Valency platform molecules comprising aminooxy groups

• US 20040224366A1
• Filed: 06/14/2004
• Published: 11/11/2004
• Est. Priority Date: 06/08/1999
• Status: Abandoned Application

• Current Assignee: Anping Tao, David S. Jones, Huong-Thu Ton-Nu, Jeffrey Robert Hammaker, Tong Xu
• Original Assignee: Anping Tao, David S. Jones, Huong-Thu Ton-Nu, Jeffrey Robert Hammaker, Tong Xu
• Inventors: Tao, Anping, Ton-Nu, Huong-Thu, Xu, Tong, Hammaker, Jeffrey Robert, Jones, David S.
• Application Number:
  US10/867,874
• Publication Number:
  US 20040224366A1
• Time in Patent Office: Days
• US Class Current: 435/7.1
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• 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: C07C 251/60 of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 271/16 to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 271/20 to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 323/60 with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: C07D 295/205 Radicals derived from carbonic acid
• CPC Class Codes: C07K 14/775 Apolipopeptides
• CPC Class Codes: C08B 37/0012 Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/33396 having oxygen in addition to nitrogen
• CPC Class Codes: C08G 83/003 Dendrimers

Abstract

Molecules comprising aminooxy groups are provided, wherein the aminooxy groups provide attachment sites for the covalent attachment of other molecules. In one embodiment, polyoxyethylene molecules comprising aminooxy groups are provided that can be conjugated to wide variety of biologically active molecules including poly(amino acids). In another embodiment, valency platform molecules comprising aminooxy groups are provided. The aminooxy groups can be used to form covalent bonds with biological molecules such as poly(amino acids). The aminooxy groups can, for example, react with poly(amino acids) modified to contain carbonyl groups, such as glyoxyl groups, to form a conjugate of the valency platform molecule and the biologically active molecule via an oxime bond. The valency platform molecules comprising aminooxy groups are advantageously reactive in the formation of conjugates, and they also can be readily synthesized to form a composition with very low polydispersity.

Claims

1-53. -53. (cancelled)

54. A valency platform molecule having a formula selected from the group consisting of:

R^c[O—

C(═

O)—

NR¹-G₂—

(ONH₂)_n]_y;

R^c[C(═

O)—

NR¹-G₂—

(ONH₂)_n]_y;

R^c[NR¹—

C(═

O)-G₂-(ONH₂)_n]_y;

R^c[NR¹—

C(═

O)—

O-G₂—

(ONH₂)_n]_y;

R^c[R¹C═

N—

O-G₂—

(ONH₂)_n]_y; and

, R^c[S-G₂(ONH₂)_n]_y;

wherein;

y is 1 to 16;

n is 1 to 32;

R¹ is H, alkyl, heteroalkyl, aryl, heteroaryl or G₂—

(ONH₂)_n;

R^c and each G₂ are independently organic moieties comprising atoms selected from the group consisting of H, C, N, O, P, Si and S atoms;

(ONH₂) of the formulas above is a terminal aminooxy group; and

wherein the valency platform molecule comprises at least four of said terminal aminooxy groups.

55. The valency platform molecule of claim 54, wherein R^c and each G₂ are independently selected from the group consisting of:

hydrocarbyl groups consisting only of H and C atoms and having 1 to 5,000 carbon atoms;

organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having 1 to 5,000 carbon atoms;

organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 5,000 carbon atoms;

organic groups consisting only of carbon, oxygen, sulfur, and hydrogen atoms, and having from 1 to 5,000 carbon atoms; and

organic groups consisting only of carbon, oxygen, sulfur, nitrogen and hydrogen atoms and having from 1 to 5,000 carbon atoms.

56. The valency platform molecule of claim 55, wherein R^C and each G₂ are independently selected from the group consisting of:

hydrocarbyl groups consisting only of H and C atoms and having 1 to 500 carbon atoms;

organic groups consisting only of carbon, oxygen, and hydrogen atoms, and having 1 to 500 carbon atoms;

organic groups consisting only of carbon, oxygen, nitrogen, and hydrogen atoms, and having from 1 to 500 carbon atoms;

organic groups consisting only of carbon, oxygen, sulfur, and hydrogen atoms, and having from 1 to 500 carbon atoms; and

organic groups consisting only of carbon, oxygen, sulfur, nitrogen and hydrogen atoms and having from 1 to 500 carbon atoms.

