human Growth Hormone Dosing Solutions [0103]
  • An intracolonic dosing solution was prepared according to the procedure of Example 4, substituting a carrier having the formula [0104]
    Figure US20020119910A1-20020829-C00007
  • for the carrier. This dosing solution is designated as R-9A-DS. [0105]
    • EXAMPLE 5
  • In Vivo Recombinant Human Growth Hormone Delivery [0106]
  • Male Sprague-Dawley rats weighing 200-250 g were fasted for 24 hours and administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to dosing. The rats were administered one of the dosing solutions of Example 3 by either oral gavage or intracolonic instillation. Blood samples were collected serially from the tail artery for determination of serum rHGH concentrations. Serum rHGH concentrations were quantified by an rHGH immunoassay test kit. [0107]
  • Results are illustrated in Table 3, below. [0108]
    • Comparative Example 5A
  • In Vivo Recombinant Human Growth Hormone Delivery [0109]
  • The procedure of Example 5 was followed, substituting the dosing solutions of Comparative Examples 3A-3C for the dosing solutions. [0110]
  • Results are illustrated in Table 3, below. [0111]
    • Comparative Example 5B
  • In Vivo Recombinant Human Growth Hormone Delivery [0112]
  • The procedure of Example 5 was followed, with dosing solutions of active agent (at a dose of 1 mg of rHGH/kg (intracolonic) or 3 mg of rHGH/kg (oral) and no carrier. These dosing solutions are designated R-D-DS and R-E-DS, respectively. Results are illustrated in Table 3, below. [0113]
    TABLE 3
    In Vivo Recombinant Human Growth Hormone Delivery
    Mean Peak Serum [rHGH] ±
    Dosing Solution Standard Deviation (ng/ml)
    R-9-DS 125 ± 34 (IC)
    R-35-DS 41 ± 46 (PO)
    108 ± 56 (IC)
    R-36-DS 28 ± 11 (IC)
    R-47-DS 0 (IC)
    R-62-DS 11 ± 12 (IC)
    R-64-DS 72 ± 22 (PO)
    R-67-DS 19 ± 22 (PO)
    88 ± 24 (IC)
    R-77-DS 34 ± 10 (PO)
    R-79-DS 62 ± 51 (PO)
    R-90-DS 9 ± 13 (PO)
    R-94-DS 39 ± 35 (PO)
    R-107-DS 0 ± 0 (PO)
    R-109-DS 128 ± 25 (IC)
    R-136-DS 106 ± 72 (IC)
    R-141-DS 95 ± 14 (IC)
    R-35A-DS 17 ± 3 (IC)
    R-35B-DS 42 ± 28 (IC)
    R-9A-DS 55 ± 17 (IC)
    R-ØD-DS 0 ± 0 (IC)
    R-ØE-DS 0 ± 0 (IC)
    • EXAMPLE 6
  • In Vivo Interferon Delivery [0114]
  • An intracolonic dosing composition containing 50 mg/kg of carrier 9 and 250 μg/kg of interferon in 50% propylene glycol was prepared. Rats were administered the dosing composition by intracolonic instillation. Delivery was evaluated by use of an ELISA assay for human interferon a from Biosource, Inc. Mean peak serum interferon concentration was 2611±695. [0115]
    • Comparative Example 6A
  • In Vivo Interferon Delivery [0116]
  • Rats were administered, orally and by intracolonic instillation, dosing solutions of 1 mg/kg of interferon and no carrier. Delivery was evaluated according to the procedure of Example 6. Mean peak serum interferon concentration was 1951±1857 (PO) and 79±100 (IC). [0117]
    • EXAMPLE 7
  • Heparin Dosing Solutions [0118]
  • Intracolonic dosing compositions containing 50 mg/kg of carrier and 25 mg/kg of heparin in 25% aqueous propylene glycol or oral gavage dosing solutions containing 300 mg/kg of carrier and 100 mg/kg of heparin in 25% aqueous propylene glycol were prepared with carriers 9, 35, 47, 50, 58, 62, 64, 67, 76, 96, 102, 109, 110, 111, 117, 122, 123, 139, 141, 144, and 169. The dosing solutions are designated H-carrier number-DS. [0119]
    • Comparative Example 7A
  • Heparin Dosing Solutions [0120]
  • Comparative intracolonic dosing compositions were prepared according to the procedure of Example 7, substituting the following carriers for the carrier. [0121]
    Figure US20020119910A1-20020829-C00008
  • These dosing solutions are designated H-35A-DS, H-35B-DS, and H-109A-DS, respectively. [0122]
    • EXAMPLES 8
  • In Vivo Evaluation of Heparin in Rats [0123]
  • The dosing solutions of Example 7 were administered to fasted rats either by oral gavage or intracolonic instillation. [0124]
  • Blood samples were collected by cardiac puncture following the administration of ketamine (44 mg/kg). Heparin activity was determined by utilizing the activated partial thromboplastin time (APTT) according to the method of Henry, J. B., Clinical Diagnosis and Management by Laboratory Methods; Philadelphia, Pa.; W. B. Saunders (1979). [0125]
  • Results are in illustrated in Table 4, below. [0126]
    • Comparative Examples 8A
  • In Vivo Evaluation of Heparin in Rats [0127]
  • The dosing solutions of Comparative Example 7A were administered to fasted rats by intracolonic instillation. Blood samples were collected and heparin activity was determined by the method of Example 8. [0128]
  • Results are illustrated in Table 4, below. [0129]
    • Comparative Example 8B
  • In Vivo Evaluation of Heparin in Rats [0130]
  • An intracolonic dosing solution of 25 mg/kg of heparin and an oral gavage dosing solution of 100 mg/kg of heparin were administered to fasted rats. These dosage solutions were designated H-A-DS and H-B-DS, respectively. [0131]
  • Blood samples were collected, and heparin activity was determined by the methods of Example 8. [0132]
  • Results are illustrated in Table 4, below. [0133]
    TABLE 4
    In Vivo Evaluation of Heparin in Rats
    Dosing Solution Heparin APTT (sec)
