Cationic steroid antimicrobial diagnostic, detection, screening and imaging methods

Patent metadata

Field	Value
Publication number	US-9943614-B2
Application number	US-200913000010-A
Country	US
Kind code	B2
Filing date	Jun 16, 2009
Priority date	Jun 17, 2008
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

Abstract

The invention relates to diagnostic, detection, screening and imaging methods. In various embodiments, methods of diagnosis, detection, screening and imaging include administering a cationic steroid antimicrobial or CSA to a subject having or at risk of having an infection or a hyperproliferative disorder (e.g., a tumor, cancer or neoplasia) in an amount effective to diagnose or detect the infection or the hyperproliferative disorder (e.g., a tumor, cancer or neoplasia) in the subject. In a particular aspect, a detectable CSA, namely CSA-13 labeled with 99m Tc is used to detect the presence of an infection.

First claim

What is claimed:

1. A method of detecting a tumor, cancer or neoplasia, or diagnosing a subject having or at risk of having a tumor, cancer or neoplasia, comprising:
administering a detectably labeled cationic steroid antimicrobial (CSA) of formula V, or a pharmaceutically acceptable salt thereof, to the subject under conditions whereby the labeled CSA binds to cell membranes in cells of a tumor, cancer or neoplasia:

where:
each of fused rings A, B, C, and D is independently saturated, or is fully or partially unsaturated, provided that at least two of A, B, C, and D are saturated, wherein rings A, B, C, and D form a ring system;
each of m, n, p, and q is independently 0 or 1; and
each of R 1 through R 4 , R 6 , R 7 , R 11 , R 12 , R 15 , R 16 , R 17 , and R 18 is independently selected from the group consisting of hydrogen, hydroxyl, substituted or unsubstituted (C1-C10) alkyl, (C1-C10) hydroxyalkyl, (C1-C10) alkyloxy-(C1-C10) alkyl, (C1-C10) alkylcarboxy-(C1-C10) alkyl, (C1-C10) alkylamino-(C1-C10) alkyl, (C1-C10) alkylamino-(C1-C10) alkylamino, (C1-C10) alkylamino-(C1-C10) alkylamino-(C1-C10) alkylamino, substituted or unsubstituted (C1-C10) aminoalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamino-(C1-C10) alkyl, (C1-C10) haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, oxo, linking group attached to a second steroid, substituted or unsubstituted (C1-C10) aminoalkyloxy, substituted or unsubstituted (C1-C10) aminoalkyloxy-(C1-C10) alkyl, substituted or unsubstituted (C1-C10) aminoalkylcarboxy, substituted or unsubstituted (C1-C10) aminoalkylaminocarbonyl, substituted or unsubstituted (C1-C10) aminoalkylcarboxamido, H 2 N—HC(Q5)-C(O)—O—, H 2 N—HC(Q5)-C(O)—N(H)—, (C1-C10) azidoalkyloxy, (C1-C10) cyanoalkyloxy, P.G.—HN—HC(Q5)-C(O)—O—, (C1-C10) guanidinoalkyl oxy, (C1-C10) quaternary ammonium alkylcarboxy, and (C1-C10) guanidinoalkyl carboxy, where Q5 is a side chain of an amino acid, and P.G. is an amino protecting group, and
each of R 5 , R 8 , R 9 , R 10 , R 13 , and R 14 is independently: deleted when one of fused rings A, B, C, or D is unsaturated so as to complete the valency of the carbon atom at that site, or selected from the group consisting of hydrogen, hydroxyl, substituted or unsubstituted (C1-C10) alkyl, (C1-C10) hydroxyalkyl, (C1-C10) alkyloxy-(C1-C10) alkyl, substituted or unsubstituted (C1-C10) aminoalkyl, substituted or unsubstituted aryl, C1-C10) haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, oxo, linking group attached to a second steroid, substituted or unsubstituted (C1-C10) aminoalkyloxy, substituted or unsubstituted (C1-C10) aminoalkylcarboxy, substituted or unsubstituted (C1-C10) aminoalkylaminocarbonyl, H 2 N—HC(Q5)-C(O)—O—, H 2 N—HC(Q5)-C(O)—N(H)—, (C1-C10) azidoalkyloxy, (C1-C10) cyanoalkyloxy, P.G.—HN—HC(Q5)-C(O)—O—, (C1-C10) guanidinoalkyloxy, and (C1-C10) guanidinoalkylcarboxy, where Q5 is a side chain of any amino acid, P.G. is an amino protecting group,
provided that at least three of R 6 , R 7 , R 11 , R 12 , R 15 , R 16 , R 17 , and R 18 are disposed on the same face of the ring system and are independently selected from the group consisting of substituted or unsubstituted (C1-C10) aminoalkyloxy, (C1-C10) alkylcarboxy-(C1-C10) alkyl, (C1-C10) alkylamino-(C1-C10) alkylamino, (C1-C10) alkylamino-(C1-C10) alkylamino-(C1-C10) alkylamino, substituted or unsubstituted (C1-C10) aminoalkylcarboxy, substituted or unsubstituted arylamino-(C1-C10) alkyl, substituted or unsubstituted (C1-C10) aminoalkyloxy-(C1-C10) alkyl, substituted or unsubstituted (C1-C10) aminoalkylaminocarbonyl, (C1-C10) quaternary ammonium alkylcarboxy, H 2 NHC(Q5)-C(O)—O—, H 2 N—HC(Q5)-C(O)—N(H)—, (C1-C10) azidoalkyloxy, (C1-C10) cyanoalkyloxy, P.G.—HN—HC(Q5)-C(O)—O—, (C1-C10) guanidinoalkyloxy, and (C1-C10) guanidinoalkylcarboxy, and
wherein the detectably labeled CSA includes at least one radioisotope label selected from the group consisting of (i) a radioisotope of carbon, hydrogen, nitrogen, oxygen, or sulfur included in the structure of the CSA and (ii) a radioisotope of a metal or metal oxide covalently linked or conjugated to a basic site of the CSA selected from oxygen, sulfur, or nitrogen; and
detecting the presence, absence, or distribution of the detectably labeled CSA in a whole body, a particular region, a general area, a specific organ, a specific tissue, or a local portion of a region, organ, or tissue of the subject to ascertain the presence or absence of, a tumor, cancer or neoplasia, thereby detecting the tumor, cancer or neoplasia, or diagnosing the subject as having or not having a tumor, cancer or neoplasia.

