Compositions and methods for assessing eye vasculature

Patent metadata

Field	Value
Publication number	US-11160880-B2
Application number	US-201916694982-A
Country	US
Kind code	B2
Filing date	Nov 25, 2019
Priority date	May 12, 2015
Publication date	Nov 2, 2021
Grant date	Nov 2, 2021

Abstract

Compositions and methods for assessing blood vessels and organs of the body are disclosed herein, specifically methods for assessing the vasculature of the eye.

First claim

The invention claimed is:

1. A kit for assessing the vasculature in a subject in need thereof, comprising:
a. a compound of structural Formula I

or a salt thereof; wherein
X 1 and X 2 are independently chosen from —CO(AA), —CN, —CO 2 R 1 , —CONR 2 R 3 , —COR 4 , —NO 2 , —SOR 35 , —SO 2 R 6 , —SO 2 OR 7 and —PO 3 R 8 R 9 ; wherein at least one of X 1 and X 2 is —CO(AA);
Y 1 and Y 2 are independently chosen from —OR 10 , —SR 11 , —NR 12 R 13 , —N(R 14 )COR 15 , —CONH(PS); —P(R 16 ) 2 , —P(OR 17 ) 2 and

each Z 1 is independently chosen from a bond, —CR 18 R 19 —, —O—, —NR 20 —, —NCOR 21 —, —S—, —SO—, and —SO 2 —;
each R 1 to R 21 are independently chosen from hydrogen, C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted with hydroxyl and carboxylic acid, C 3 -C 6 polyhydroxylated alkyl, C 5 -C 10 aryl, C 5 -C 10 heteroaryl, C 3 -C 5 heterocycloalkyl, C 3 -C 5 heterocycloalkyl substituted with C(O), (CH 2 ) a CO 2 H, —(CH 2 ) a CO 2 H substituted with C 5 -C 10 heteroaryl, —(CH 2 ) a CONR 30 R 31 , —(CH 2 ) a NHSO 3 − , —(CH 2 ) a NHSO 3 H, —(CH 2 ) a OH, —(CH 2 ) a OPO 3 − , —(CH 2 ) a OPO 3 H 2 , —(CH 2 ) a OPO 3 H − , —(CH 2 ) a OR 22 , —(CH 2 ) a OSO 3 , —(CH 2 ) a OSO 3 H, —(CH 2 ) a PO 3 − —(CH 2 ) a PO 3 H 2 , —(CH 2 ) a PO 3 H − , —(CH 2 ) a SO 3 − , —(CH 2 ) a SO 3 H, —(CH 2 ) d CO(CH 2 CH 2 O) c R 23 , —(CHCO 2 H) a CO 2 H, —CH 2 (CHNH 2 ) a CH 2 NR 25 R 26 , —CH 2 (CHOH) a CO 2 H, —CH 2 (CHOH) a R 27 , —CH[(CH 2 ) b NH 2 ] a CH 2 OH, —CH[(CH 2 ) b NH 2 ] a CO 2 H, and —(CH 2 ) a NR 28 R 29 ;
each R 22 to R 31 are independently chosen from hydrogen, C 1 -C 10 alkyl, and C 1 -C 5 -dicarboxylic acid;
R 35 is chosen from C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted with hydroxyl and carboxylic acid, C 3 -C 6 polyhydroxylated alkyl, C 5 -C 10 aryl, C 5 -C 10 heteroaryl, C 3 -C 5 heterocycloalkyl, C 3 -C 5 heterocycloalkyl substituted with C(O), (CH 2 ) a CO 2 H, (CH 2 ) a CO 2 H substituted with C 5 -C 10 heteroaryl, —(CH 2 ) a CONR 30 R 31 , —(CH 2 ) a NHSO 3 − , —(CH 2 ) a NHSO 3 H, —(CH 2 ) a OH, —(CH 2 ) a OPO 3 − , (CH 2 ) a OPO 3 H 2 , —(CH 2 ) a OPO 3 H − , —(CH 2 ) a OR 22 , (CH 2 ) a OSO 3 − , —(CH 2 ) a OSO 3 H, —(CH 2 ) a PO 3 − , —(CH 2 ) a PO 3 H 2 , —(CH 2 ) a PO 3 H − , —(CH 2 ) a SO 3 , (CH 2 ) a SO 3 H, —(CH 2 ) d CO(CH 2 CH 2 O) c R 23 , —(CH 2 ) d (CH 2 CH 2 O) c R 24 , —(CHCO 2 H) a CO 2 H, —CH 2 (CHNH 2 ) a CH 2 NR 25 R 26 , —CH 2 (CHOH) a CO 2 H, CH 2 (CHOH) a R 27 , —CH[(CH 2 ) b NH 2 ] a CH 2 OH, —CHRCH 2 ) b NH 2 ] a CO 2 H, and —(CH 2 ) a NR 28 R 29 ;
(AA) is a polypeptide chain comprising one or more natural or unnatural amino acids linked together by peptide bonds;
(PS) is a sulfated or non-sulfated polysaccharide chain comprising one or more monosaccharide units connected by glycosidic linkages; and
each ‘a’, and ‘d’ are independently chosen from 0 to 10, ‘c’ is chosen from 1 to 100 and each of ‘m’ and ‘n’ independently is an integer from 1 to 3; and
b. written instructions for assessing the eye vasculature in the subject, comprising the steps of:
i. administering an effective amount of the compound of structural Formula I to be detected in the eye vasculature;
ii. irradiating the subject's eye vasculature with non-ionizing radiation, wherein the radiation causes the compound to fluoresce;
iii. detecting the fluorescence of the compound in the subject's eye vasculature; and
iv. visualizing the eye vasculature within the subject based on the detected fluorescence.