    H-9-DS 48 ± 18 (IC)
    H-35-DS 54 ± 27 (PO), 177 ± 85 (IC)
    H-47-DS 30 ± 14 (IC)
    H-50-DS 40 ± 22 (IC)
    H-58-DS 24 ± 4 (IC)
    H-62-DS 37 ± 13 (IC)
    H-64-DS 59 ± 28 (PO), 168 ± 75 (IC)
    H-67-DS 76 ± 36 (IC)
    H-76-DS 63 ± 27 (PO)
    H-96-DS 36 ± 8 (IC)
    H-102-DS 111 ± 108 (IC)
    H-109-DS 56 ± 28 (IC)
    H-110-DS 37 ± 9 (IC)
    H-111-DS 71 ± 39 (IC)
    H-117-DS 140 ± 128 (IC)
    H-122-DS 49 ± 21 (IC), 207 ± 7 (PO)
    H-123-DS 42 ± 14 (PO)
    H-139-DS 31 ± 11 (IC)
    H-141-DS 59 ± 26 (IC)
    H-144-DS 26 ± 3 (IC)
    H-35A-DS 61 ± 29 (IC)
    H-35B-DS 51 ± 30 (IC)
    H-169-DS 23 ± 2 (IC)
    H-ØA-DS 23 ± 2 (PO)
    H-ØB-DS 33 ± 6 (IC)
  • The above mentioned patents, applications, test methods, and publications are hereby incorporated by reference in their entirety. [0134]
  • Many variations of the present invention will suggest themselves to those skilled in the art in light of the above detailed description. All such obvious variations are within the full intended scope of the appended claims. [0135]

Claims (31)

What is claimed is:
1. A composition comprising:
(A) at least one active agent; and
(B) at least one carrier selected from the group consisting of
Figure US20020119910A1-20020829-C00009
 1 6-N-(3,5-dichloro-2-hydroxybenzoyl)aminocaproic acid
Figure US20020119910A1-20020829-C00010
 2 8(2-aminobenzoylamino)caprylic acid
Figure US20020119910A1-20020829-C00011
 3 8(2-trifluoromethoxy)benzoylamino caprylic acid
Figure US20020119910A1-20020829-C00012
 4 N-(2-hydroxybenzoyl)isonipecotic acid
Figure US20020119910A1-20020829-C00013
 5 4-[4-(2-aminobenzoylamino)phenyl]butyrylhydroxamic acid
Figure US20020119910A1-20020829-C00014
 6 4-(4-pentafluorobenzoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00015
 7 4-(4-(3-anisoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00016
 8 8-(3-anisoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00017
 10 4-(4-(2-nitrobenzenesulfonyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00018
 11 8-(2-nitrobenzenesulfonyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00019
 12 6-(4-(salicyloyl)aminophenyl)hexanoic acid
Figure US20020119910A1-20020829-C00020
 13 8-(2-methoxylbenzoyl)amino caprylic acid
Figure US20020119910A1-20020829-C00021
 14 2-[4-Salicyloylamino)phenyl]ethyl methyl sulfone
Figure US20020119910A1-20020829-C00022
 15 1-Salicyloyl-2-succinyl hydrazide
Figure US20020119910A1-20020829-C00023
 16 3-(4-(2,5-dimethoxycinnamoyl)aminophenyl)propionic acid
Figure US20020119910A1-20020829-C00024
 17 4-(4-(2,5-dimethoxycinnamoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00025
 18 1-salicyloyl-2-glutaryl hydrazide
Figure US20020119910A1-20020829-C00026
 19 Succinyl-4-aminosalicylic acid
Figure US20020119910A1-20020829-C00027
 20 8-(Phenoxyacetylamino)caprylic acid
Figure US20020119910A1-20020829-C00028
 21 8-(2-pyrazinecarbonyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00029
 22 4-(4-(2-pyrazinecarbonyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00030
 23 6-(4-(N-2-Nitrobenzoyl)aminophenyl)hexanoic acid
Figure US20020119910A1-20020829-C00031
 24 6-(4-(N-2-aminobenzoyl)aminophenyl)hexanoic acid
Figure US20020119910A1-20020829-C00032
 25 4-(4-(2-(3-carboxyl)pyrazinecarboxyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00033
 26 4(2-Nitrobenzoyl)aminophenylsuccinic acid
Figure US20020119910A1-20020829-C00034
 27 8-(2-(trifluoromethoxy)benzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00035
 28
Figure US20020119910A1-20020829-C00036
 29 8-(Benzylcarbonylamino)caprylic acid
Figure US20020119910A1-20020829-C00037
 30 8-(phenylcarbonylamino)caprylic acid
Figure US20020119910A1-20020829-C00038
 31 2-[4-(2-Methoxybenzoylamino)phenyl]ethyl H2PO4
Figure US20020119910A1-20020829-C00039
 32 1-salicyloyl-2-suberyl hydrazide
Figure US20020119910A1-20020829-C00040
 33 4-(4-benzyloxycarbonylaminophenyl)butyric acid
Figure US20020119910A1-20020829-C00041
 34 4-(4-(2-hydroxynicotinoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00042
 36 4-(4-phenyloxycarbonylaminophenyl)butyric acid
Figure US20020119910A1-20020829-C00043
 37 3-(2-methoxybenzoylamino)-1-propanol
Figure US20020119910A1-20020829-C00044
 38 8-(2-Hydroxynicotinoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00045
 39 6-(2-methoxybenzoyl)amino nicotinic acid
Figure US20020119910A1-20020829-C00046
 40 salicyloylglycine
Figure US20020119910A1-20020829-C00047
 41 4-(1-(2-pyrimidyl)piperazinoyl)butyric acid
Figure US20020119910A1-20020829-C00048
 42 8-(chromone-3-carbonyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00049
 43 8-(vinylbenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00050
 44 4-(4-(chromone-3-carbonyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00051
 45 8-cinnamoylaminocaprylic acid
Figure US20020119910A1-20020829-C00052
 46 5-(N-salicyloylamino)valeric acid
Figure US20020119910A1-20020829-C00053
 47 9-(2-hydroxybenzamido)nonanic acid
Figure US20020119910A1-20020829-C00054
 48 N-(4-salicyloylamino)-6-caproic acid
Figure US20020119910A1-20020829-C00055
 49 4′-flavonic acid
Figure US20020119910A1-20020829-C00056
 50 11-cinnamoylaminoundecanoic acid
Figure US20020119910A1-20020829-C00057
 51 4-octanoylamino-3-hydroxybenzoic acid
Figure US20020119910A1-20020829-C00058
 52 (3Phenyl2,3dihydroxypropanoyl)8aminocaprylic acid
Figure US20020119910A1-20020829-C00059
