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US5449761A
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Metal-binding targeted polypeptide constructs
Assignee: Cytogen Corp
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Filing: 1993-09-28
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Granted: 1995-09-12
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Expires: 2013-09-28
Abstract
Abstract This invention relates to the preparation and use of novel open-chain or cyclic polypeptide constructs in which two or more polypeptide chains, in an open-chain construct, or one or more chains, in a cyclic construct, are chemically derivatized such that the resulting construct exhibits both metal-binding capability and tissue-, organ- or cell-targeting selectivity. In particular, the polypeptide constructs of the present invention comprise compounds of the formula (I): <IMAGE> (I) in which, "B" is a hydrocarbon backbone, "P" is a polypeptide capable of targeting particular cells, tissues or organs of the body, "A" may be the group -NR'-NR''- or the group -NR'-NR''-L- in which L may be an aliphatic or aromatic linker group, R, R' and R'' may be the same or different and may be hydrogen or an aliphatic group, m is an integer >/=2, provided that the groups R, R', R', L and "P" of a given chain may be the same or different from the groups R, R', R'', L and "P" of another chain, n is an integer >/=0; or a pharmaceutically acceptable salt thereof. The constructs of the present invention are capable of binding a variety of metallic species.
Inventors
- 👤 Benjamin A. Belinka, Jr.
- 👤 Daniel J. Coughlin
- 👤 Vernon L. Alvarez
- 👤 Richard Wood
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 20:19
CPC Classifications
A; A61; A61K; A61K49/00; A61K49/06; A61K49/08; A61K49/10; A61K49/12; A61K49/122; A61K49/085; A61K49/14; A61K51/00; A61K51/02; A61K51/04; A61K51/08; A61K51/088; A61K2121/00; A61K2123/00
Claims Analysis
Total Claims: 23
Claim 1
Independent Claim
198 words
A compound of the formula (I): ##STR12## in which, "B" is a saturated or unsaturated aliphatic or aromatic hydrocarbon backbone comprising 1-20 carbon atoms and, optionally, one or more heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur; "P" is a polypeptide comprising 2-100 amino acids, said polypeptide capable of targeting particular cells, tissues or organs of the body; "A" may be the group --NR'--NR"-- or the group --NR'--NR"--L-- in which L may be an aliphatic or aromatic linker group comprising 1-12 carbon atoms and, optionally, one or more heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur; R' and R" may be the same or different and may be hydrogen or an aliphatic group comprising 1-6 carbon atoms and, optionally, one or more heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur; m is an integer ≧2, provided that the groups R, R', R", L and "P" of a given --NR(CS)(A) n --P chain may be the same or different from the groups R, R', R", L and "P" of another --NR(CS)(A) n --P chain; n is an integer ≧0 and ≦2; or a pharmaceutically acceptable salt thereof.
Claim 2
Dependent Claim
198 words
A compound of the formula (I): ##STR12## in which, "B" is a saturated or unsaturated aliphatic or aromatic hydrocarbon backbone comprising 1-20 carbon atoms and, optionally, one or more heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur; "P" is a polypeptide comprising 2-100 amino acids, said polypeptide capable of targeting particular cells, tissues or organs of the body; "A" may be the group --NR'--NR"-- or the group --NR'--NR"--L-- in which L may be an aliphatic or aromatic linker group comprising 1-12 carbon atoms and, optionally, one or more heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur; R' and R" may be the same or different and may be hydrogen or an aliphatic group comprising 1-6 carbon atoms and, optionally, one or more heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur; m is an integer ≧2, provided that the groups R, R', R", L and "P" of a given --NR(CS)(A) n --P chain may be the same or different from the groups R, R', R", L and "P" of another --NR(CS)(A) n --P chain; n is an integer ≧0 and ≦2; or a pharmaceutically acceptable salt thereof.
Claim 3
Dependent Claim
24 words
The compound of claim 1 in which "A" is --NR'--NR'-- when "P" is attached to "A" by a carboxylic acid group of said polypeptide.
Claim 4
Dependent Claim
23 words
The compound of claim 1 in which "A" is --NR'--NR'--L-- when "P" is attached to "A" by an amino group of said polypeptide.
Claim 5
Dependent Claim
24 words
The compound of claim 1 in which "P" is attached to the thiocarbonyl group ##STR13## by an amino group of said polypeptide when n=0.
Claim 6
Dependent Claim
27 words
The compound of claim 1 in which at least one set of the groups R and R' forms a cyclic array with the thiourea group when n≠0.
