CHEMICALLY MODIFIED SMALL MOLECULES

• US 20100305147A1
• Filed: 06/24/2010
• Published: 12/02/2010
• Est. Priority Date: 12/16/2003
• Status: Active Grant

• Current Assignee: Nektar Therapeutics Incorporated
• Original Assignee: Nektar Therapeutics Incorporated
• Inventors: Goodin, Richard R., Viegas, Tracey X., Zhao, Xuan, Bentley, Michael D., Cheng, Lin
• Granted Patent: US 8,034,825 B2
• Time in Patent Office: Days
• US Class Current: 514/282
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C08G 65/332 containing carboxyl groups, or halides, or esters thereof
• CPC Class Codes: C08G 65/33317 heterocyclic
• CPC Class Codes: C08G 65/33396 having oxygen in addition to nitrogen
• CPC Class Codes: C08G 65/337 containing other elements organic compounds containing halogens only as halides of a carboxyl group C08G65/332
• CPC Class Codes: C08L 2203/02 for biomedical use

Abstract

The invention provides small molecule drugs that are chemically modified by covalent attachment of a water-soluble oligomer obtained from a monodisperse or bimodal water-soluble oligomer composition. A conjugate of the invention, when administered by any of a number of administration routes, exhibits a reduced biological membrane crossing rate as compared to the biological membrane crossing rate of the small molecule drug not attached to the water-soluble oligomer.

Claims

1-55. -55. (canceled)

56. A compound selected from the group consisting of:

6-CH₃—

(OCH₂CH₂)₅—

O-naloxol;

6-CH₃—

(OCH₂CH₂)₆—

O-naloxol;

6-CH₃—

(OCH₂CH₂)₈—

O-naloxol; and

6-CH₃—

(OCH₂CH₂)₉—

O-naloxol;

or pharmaceutically acceptable salt thereof, wherein the compound is an α

-6 isomer, a β

-6 isomer or a mixture of α

-6 and β

-6 isomers.

57. The compound of claim 56, wherein the compound is selected from the group consisting of

α

,β

-6-CH₃—

(OCH₂CH₂)₅—

O-naloxol;

α

,β

-6-CH₃—

(OCH₂CH₂)₆—

O-naloxol;

α

,β

-6-CH₃—

(OCH₂CH₂)₈—

O-naloxol; and

α

,β

-6-CH₃—

(OCH₂CH₂)₉—

O-naloxol;

or pharmaceutically acceptable salt thereof

58. The compound of claim 57, wherein the compound is α

,β

-6-CH₃—

(OCH₂CH₂)₅—

O-naloxol or pharmaceutically acceptable salt thereof.

59. The compound of claim 57, wherein the compound is α

,β

-6-CH₃—

(OCH₂CH₂)₆—

O-naloxol or pharmaceutically acceptable salt thereof.

60. The compound of claim 57, wherein the compound is α

,β

-6-CH₃—

(OCH₂CH₂)₈—

O-naloxol or pharmaceutically acceptable salt thereof.

61. The compound of claim 57, wherein the compound is α

,β

-6-CH₃—

(OCH₂CH₂)₉—

O-naloxol or pharmaceutically acceptable salt thereof.

62. The compound of claim 56, wherein the compound is selected from the group consisting of

α

-6-CH₃—

(OCH₂CH₂)₅—

O-naloxol;

α

-6-CH₃—

(OCH₂CH₂)₆—

O-naloxol;

α

-6-CH₃—

(OCH₂CH₂)₈—

O-naloxol; and

α

-6-CH₃—

(OCH₂CH₂)₉—

O-naloxol;

or pharmaceutically acceptable salt thereof

63. The compound of claim 62, wherein the compound is α

-6-CH₃—

(OCH₂CH₂)₅—

O-naloxol or pharmaceutically acceptable salt thereof.

64. The compound of claim 62, wherein the compound is α

-6-CH₃—

(OCH₂CH₂)₆—

O-naloxol or pharmaceutically acceptable salt thereof.

65. The compound of claim 62, wherein the compound is α

-6-CH₃—

(OCH₂CH₂)₈—

O-naloxol or pharmaceutically acceptable salt thereof.

66. The compound of claim 62, wherein the compound is α

-6-CH₃—

(OCH₂CH₂)₉—

O-naloxol or pharmaceutically acceptable salt thereof.

67. The compound of claim 56, wherein the compound is selected from the group consisting of

β

-6-CH₃—

(OCH₂CH₂)₅—

O-naloxol;

β

-6-CH₃—

(OCH₂CH₂)₆—

O-naloxol;

β

-6-CH₃—

(OCH₂CH₂)₈—

O-naloxol; and

β

-6-CH₃—

(OCH₂CH₂)₉—

O-naloxol;

or pharmaceutically acceptable salt thereof

68. The compound of claim 67, wherein the compound is β

-6-CH₃—

(OCH₂CH₂)₅—

O-naloxol or pharmaceutically acceptable salt thereof.

69. The compound of claim 67, wherein the compound is β

-6-CH₃—

(OCH₂CH₂)₆—

O-naloxol or pharmaceutically acceptable salt thereof.

70. The compound of claim 67, wherein the compound is β

-6-CH₃—

(OCH₂CH₂)₈—

O-naloxol or pharmaceutically acceptable salt thereof.

71. The compound of claim 67, wherein the compound is β

-6-CH₃—

(OCH₂CH₂)₉—

O-naloxol or pharmaceutically acceptable salt thereof.

72. A pharmaceutical composition comprising a compound of any one of claims 56-71 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.