 53 8-[N-(3-coumarincarbonyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00060
 54 8-[N-(4-chlorobenzoyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00061
 55 8-[N-3-fluorobenzoyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00062
 56 8-(N-2,5-Dihydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00063
 57 8-(N-2,3-Dimethoxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00064
 58 8-(N-2,4-Dihydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00065
 59 8-(N-2,5-Dimethoxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00066
 60 8-(N-3,5-Diacetyloxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00067
 61 8-(N-4-Hydroxybenzoyl)aminocaprylic acid (dimer)
Figure US20020119910A1-20020829-C00068
 62 8-(N-2,4-Dihydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00069
 63 10-(N-2-Methoxyanilino)sebalic acid
Figure US20020119910A1-20020829-C00070
 65 2-Methoxybenzenaminodecanoic acid
Figure US20020119910A1-20020829-C00071
 66 8-(N-benzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00072
 68 8-[N-(4-fluorobenzoyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00073
 69 8-[N-(3-bromobenzoyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00074
 70 8-(4-(1,2-dihydroxyethyl)benzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00075
 71 8-[N-(4-bromobenzoyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00076
 72 8-[N-(4-iodobenzoyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00077
 73 4-{4-[N-(2-iodoenzoyl)aminophenyl]}butyric acid
Figure US20020119910A1-20020829-C00078
 74 4-{4-[N-(1-hydroxy-2-naphthoyl)aminophenyl]}butyric acid
Figure US20020119910A1-20020829-C00079
 75 4-(4-(2,4-dimethoxylbenzoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00080
 76 4-(o-anisoyl)aminophenylacetic acid
Figure US20020119910A1-20020829-C00081
 77 3-[4-(2,4-dimethoxybenzoyl)aminophenyl]propionic acid
Figure US20020119910A1-20020829-C00082
 78 4-{4-[N-(4-iodobenzoyl)]aminophenyl}butyric acid
Figure US20020119910A1-20020829-C00083
 80 4-{[N-2-bromobenzoyl)]aminophenyl}butyric acid
Figure US20020119910A1-20020829-C00084
 81 4-{4-[N-3-bromobenzoyl)aminophenyl]}butyric acid
Figure US20020119910A1-20020829-C00085
 82 8-(N-3,5 Dihydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00086
 83 8-(N-3,5-Dimethoxy 4-hydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00087
 84 8-(N-2-6-Dimethoxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00088
 85 4-{4-[N-(4-bromobenzoyl)aminophenyl]}butyric acid
Figure US20020119910A1-20020829-C00089
 86 8-(2-hydroxy-4-chlorobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00090
 87 8-(N-2,6-Dihydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00091
 88 8-(N-2-Hydroxy6-methoxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00092
 89 8-(5-chloro-o-anisoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00093
 90 4-(4-(2,3-dimethoxybenzoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00094
 91 4-(4-(5-chloro-o-anisoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00095
 92 4-(4-(4-chloro-o-anisoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00096
 93 8-(4-chloro-o-anisoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00097
 94 3-(4-(2,5-dimethoxybenzoyl)aminophenyl)propionic acid
Figure US20020119910A1-20020829-C00098
 95 4-{N-[4-(3-iodobenzoyl)aminophenyl]}butyric acid
Figure US20020119910A1-20020829-C00099
 96 7-cinnamoylaminoheptanoic acid
Figure US20020119910A1-20020829-C00100
 97 8-N-(3-iodobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00101
 98 8-N-(4-methoxy-3-nitrobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00102
 99 8-N-(2-methoxy-4-nitrobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00103
 100 4-{N-[4-(2-methoxy-2-nitrobenzoyl)aminophenyl]}butyric acid
Figure US20020119910A1-20020829-C00104
 101 4-(4-(2,5-dimethyoxybenzoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00105
 103 3-Indolebutyric acid
Figure US20020119910A1-20020829-C00106
 104
Figure US20020119910A1-20020829-C00107
 105
Figure US20020119910A1-20020829-C00108
 106
Figure US20020119910A1-20020829-C00109
 108 4-[4-N-(4-methoxy-3-nitrobenzoyl)aminophenyl]butyric acid
Figure US20020119910A1-20020829-C00110
 110 8-(N-2-hydroxy-5-iodobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00111
 112 8-(N-2-hydroxy-4-nitrobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00112
 113 4-[-N-(2-hydroxy-4-bromobenzoyl)aminophenyl]butyric acid
Figure US20020119910A1-20020829-C00113
 114 8-(N-2,3-Dihydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00114
 115 8-(N-3-methylsalicyloyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00115
 116 8-(N-5-methylsalicyloyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00116
 118 4-(4-(2-chloro-5-nitrobenzoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00117
 119 4-{-[N-(2-hydroxy-5-iodobenzoyl)]aminophenyl}butyric acid
Figure US20020119910A1-20020829-C00118
 120 N-2-nitrophenyl-N′-(8-octanoic acid) urea
Figure US20020119910A1-20020829-C00119
 121 N-(2-methoxy-5-nitrophenyl) sebecoyl amide acid
Figure US20020119910A1-20020829-C00120
 123 8-[N-(2-acetoxy-3,5-dibromobenzoyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00121
 124 8-N-(2-chloro-6-fluorobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00122
 125
Figure US20020119910A1-20020829-C00123
 126 8-N-(4-hydroxy-3-nitrobenzoyl)caprylic acid