Claim 7
Dependent Claim
18 words
The compound of claim 5 in which said cyclic array is covalently linked to said hydrocarbon backbone "B".
Claim 8
Dependent Claim
29 words
The compound of claim 1 in which a "P" of one --NR(CS) (A) n --P chain is covalently linked to a "P" of another --NR(CS) (A) n --P chain.
Claim 9
Dependent Claim
34 words
The compound of claim 1 in which a single "P" is shared by two or more --NR(CS) (A) n --P chains, provided that said single "P" is comprised of three or more amino acids.
Claim 10
Dependent Claim
15 words
The compound of claim 1 in which said hydrocarbon backbone "B" comprises a phenyl group.
Claim 11
Dependent Claim
19 words
The compound of claim 1 in which said hydrocarbon backbone "B" comprises an alkylene chain of 2-6 carbon atoms.
Claim 12
Dependent Claim
16 words
The compound of claim 1 in which said hydrocarbon backbone "B" further comprises a functional group.
Claim 13
Dependent Claim
39 words
The compound of claim 11 in which said functional group is selected from the group consisting of hydroxy, amino, halo, epoxy, formyl, carboxylic acid, ester, amide, carboxylic acid hydrazide, semicarbazide, thiosemicarbazide, isothiocyanate, a double bond, and a triple bond.
Claim 14
Dependent Claim
13 words
The compound of claim 1 in which said polypeptide comprises 3-50 amino acids.
Claim 15
Dependent Claim
13 words
The compound of claim 1 in which said polypeptide comprises 3-25 amino acids.
Claim 16
Dependent Claim
26 words
The compound of claim 1 wherein "B" is a benzoic acid moiety further substituted at the 3- and 5-positions by --NR(CS)--P, wherein "P" is Neuromedin C.
Claim 17
Dependent Claim
21 words
The compound of claim 1 wherein said compound is a benzoic acid bisthiosemicarbazide derived from N-acetyl-Neuromedin C-hydrazide (SEQ. ID NO: 56).
Claim 18
Dependent Claim
20 words
The compound of claim 1 wherein said compound is benzoic acid bis-thiourea derived from Neuromedin C (SEQ. ID NO: 56).
Claim 19
Dependent Claim
15 words
The compound of claim 1 wherein said compound is lysine-alpha (epsilon-Neuromedin C-thiourea) Neuromedin C thiohydantoin.
Claim 20
Dependent Claim
9 words
The compound of claim 1 wherein "P" is somatostatin.
Claim 21
Dependent Claim
15 words
A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier, subject.
Claim 22
Dependent Claim
202 words
A compound of the formula (III): ##STR14## in which, "B" is a saturated or unsaturated aliphatic or aromatic hydrocarbon backbone comprising 1-20 carbon atoms and, optionally, one or more heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur; "P" is a polypeptide comprising 2-100 amino acids, said polypeptide capable of targeting particular cells, tissues or organs of the body; "A" may be the group --NR'--NR"-- or the group --NR'--NR"--L-- in which L may be an aliphatic or aromatic linker group comprising 1-12 carbon atoms and, optionally, one or more heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur; R, R', and R" may be the same or different and may be hydrogen or an aliphatic group comprising 1-6 carbon atoms and, optionally, one or more heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur; m is an integer ≧1, provided that the groups R, R', R", L and "P" of a given NR(CS)A n --P chain may be the same or different from the groups R, R', R", L and "P" of another NR(CS)A n --P chain; n is an integer ≧0≦2; q is an integer ≧1; or a pharmaceutically acceptable salt thereof.
Claim 23
Dependent Claim
202 words
A compound of the formula (III): ##STR14## in which, "B" is a saturated or unsaturated aliphatic or aromatic hydrocarbon backbone comprising 1-20 carbon atoms and, optionally, one or more heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur; "P" is a polypeptide comprising 2-100 amino acids, said polypeptide capable of targeting particular cells, tissues or organs of the body; "A" may be the group --NR'--NR"-- or the group --NR'--NR"--L-- in which L may be an aliphatic or aromatic linker group comprising 1-12 carbon atoms and, optionally, one or more heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur; R, R', and R" may be the same or different and may be hydrogen or an aliphatic group comprising 1-6 carbon atoms and, optionally, one or more heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur; m is an integer ≧1, provided that the groups R, R', R", L and "P" of a given NR(CS)A n --P chain may be the same or different from the groups R, R', R", L and "P" of another NR(CS)A n --P chain; n is an integer ≧0≦2; q is an integer ≧1; or a pharmaceutically acceptable salt thereof.
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