2. A method of imaging a tumor, cancer or neoplasia in a subject having or at risk of having a tumor, cancer or neoplasia, comprising:
administering a detectably labeled cationic steroid antimicrobial (CSA) of formula V, or a pharmaceutically acceptable salt thereof, to the subject under conditions whereby the labeled CSA binds to cell membranes in cells of a tumor, cancer or neoplasia:

where:
each of fused rings A, B, C, and D is independently saturated, or is fully or partially unsaturated, provided that at least two of A, B, C, and D are saturated, wherein rings A, B, C, and D form a ring system;
each of m, n, p, and q is independently 0 or 1; and
each of R 1 through R 4 , R 6 , R 7 , R 11 , R 12 , R 15 , R 16 , R 17 , and R 18 is independently selected from the group consisting of hydrogen, hydroxyl, substituted or unsubstituted (C1-C10) alkyl, (C1-C10) hydroxyalkyl, (C1-C10) alkyloxy-(C1-C10) alkyl, (C1-C10) alkylcarboxy-(C1-C10) alkyl, (C1-C10) alkylamino-(C1-C10) alkyl, (C1-C10) alkylamino-(C1-C10) alkylamino, (C1-C10) alkylamino-(C1-C10) alkylamino-(C1-C10) alkylamino, substituted or unsubstituted (C1-C10) aminoalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylamino-(C1-C10) alkyl, (C1-C10) haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, oxo, linking group attached to a second steroid, substituted or unsubstituted (C1-C10) aminoalkyloxy, substituted or unsubstituted (C1-C10) aminoalkyloxy-(C1-C10) alkyl, substituted or unsubstituted (C1-C10) aminoalkylcarboxy, substituted or unsubstituted (C1-C10) aminoalkylaminocarbonyl, substituted or unsubstituted (C1-C10) aminoalkylcarboxamido, H 2 N—HC(Q5)-C(O)—O—, H 2 N—HC(Q5)-C(O)—N(H)—, (C1-C10) azidoalkyloxy, (C1-C10) cyanoalkyloxy, P.G.—HN—HC(Q5)-C(O)—O—, (C1-C10) guanidinoalkyl oxy, (C1-C10) quaternary ammonium alkylcarboxy, and (C1-C10) guanidinoalkyl carboxy, where Q5 is a side chain of an amino acid, and P.G. is an amino protecting group, and
each of R 5 , R 8 , R 9 , R 10 , R 13 , and R 14 is independently: deleted when one of fused rings A, B, C, or D is unsaturated so as to complete the valency of the carbon atom at that site, or selected from the group consisting of hydrogen, hydroxyl, substituted or unsubstituted (C1-C10) alkyl, (C1-C10) hydroxyalkyl, (C1-C10) alkyloxy-(C1-C10) alkyl, substituted or unsubstituted (C1-C10) aminoalkyl, substituted or unsubstituted aryl, C1-C10 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, oxo, linking group attached to a second steroid, substituted or unsubstituted (C1-C10) aminoalkyloxy, substituted or unsubstituted (C1-C10) aminoalkylcarboxy, substituted or unsubstituted (C1-C10) aminoalkylaminocarbonyl, H 2 N—HC(Q5)-C(O)—O—, H 2 N—HC(Q5)-C(O)—N(H)—, (C1-C10) azidoalkyloxy, (C1-C10) cyanoalkyloxy, P.G.—HN—HC(Q5)-C(O)—O—, (C1-C10) guanidinoalkyloxy, and (C1-C10) guanidinoalkylcarboxy, where Q5 is a side chain of any amino acid, P.G. is an amino protecting group,
provided that at least three of R 6 , R 7 , R 11 , R 12 , R 15 , R 16 , R 17 , and R 18 are disposed on the same face of the ring system and are independently s

Assignees

• Savage Paul B
• Univ Brigham Young

Inventors

• Savage Paul B

Classifications

• C07J41/0088

  containing unsubstituted amino radicals · CPC title

• C07J41/0038

  with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not being part of an amide group · CPC title

• C07J17/00

  Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton (cardanolide, bufanolide C07J19/00) · CPC title

• C07J41/0005

  the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title