Figure US20020119910A1-20020829-C00124
 127 4-(4-salicyloylaminophenyl)-4-oxobutyric acid
Figure US20020119910A1-20020829-C00125
 128 12-cinnamoyldodecanoic acid
Figure US20020119910A1-20020829-C00126
 129 4-{4-[N-(3-hydroxy-2-napthoyl)aminophenyl]}butyric acid
Figure US20020119910A1-20020829-C00127
 130 8-(4-chloro-3-nitrobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00128
 131 8-(2-chloronicotinoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00129
 132 8-(2-chloro-5-nitrobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00130
 133 4-(4-phthalimidophenyl)butyric acid
Figure US20020119910A1-20020829-C00131
 134 4-{4-[N-(3-hydroxy-2-napthoyl)aminophenyl]}propanoic acid
Figure US20020119910A1-20020829-C00132
 135 3-(4-(2,6-dimethoxybenzoyl)aminophenyl)propionic acid
Figure US20020119910A1-20020829-C00133
 137 8-(N-2-chloro-4-fluorobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00134
 138 8-(2(1,2-dihydroisoindole-1-one))octanoic acid
Figure US20020119910A1-20020829-C00135
 139 8-(N-1-hyroxy-2-naphthoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00136
 140 8-(phthalimido)caprylic acid
Figure US20020119910A1-20020829-C00137
 142 6-(anisoyl)aminocaproic acid
Figure US20020119910A1-20020829-C00138
 143 4-(4-(4-chloro-3-nitrobenzoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00139
 144 11-N-(1-hydroxy-2-naphthoyl)aminoundecanoic acid
Figure US20020119910A1-20020829-C00140
 145 Bis(N-2carboxylphenyl-N-(N′-8-octanoic acid)ureal) oxalyl diamide
Figure US20020119910A1-20020829-C00141
 146 2-[2-N-(2-chlorobenzoyl)aminoethoxy]ethanol
Figure US20020119910A1-20020829-C00142
 147 2-[2-N-(4-chlorobenzoyl)aminoethoxy]ethanol
Figure US20020119910A1-20020829-C00143
 148 4-(2-methoxybenzoyl)amino 3-carboxysulfoxide
Figure US20020119910A1-20020829-C00144
 149 4-(2-methoxybenzoyl)amino 3-carboxypropylsulfone
Figure US20020119910A1-20020829-C00145
 150 4-(4-(3-hydroxyphthalimido)phenyl)butyric acid
Figure US20020119910A1-20020829-C00146
 151 2-[2-N-(2-methoxybenzoyl)aminoethoxy)]ethanol
Figure US20020119910A1-20020829-C00147
 152 2-[2-N-(3-chlorobenzoyl)aminoethoxy)]ethanol
Figure US20020119910A1-20020829-C00148
 153 Bis(N-2-carboxyphenyl-N-(N′-3(4-aminophenyl)propionic acid)ureal) oxaylyl diamide
Figure US20020119910A1-20020829-C00149
 154 trans-4-(2-aminobenzamidomethyl)cyclohexamecarboxylic acid
Figure US20020119910A1-20020829-C00150
 155 11-N-(3,5-dichloro-2-hydroxybenzoyl)aminoundecanoic acid
Figure US20020119910A1-20020829-C00151
 156 2-[N-(2-bromobenzoyl)aminoethoxy]ethanol
Figure US20020119910A1-20020829-C00152
 157 7-N-(3,5-dichloro-2-hydroxybenzoyl)aminoheptanoic acid
Figure US20020119910A1-20020829-C00153
 158 N-[3,5-dichloro-2-hydroxybenzoyl-4(4-aminophenyl)]butyric acid
Figure US20020119910A1-20020829-C00154
 159 trans-4-(N-salicyloylaminomethyl)cyclohexane carboxylic acid
Figure US20020119910A1-20020829-C00155
 160 N-[3,5-dichloro-2-hydroxybenzoyl-3-(4-aminophenyl)]propionic acid
Figure US20020119910A1-20020829-C00156
 161 12-N-(3,5-dichloro-2-hydroxybenzoyl)aminododecanoic acid
Figure US20020119910A1-20020829-C00157
 162 N-(2-hydroxy-4-carboxy)-6-heptenamide
Figure US20020119910A1-20020829-C00158
 163 N-(2-bromobenzoyl)morpholine
Figure US20020119910A1-20020829-C00159
 164 8-N-cyclohexanoylaminocaprylic acid
Figure US20020119910A1-20020829-C00160
 165 2-[N-(2-iodobenzoyl)aminoethoxy]ethanol
Figure US20020119910A1-20020829-C00161
 166 5-(4-chloro-2-hydroxyanilinocarbonyl)valeric acid
Figure US20020119910A1-20020829-C00162
 167 8-(2-hydroxyphenoxy)-aminocaprylic acid
Figure US20020119910A1-20020829-C00163
 168 N-Salicoyl-5-(3-aminophenyl)valeric acid
Figure US20020119910A1-20020829-C00164
 169 4-(4-(2-ethoxylbenzoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00165
 170 9-[2-(3-hydroxy)pyridylaminocarbonyl]nonanic acid
Figure US20020119910A1-20020829-C00166
 171 7-(2-hydroxyphenoxyacetyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00167
 172 2-[N-(2-hydroxybenzoylamino)ethoxy]ethanol
Figure US20020119910A1-20020829-C00168
 173 4-[N-(3,5-dichloro-2-hydroxybenzoyl)]aminophenylacetic acid
Figure US20020119910A1-20020829-C00169
 174 8-(2-hydroxy-5-chloroanilinocarbonyl)octanoic acid
Figure US20020119910A1-20020829-C00170
 175 N-salicoyl-5-(4-aminophenyl)valeric acid
Figure US20020119910A1-20020829-C00171
 176 9-(2-hydroxy-5-methylanilinocarbonyl)nonanoic acid
Figure US20020119910A1-20020829-C00172
 177 5-(2-hydroxy-5-methylanilinocarbonyl)valeric acid
Figure US20020119910A1-20020829-C00173
 178 8-(pentafluorobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00174
 179 3-(3-(salicyloyl)aminophenyl)propionic acid
Figure US20020119910A1-20020829-C00175
 180 8-(2-ethoxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00176
 181 4-(4-(2-Dimethylamino benzoic)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00177
 182 8-(3-Phenoxylpropionylamino)caprylic acid
Figure US20020119910A1-20020829-C00178
 183 4-(salicyloyl)aminophenylethyltetrazole
Figure US20020119910A1-20020829-C00179
 184 8(-(4(N-Saliciloyl-4aminophenyl)butyric)aminocaprylic acid [sic]
Figure US20020119910A1-20020829-C00180
 185 4-(4-(N-(2-Fluorocinnamoyl))aminophenyl) butyric
Figure US20020119910A1-20020829-C00181
 186 4-(4-(N-8(N-Salicyloyl)aminocaprylic)aminiphenyl)butyric acid
Figure US20020119910A1-20020829-C00182
 187 8-(p-anisoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00183