57. The valency platform molecule of claim 54, wherein R^c is selected from the group consisting of a C_1-200 hydrocarbon moiety;

a C_1-200 alkoxy moiety; and

a C_1-200 hydrocarbon moiety comprising an aromatic group.

58. The valency platform molecule of claim 54, wherein R^c comprises an oxyalkylene moiety.

59. The valency platform molecule of claim 54, wherein R^c comprises an oxyethylene moiety.

60. The valency platform molecule of claim 54, wherein R^c comprises oxyethylene units:

—

(CH₂CH₂O)_n—

;

wherein n is 1 to 5,000.

61. The valency platform molecule of claim 54, wherein G₂ comprises a functional group selected from the group consisting of alkyl, heteroalkyl, aryl, and heteroaryl.

62. The valency platform molecule of claim 54, wherein G₂ comprises a functional group selected from the group consisting of a C_1-200 hydrocarbon moiety;

a C_1-200 alkoxy moiety; and

a C_1-200 hydrocarbon moiety comprising an aromatic group.

63. The valency platform molecule of claim 54, wherein G₂ comprises an oxyalkylene moiety.

64. The valency platform molecule of claim 54, wherein G₂ comprises an oxyethylene moiety.

65. The valency platform molecule of claim 54, wherein G₂ comprises oxyethylene units:

—

(CH₂CH₂O)_n—

;

wherein n is 1 to 500.

66. The valency platform molecule of claim 54, wherein each G₂ independently comprises a functional group selected from the group consisting of amine;

amide;

ester;

ether;

ketone;

aldehyde;

carbamate;

thioether;

piperazinyl;

piperidinyl;

alcohol;

polyamine;

polyether;

hydrazide;

hydrazine;

carboxylic acid;

anhydride;

halo;

sulfonyl;

sulfonate;

sulfone;

imidate;

cyanate;

isocyanate;

isothiocyanate;

formate;

carbodiimide;

thiol;

oxime;

imine;

aminooxy; and

maleimide.

67. The valency platform molecule of claim 54 having the formula:

R^c[O—

C(═

O)—

NR¹-G₂—

(ONH₂)_n]_y.

68. The valency platform molecule of claim 54 having the formula:

R^c[C(═

O)—

NR¹-G₂—

(ONH₂)_n]_y.

69. The valency platform molecule of claim 54 having the formula:

R^c[NR¹—

C(═

O)-G₂—

(ONH₂)_n]_y.

70. The valency platform molecule of claim 54 having the formula:

R^c[NR¹—

C(═

O)—

O-G₂—

(ONH₂)_n]_y.

71. The valency platform molecule of claim 54 having the formula:

R^c[R¹C═

N—

O-G₂—

(ONH₂)_n]_y.

72. The valency platform molecule of claim 54 having the formula:

R^c[S-G₂(ONH₂)_n]_y.

73. The valency platform molecule of claim 54, wherein each G₂—

ONH₂ is independently selected from the group consisting of;

74. The valency platform molecule of claim 54 having a formula selected from the group consisting of:

75. The valency platform molecule of claim 74, wherein G₂ comprises an oxyethylene group.

76. A valency platform molecule of claim 54, having the structure:

77. A valency platform molecule of claim 54, having the structure:

78. A valency platform molecule of claim 54 having the structure:

79. The valency platform molecule of claim 67, wherein:

R^c is C(CH₂—

)₄;

R¹ is H;

n is 1;

y is 4;

wherein G₂ comprises —

(CH₂CH₂O)_p-1—

CH₂CH₂—

, wherein p is from 2 to about 500;

and wherein G₂ further comprises an amide moiety and a terminal aminooxy moiety.

80. The platform molecule of claim 67, wherein:

R^c is C(CH₂—

)₄;

R¹ is H;

n is 1;

y is 4;

wherein G₂ comprises —

(CH₂CH₂O)_p—

, wherein p is from 200 to 500;

and wherein G₂ further comprises an amide moiety and a terminal aminooxy moiety.

81. The valency platform molecule of claim 54, having the following formula:

82. The valency platform molecule of claim 60 or 74, wherein n is 1 to 500.

83. The valency platform molecule of claim 60 or 74, wherein n is 200 to 500.

84. The valency platform molecule of claim 54, wherein G₂ comprises an organic group consisting only of carbon, oxygen, and hydrogen atoms, and having from 1 to 5,000 carbon atoms.