2. The kit of claim 1 , wherein said amino acids are chosen from a-amino acids, β-amino acids, and γ-amino acids.

3. The kit of claim 1 , wherein the written instructions comprise a step for administering the compound intravenously.

4. The kit of claim 1 , wherein the written instructions comprise a step for irradiating the subject's eye vasculature with non-ionizing radiation having a wavelength of at least 350 nm.

5. The kit of claim 1 , wherein the written instructions comprise a step for measuring the detected fluorescence of the compound of structural Formula I in the subject's eye vasculature over time.

6. The kit of claim 1 , wherein the kit further comprises additional written instructions for assessing the subject's pulmonary and cardiac vasculature.

7. The kit of claim 6 , wherein assessing the subject's pulmonary and cardiac vasculature comprises identifying abnormalities chosen from stenosis, occlusions, aneurysms, and combinations thereof.

8. The kit of claim 6 , wherein assessing the subject's pulmonary and cardiac vasculature comprises comparing the detected fluorescence in the subject's pulmonary and cardiac vasculature to that of normal pulmonary and cardiac vasculature under similar conditions.

9. The kit of claim 1 , wherein assessing the subject's eye vasculature comprises identifying ocular abnormalities.

10. The kit of claim 9 , wherein the ocular characteristics are selected from the group consisting of: blood vessel architecture, ischemic spots, choroidal infarcts, Elschnig's spots, exudates, hemorrhages, and combinations thereof.

11. The kit of claim 9 , wherein the ocular characteristics are selected from the group consisting of: vessel crossovers, vessel tortuosity, evidence of exudates, and combinations thereof.

12. The kit of claim 1 , wherein assessing the subject's eye vasculature comprises comparing the detected fluorescence in the subject's eye to that of a normal eye under similar conditions.

13. The kit of claim 1 , wherein X 1 and X 2 are each —CO(AA) and Y 1 and Y 2 are each
—NR 12 R 13 wherein one of R 12 and R 13 is hydrogen and the other of R 12 and R 13 is chosen from hydrogen and C 1 -C 10 alkyl.

14. The kit of claim 13 wherein each of R 12 and R 13 is hydrogen.

15. The method of claim 1 wherein the compound formula I is

3, 6-diamino-N 2 ,N 5 -bis(D-serine)-pyrazine-2,5-dicarboxamide.

Assignees

• Medibeacon Inc

Inventors

• Dorshow Richard B
• Rogers Thomas E

Classifications

• C07D241/20

  Nitrogen atoms (nitro radicals C07D241/16) · CPC title

• A61K49/0021 Primary

  the fluorescent group being a small organic molecule · CPC title

• C07K5/06139

  with the first amino acid being heterocyclic · CPC title

• A61B1/042

  characterised by a proximal camera, e.g. a CCD camera · CPC title

• A61B5/0261

  using optical means, e.g. infrared light · CPC title