 188 8-(4-Hydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00184
 189 8-(3-Hydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00185
 190 8-(3,4,5-Trimethoxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00186
 191 8-(N-4-Methylsalicyloyl)aminocaprillic acid[sic]
Figure US20020119910A1-20020829-C00187
 192 N-10-(2-hydroxy-5-nitroanilino)decanoic acid
Figure US20020119910A1-20020829-C00188
 193 4-(4-(2-chloronicotinoyl)aminophenyl)butyric acid
and a salt of any of the foregoing.
2. A composition as defined in claim 1, wherein said active agent is selected from the group consisting of a biologically active agent, a chemically active agent, or a combination thereof.
3. A composition as defined in claim 2, wherein said biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid.
4. A composition as defined in claim 2, wherein said biologically active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, samatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone, desferrioxamine (DFO), or any combination thereof.
5. A composition as defined in claim 4, wherein said biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, oxytosin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinations thereof.
6. A composition as defined in claim 1, wherein said carrier comprises a poly(amino acid).
7. A composition as defined in claim 1, wherein said carrier comprises a polypeptide.
8. A dosage unit form comprising
(A) a composition as defined in claim 1; and
(B) (a) an excipient
(b) a diluent,
(c) a disintegrant,
(d) a lubricant,
(e) a plasticizer,
(f) a colorant,
(g) a dosing vehicle, or
(h) any combination thereof.
9. A composition as defined in claim 8, wherein said active agent is selected from the group consisting of a biologically active agent, a chemically active agent, or a combination thereof.
10. A composition as defined in claim 9, wherein said biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid.
11. A composition as defined in claim 9, wherein said biologically active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, samatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone, desferrioxamine (DFO), or any combination thereof.
12. A composition as defined in claim 11, wherein said biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, oxytosin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinations thereof.
13. A dosage unit form comprising
(A) a composition as defined in claim 6; and
(B) (a) an excipient
(b) a diluent,
(c) a disintegrant,
(d) a lubricant,
(e) a plasticizer,
(f) a colorant,
(g) a dosing vehicle, or
(h) any combination thereof.
14. A composition as defined in claim 13, wherein said active agent is selected from the group consisting of a biologically active agent, a chemically active agent, or a combination thereof.
15. A composition as defined in claim 14, wherein said biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid.
16. A composition as defined in claim 14, wherein said biologically active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, samatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone, desferrioxamine (DFO), or any combination thereof.
17. A composition as defined in claim 16, wherein said biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, oxytosin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinations thereof.
18. A dosage unit form comprising
(A) a composition as defined in claim 7; and
(B) (a) an excipient
(b) a diluent,
(c) a disintegrant,
(d) a lubricant,
(e) a plasticizer,
(f) a colorant,
(g) a dosing vehicle, or
(h) any combination thereof.
19. A composition as defined in claim 18, wherein said active agent is selected from the group consisting of a biologically active agent, a chemically active agent, or a combination thereof.
20. A composition as defined in claim 19, wherein said biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid.
21. A composition as defined in claim 19, wherein said biologically active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, samatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone, desferrioxamine (DFO), or any combination thereof.
22. A composition as defined in claim 21, wherein said biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, oxytosin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinations thereof.
23. A dosage unit form as defined in claim 8, comprising a tablet, a capsule, or a liquid.
24. A dosage unit form as defined in claim 23, wherein said dosing vehicle is selected from the group consisting of water, 1,2-propane diol, ethanol, or any combination thereof.
25. A dosage unit form as defined in claim 13, comprising a tablet, a capsule, or a liquid.
26. A dosage unit form as defined in claim 25, wherein said dosing vehicle is selected from the group consisting of water, 1,2-propane diol, ethanol, or any combination thereof.
27. A dosage unit form as defined in claim 18, comprising a tablet, a capsule, or a liquid.
28. A dosage unit form as defined in claim 27, wherein said dosing vehicle is selected from the group consisting of water, 1,2-propane diol, ethanol, or any combination thereof.
29. A method for administering a biologically-active agent to an animal in need of said agent, said method comprising administering orally to said animal a composition as defined in claim 2.