85. The valency platform molecule of claim 84, wherein G₂ comprises oxyethylene units:

—

(CH₂CH₂O)_n—

;

wherein n is 1 to 200.

86. The valency platform molecule of claim 84, wherein G₂ comprises oxyethylene units:

—

(CH₂CH₂O)_n—

;

wherein n is 200 to 500.

87. The valency platform molecule of claim 54, wherein the valency platform molecule is symmetric.

88. The valency platform molecule of claim 54, wherein the valency platform molecule has a valence of four.

89. The valency platform molecule of any of claims 54, 60, 65, 67, 73 and 74, wherein the valency platform molecule further comprises one or more bivalent linker molecules that may be used for linking a biologically active molecule to the valency platform molecule, wherein the linker molecules comprise aminooxy groups that are optionally protected with an aminooxy protecting group, and wherein the bivalent linker molecules are bonded to the valency platform molecule such that a linkage bond is formed between the bivalent linker molecule and the valency platform molecule.

90. The valency platform molecule of claim 89, wherein the linkage bond that is formed is selected from the group consisting of:

an amide linkage, a carbamate linkage, a thioether linkage and an oxime linkage.

91. The valency platform molecule of claim 90, wherein the linkage bond is formed by reacting the valency platform molecule with the bivalent linker molecule, wherein the bivalent linker molecule comprises a functional moiety that is selected from the group consisting of:

amine, acid carbonate ester, thiol, aminooxy, and carboxylic acid.

92. The valency platform molecule of claim 54, wherein the valency platform molecule is dendritic.

93. The valency platform molecule of claim 67 or 68, wherein the valency platform molecule has a valence of four.

94. The valency platform molecule of claim 74, wherein n is 1 to 200.

95. A composition comprising two or more valency platform molecules according to claim 54, wherein the valency platform molecules have a polydispersity less than about 1.2.

96. A conjugate of a molecule according to any one of claims 54, 55, 60, 65, 67, 68, 73, 74, 79 or 80, and one or more biologically active molecules.

97. The conjugate of claim 96, wherein the biologically active molecules are selected from the group consisting of:

oligonucleotides, peptides, polypeptides, proteins, antibodies, saccharides, polysaccharides, epitopes, mimotopes, enzymes, hormones, drugs, nucleic acids, lipids, fatty acids, and mixtures thereof.

98. The conjugate of claim 97, wherein the biologically active molecules comprise a polypeptide.

99. The conjugate of claim 97, wherein the biologically active molecules comprise a nucleic acid.

100. The conjugate of claim 97, wherein the biologically active molecules comprise an oligonucleotide.

101. The conjugate of claim 98, wherein the polypeptide lacks a T cell epitope.

102. The conjugate of claim 98, wherein the biologically active molecules comprise a domain 1 polypeptide of O₂GPI.

103. The conjugate of claim 102, wherein the polypeptide lacks a T cell epitope.

104. The conjugate of claim 102, wherein the conjugate comprises a linker that attaches the domain 1 polypeptide of O₂GPI to the valency platform molecule.

105. The conjugate according to claim 96, wherein the biologically active molecules interact specifically with proteinaceous receptors.

106. The conjugate according to claim 96, wherein the conjugate is a toleragen.

107. The conjugate according to claim 96, wherein the conjugate induces specific B cell anergy to an immunogen.

108. A method of making the conjugate according to claim 96, comprising:

covalently bonding biologically active molecules to a valency platform molecule such that an oxime bond, or modified form thereof, is formed.

109. The method of claim 108, wherein the modified oxime bond is a reduced or alkylated oxime bond.

110. The method of claim 108, wherein the valency platform molecule comprises an aminooxy group and the biologically active molecules comprise a reactive functional group such that an oxime bond is formed upon bonding the biologically active molecules to the valency platform molecule.

111. The method of claim 110, wherein the reactive functional group is a carbonyl group of an aldehyde or ketone moiety.

112. The method of claim 111, wherein the biologically active molecules comprise a polypeptide;

and, wherein the method comprises modifying the polypeptide prior to bonding with an aminooxy group on the valency platform molecule, such that the polypeptide comprises a terminal aldehyde group.

113. A pharmaceutical composition comprising the conjugate of any of claims 96, and 98-107, and a pharmaceutically acceptable carrier.