30. A compound selected from the group consisting of
Figure US20020119910A1-20020829-C00189
 1 6-N-(3,5-dichloro-2-hydroxybenzoyl)aminocaproic acid
Figure US20020119910A1-20020829-C00190
 2 8(2-aminobenzoylamino)caprylic acid
Figure US20020119910A1-20020829-C00191
 3 8(2-trifluoromethoxy)benzoylamino caprylic acid
Figure US20020119910A1-20020829-C00192
 4 N-(2-hydroxybenzoyl)isonipecotic acid
Figure US20020119910A1-20020829-C00193
 5 4-[4-(2-aminobenzoylamino)phenyl]butyrylhydroxamic acid
Figure US20020119910A1-20020829-C00194
 6 4-(4-pentafluorobenzoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00195
 7 4-(4-(3-anisoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00196
 8 8-(3-anisoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00197
 10 4-(4-(2-nitrobenzenesulfonyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00198
 11 8-(2-nitrobenzenesulfonyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00199
 12 6-(4-salicyloyl)aminophenyl)hexanoic acid
Figure US20020119910A1-20020829-C00200
 13 8-(2-methoxylbenzoyl)amino caprylic acid
Figure US20020119910A1-20020829-C00201
 14 2-[4-Salicyloylamino)phenyl]ethyl methyl sulfone
Figure US20020119910A1-20020829-C00202
 15 1-Salicyloyl-2-succinyl hydrazide
Figure US20020119910A1-20020829-C00203
 16 3-(4-(2,5-dimethoxycinnamoyl)aminophenyl)propionic acid
Figure US20020119910A1-20020829-C00204
 17 4-(4-(2,5-dimethoxycinnamoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00205
 18 1-salicyloyl-2-glutaryl hydrazide
Figure US20020119910A1-20020829-C00206
 19 Succinyl-4-aminosalicylic acid
Figure US20020119910A1-20020829-C00207
 20 8-(Phenoxyacetylamino)caprylic acid
Figure US20020119910A1-20020829-C00208
 21 8-(2-pyrazinecarbonyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00209
 22 4-(4-(2-pyrazinecarbonyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00210
 23 6-(4-(N-2-Nitrobenzoyl)aminophenyl)hexanoic acid
Figure US20020119910A1-20020829-C00211
 24 6-(4-(N-2-aminobenzoyl)aminophenyl)hexanoic acid
Figure US20020119910A1-20020829-C00212
 25 4-(4-(2-(3-carboxyl)pyrazinecarboxyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00213
 26 4(2-Nitrobenzoyl)aminophenylsuccinic acid
Figure US20020119910A1-20020829-C00214
 27 8-(2-trifluoromethoxy)benzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00215
 28
Figure US20020119910A1-20020829-C00216
 29 8-(Benzylcarbonylamino)caprylic acid
Figure US20020119910A1-20020829-C00217
 30 8-(phenylcarbonylamino)caprylic acid
Figure US20020119910A1-20020829-C00218
 31 2-[4-(2-Methoxybenzoylamino)phenyl]ethyl H2PO4
Figure US20020119910A1-20020829-C00219
 32 1-salicyloyl-2-suberyl hydrazide
Figure US20020119910A1-20020829-C00220
 33 4-(4-benzyloxycarbonylaminophenyl)butyric acid
Figure US20020119910A1-20020829-C00221
 34 4-(4-(2-hydroxynicotinoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00222
 36 4-(4-phenyloxycarbonylaminophenyl)butyric acid
Figure US20020119910A1-20020829-C00223
 37 3-(2-methoxybenzoylamino)-1-propanol
Figure US20020119910A1-20020829-C00224
 38 8-(2-Hydroxynicotinoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00225
 39 6-(2-methoxybenzoyl)amino nicotinic acid
Figure US20020119910A1-20020829-C00226
 40 salicyloylglycine
Figure US20020119910A1-20020829-C00227
 41 4-(1-(2-pyrimidyl)piperazinoyl)butyric acid
Figure US20020119910A1-20020829-C00228
 42 8-(chromone-3-carbonyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00229
 43 8-(vinylbenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00230
 44 4-(4-(chromone-3-carbonyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00231
 45 8-cinnamoylaminocaprylic acid
Figure US20020119910A1-20020829-C00232
 46 5-(N-salicyloylamino)valeric acid
Figure US20020119910A1-20020829-C00233
 47 9-(2-hydroxybenzamido)nonanic acid
Figure US20020119910A1-20020829-C00234
 48 N-(4-salicyloylamino)-6-caproic acid
Figure US20020119910A1-20020829-C00235
 49 4′-flavonic acid
Figure US20020119910A1-20020829-C00236
 50 11-cinnamoylaminoundecanoic acid
Figure US20020119910A1-20020829-C00237
 51 4-octanoylamino-3-hydroxybenzoic acid
Figure US20020119910A1-20020829-C00238
 52 (3Phenyl2,3dihydroxypropanoyl)8aminocaprylic acid
Figure US20020119910A1-20020829-C00239
 53 8-[N-(3-coumarincarbonyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00240
 54 8-[N-(4-chlorobenzoyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00241
 55 8-[N-3-fluorobenzoyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00242
 56 8-(N-2,5-Dihydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00243
 57 8-(N-2,3-Dimethoxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00244
 58 8-(N-2,4-Dihydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00245
 59 8-(N-2,5-Dimethoxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00246
 60 8-(N-3,5-Diacetyloxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00247
 61 8-(N-4-Hydroxybenzoyl)aminocaprylic acid (dimer)
Figure US20020119910A1-20020829-C00248
 62 8-(N-2,4-Dihydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00249
 63 10-(N-2-Methoxyanilino)sebalic acid
Figure US20020119910A1-20020829-C00250
 65 2-Methoxybenzenaminodecanoic acid
Figure US20020119910A1-20020829-C00251
 66 8-(N-benzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00252
 68 8-[N-(4-fluorobenzoyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00253
 69 8-[N-(3-bromobenzoyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00254
 70 8-(4-(1,2-dihydroxyethyl)benzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00255
 71 8-[N-(4-bromobenzoyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00256
 72 8-[N-(4-iodobenzoyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00257
 73 4-{4-[N-(2-iodobenzoyl)aminophenyl]}butyric acid
Figure US20020119910A1-20020829-C00258
 74 4-{4-[N-(1-hydroxy-2-naphthoyl)aminophenyl]}butyric acid
Figure US20020119910A1-20020829-C00259
 75 4-(4-(2,4-dimethoxylbenzoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00260
 76 4-(o-anisoyl)aminophenylacetic acid
Figure US20020119910A1-20020829-C00261
 77 3-[4-(2,4-dimethoxybenzoyl) aminophenyl] propionic acid
Figure US20020119910A1-20020829-C00262
 78 4-{4-[N-(4-iodobenzoyl)] aminophenyl} butyric acid
Figure US20020119910A1-20020829-C00263
 80 4-{4-[N-2-bromobenzoyl)] aminophenyl} butyric acid
Figure US20020119910A1-20020829-C00264
 81 4{4-[N-3-bromobenzoyl) aminophenyl]} butyric acid
Figure US20020119910A1-20020829-C00265
 82 8-(N-3,5 Dihydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00266
 83 8-(N-3,5-Dimethoxy 4-hydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00267
 84 8-(N-2-6-Dimethoxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00268
 85 4-{[N-(4-bromobenzoyl)aminophenyl]}butyric acid
Figure US20020119910A1-20020829-C00269
 86 8-(2-hydroxy-4-chlorobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00270
 87 8-(N-2,6-Dihydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00271
 88 8-(N-2-Hydroxy6-methoxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00272
 89 8-(5-chloro-o-anisoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00273
 90 4-(2-(2,3-dimethoxybenzoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00274
 91 4-(4-(5-chloro-o-anisoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00275
 92 4-(4-(4-chloro-o-anisoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00276
 93 8-(4-chloro-o-anisoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00277
 94 3-(4-(2,5-dimethoxybenzoyl)aminophenyl)propionic acid
Figure US20020119910A1-20020829-C00278
 95 4-{N-[4-(3-iodobenzoyl)aminophenyl]}butyric acid
Figure US20020119910A1-20020829-C00279
 96 7-cinnamoylaminoheptanoic acid
Figure US20020119910A1-20020829-C00280
 97 8-N-(3-iodobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00281
 98 8-N-(4-methoxy-3-nitrobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00282
 99 8-N-(2-methoxy-4-nitrobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00283
 100 4-{N-[4-(2-methoxy-4-nitrobenzoyl)aminophenyl]}butyric acid
Figure US20020119910A1-20020829-C00284
 101 4-(4-(2,5-dimethoxybenzoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00285
 104
Figure US20020119910A1-20020829-C00286
 105
Figure US20020119910A1-20020829-C00287
 106
Figure US20020119910A1-20020829-C00288
 107 4-(4-(2,6-dimethoxybenzoyl)aminophenylbutyric acid
Figure US20020119910A1-20020829-C00289
 108 4-[4-N-(4-methoxy-3-nitrobenzoyl)aminophenyl]butyric acid
Figure US20020119910A1-20020829-C00290
 110 8-(N-2-hydroxy-5-iodobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00291
 112 8-(N-2-hydroxy-4-nitrobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00292
 113 4-[-N-(2-hydroxy-4-bromobenzoyl)aminophenyl]butyric acid
Figure US20020119910A1-20020829-C00293
 114 8-(N-2,3-Dihydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00294
 115 8-(N-3-methylsalicyloyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00295
 116 8-(N-5-methylsalicyloyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00296
 118 4-(4-(2-chloro-5-nitrobenzoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00297
 119 4-{-[N-(2-hydroxy-5-iodobenzoyl)]aminophenyl}butyric acid
Figure US20020119910A1-20020829-C00298
 120 N-2-nitrophenyl-N′-(8-octanoic acid) urea
Figure US20020119910A1-20020829-C00299
 121 N-(2-methoxy-5-nitrophenyl) sebecoyl amide acid
Figure US20020119910A1-20020829-C00300
 123 8-[N-(2-acetoxy-3,5-dibromobenzoyl)]aminocaprylic acid
Figure US20020119910A1-20020829-C00301
 124 8-N-(2-chloro-6-fluorobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00302
 125
Figure US20020119910A1-20020829-C00303
 126 8-N-(4-hydroxy-3-nitrobenzoyl)caprylic acid
Figure US20020119910A1-20020829-C00304
 127 4-(4-Salicyloylaminophenyl)-4-oxobutyric acid
Figure US20020119910A1-20020829-C00305
 128 12-cinnamoyldodecanoic acid
Figure US20020119910A1-20020829-C00306
 129 4-{4-[N-(3-hydroxy-2-napthoyl)aminophenyl]}butyric acid
Figure US20020119910A1-20020829-C00307
 130 8-(4-chloro-3-nitrobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00308
 131 8-(2-chloronicotinoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00309
 132 8-(2-chloro-5-nitrobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00310
 133 4-(4-phthalimidophenyl)butyric acid
Figure US20020119910A1-20020829-C00311
 134 4-{4-[N-(3-hydroxy-2-napthoyl)aminophenyl]}propanoic acid
Figure US20020119910A1-20020829-C00312
 135 3-(4-(2,6-dimethoxybenzoyl)aminophenyl)propionic acid
Figure US20020119910A1-20020829-C00313
 137 8-(N-2-chloro-4-fluorobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00314
 138 8-(2-(1,2-dihydroisoindole-1-one))octanoic acid
Figure US20020119910A1-20020829-C00315
 139 8-(N-1-hydroxy-2-naphthoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00316
 140 8-(phthalimido)caprylic acid
Figure US20020119910A1-20020829-C00317
 142 6-(anisoyl)aminocaproic acid
Figure US20020119910A1-20020829-C00318
 143 4-(4-(4-chloro-3-nitrobenzoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00319
 144 11-N-(1-hydroxy-2-naphthoyl)aminoundecanoic acid
Figure US20020119910A1-20020829-C00320
 145 Bis(N-2carboxylphenyl-N-(N′-8-octanoic acid)ureal)oxalyl diamide
Figure US20020119910A1-20020829-C00321
 146 2-[2-N-(2-chlorobenzoyl)aminoethoxy]ethanol
Figure US20020119910A1-20020829-C00322
 147 2-[2-N-(4-chlorobenzoyl)aminoethoxy]ethanol
Figure US20020119910A1-20020829-C00323
 148 4-(2-methoxybenzoyl)amino 3-carboxysulfoxide
Figure US20020119910A1-20020829-C00324
 149 4-(2-methoxybenzoyl)amino 3-carboxypropylsulfone
Figure US20020119910A1-20020829-C00325
 150 4-(4-(3-hydroxyphthalimido)phenyl)butyric acid
Figure US20020119910A1-20020829-C00326
 151 2-[2-N-(2-methoxybenzoyl)aminoethoxy)]ethanol
Figure US20020119910A1-20020829-C00327
 152 2-[2-N-(3-chlorobenzoyl)aminoethoxy)]ethanol
Figure US20020119910A1-20020829-C00328
 153 Bis(N-2-carboxyphenyl-N-(N′-3(4-aminophenyl)propionic acid)ureal)oxaylyl diamide
Figure US20020119910A1-20020829-C00329
 154 trans-4-(2-aminobenzamidomethyl)cyclohexamecarboxylic acid
Figure US20020119910A1-20020829-C00330
 155 11-N-(3,5-dichloro-2-hydroxybenzoyl)aminoundecanoic acid
Figure US20020119910A1-20020829-C00331
 156 2-[N-(2-bromobenzoyl)aminoethoxy]ethanol
Figure US20020119910A1-20020829-C00332
 157 7-N-(3,5-dichloro-2-hydroxybenzoyl)aminoheptanoic acid
Figure US20020119910A1-20020829-C00333
 158 N-[3,5-dichloro-2-hydroxybenzoyl-4(4-aminophenyl)]butyric acid
Figure US20020119910A1-20020829-C00334
 159 trans-4-(N-salicyloylaminomethyl)cyclohexane carboxylic acid
Figure US20020119910A1-20020829-C00335
 160 N-[3,5-dichloro-2-hydroxybenzoyl-3-(4-aminophenyl)]propionic acid
Figure US20020119910A1-20020829-C00336
 161 12-N-(3,5-dichloro-2-hydroxybenzoyl)aminododecanoic acid
Figure US20020119910A1-20020829-C00337
 162 N-(2-hydroxy-4-carboxy)-6-heptenamide
Figure US20020119910A1-20020829-C00338
 163 N-(2-bromobenzoyl)morpholine
Figure US20020119910A1-20020829-C00339
 164 8-N-cyclohexanoylaminocaprylic acid
Figure US20020119910A1-20020829-C00340
 165 2-[N-(2-iodobenzoyl)aminoethoxy]ethanol
Figure US20020119910A1-20020829-C00341
 166 5-(4-chloro-2-hydroxyanilinocarbonyl)valeric acid
Figure US20020119910A1-20020829-C00342
 167 8-(2-hydroxyphenoxy)-aminocaprylic acid
Figure US20020119910A1-20020829-C00343
 168 N-Salicoyl-5-(3-aminophenyl)valeric acid
Figure US20020119910A1-20020829-C00344
 169 4-(4-(2-ethoxylbenzoyl)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00345
 170 9-[2-(3-hydroxy)pyridylaminocarbonyl] nonanic acid
Figure US20020119910A1-20020829-C00346
 171 7-(2-hydroxyphenoxyacetyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00347
 172 2-[N-(2-hydroxybenzoylamino)ethoxy]ethanol
Figure US20020119910A1-20020829-C00348
 173 4-[N-(3,5-dichloro-2-hydroxybenzoyl)]aminophenylacetic acid
Figure US20020119910A1-20020829-C00349
 174 8-(2-hydroxy-5-chloroanilinocarbonyl)octanoic acid
Figure US20020119910A1-20020829-C00350
 175 N-salicoyl-5-(4-aminophenyl)valeric acid
Figure US20020119910A1-20020829-C00351
 176 9-(2-hydroxy-5-methylanilinocarbonyl)nonanoic acid
Figure US20020119910A1-20020829-C00352
 177 5-(2-hydroxy-5-methylanilinocarbonyl)valeric acid
Figure US20020119910A1-20020829-C00353
 178 8-(pentafluorobenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00354
 179 3-(3-(salicyloyl)aminophenyl)propionic acid
Figure US20020119910A1-20020829-C00355
 180 8-(2-ethoxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00356
 181 4-(4-(2-Dimethylamino benzoic)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00357
 182 8-(3-Phenoxylpropionylamino)caprylic acid
Figure US20020119910A1-20020829-C00358
 183 4-(Salicyloyl)aminophenylethyltetrazole
Figure US20020119910A1-20020829-C00359
 184 8(-(4(N-Saliciloyl-4aminophenyl)butyric)aminocaprylic acid [sic]
Figure US20020119910A1-20020829-C00360
 185 4-(4-(N-(2-Fluorocinnamoyl))aminophenyl) butyric
Figure US20020119910A1-20020829-C00361
 186 4-(4-(N-8(N-Salicyloyl)aminocaprylic)aminophenyl)butyric acid
Figure US20020119910A1-20020829-C00362
 187 8-(p-anisoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00363
 188 8-(4-Hydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00364
 189 8-(3-Hydroxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00365
 190 8-(3,4,5-Trimethoxybenzoyl)aminocaprylic acid
Figure US20020119910A1-20020829-C00366
 191 8-(N-4-Methylsalicyloyl)aminocaprillic acid [sic]
Figure US20020119910A1-20020829-C00367
 192 N-10-(2-hydroxy-5-nitroanilino)decanoic acid
Figure US20020119910A1-20020829-C00368
 193 4-(4-(2-chloronicotinoyl)aminophenyl)butyric acid
and a salt of any of the foregoing.
31. A method for preparing a composition, said method comprising mixing:
(A) at least one active agent;
(B) at least one compound as defined in claim 31; and
(C) optionally, a dosing vehicle.
US09/746,548 1997-02-07 2000-12-19 Compounds and compositions for delivering active agents Abandoned US20020119910A1 (en)

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