# US 2019/0375792 A1 · Cyclic Peptide Antiviral Agents and Methods Using Same

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- Number: US 2019/0375792 A1
- Document ID: US20190375792A1
- Status: Published application
- Kind: A1
- Application number: 16/331,861
- Filed: 2017-09-13
- Published: 2019-12-12
- Earliest claimed: 2016-09-14
- Assignees: Drexel University
- Applicants: Drexel University
- Inventors: Irwin M. Chaiken; Adel Ahmed Rashad Ahmed
- Web page: https://patentgrep.com/patent/US20190375792A1

## CPC

- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- C07K 7/56: the cyclisation not occurring through 2,4-diamino-butanoic acid
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 47/6923: {the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb}
- A61K 47/6929: {the form being a nanoparticle, e.g. an immuno-nanoparticle}
- A61P 31/18: for HIV
- C07K 7/64: Cyclic peptides containing only normal peptide links
- C07K 16/1145: {Env proteins, e.g. gp41, gp110/120, gp160, V3, principal neutralising domain [PND] or CD4-binding site}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 47/32: Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone}
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention includes novel cyclic peptides of formula (I). The present invention further includes novel cyclic peptides conjugated with a gold nanoparticle, and methods of using the same. The invention further provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one cyclic compound of the invention. The invention further provides a method of treating, reducing, or preventing HIV-1 infection in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of the invention.

## Claims

### Claim 1

A cyclic compound of formula (I), or a salt, solvate, enantiomer or diastereoisomer thereof:
Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-P1 (I),
wherein in (I):
Xaa1 is selected from the group consisting of absent, Glu and Arg;
Xaa2 is selected from the group consisting of absent, Gly, Phe, Lys, Asp, Glu, Ile, Arg and Cit;
Xaa3 is selected from the group consisting of absent, Asn, Asp, Ile, Glu, butanedioic acid, and 2-cyclohexylglycine;
Xaa4 is selected from the group consisting of Asn and Asp;
Xaa5 is a modified glycine of formula (III)
wherein RIII is selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl;
Xaa6 is the modified proline of formula (IV)
wherein in (IV):
RIV is selected from the group consisting of: adamantyl substituted with 0-2 C1-C6 alkyl groups; —(C0-C4 alkyl) phenyl, wherein the phenyl is substituted with 0-2 C1-C6 alkyl groups; phenyl substituted with R1 and with 0-2 C1-C6 alkyl groups;
and heteroaryl substituted with R1 and with 0-2 C1-C6 alkyl groups;
wherein each occurrence of R1 is independently selected from the group consisting of phenyl substituted with 0-2 C1-C6 alkyl groups and heteroaryl substituted with 0-2 C1-C6 alkyl groups; and
wherein each occurrence of heteroaryl is independently selected from the group consisting of pyridine, pyrimidine, thiophene, furan, pyrrole, imidazole, oxazole, oxadiazole, thiazole, thiadiazolyl, isothiazole, and tetrazole;
Xaa7 is selected from the group consisting of Trp and 3-(3-benzothienyl)-L-alanine;
Xaa8 is selected from the group consisting of Ser, Thr, 2,4-diaminobutanoic acid, Orn and Lys;
Xaa9 is selected from the group consisting of absent, 2,4-diaminobutanoic acid, Orn, Lys, Glu, Glu-Ala, Glu-Ala-Met, Glu-Ala-Met-Met, and 2-(2-(2-aminoethoxy)ethoxy)acetic acid;
P1 is absent, or is a group that comprises at least one thiol group and is covalently linked through an amide bond to (i) the C-terminus of Xaa9 if Xaa9 is not absent, or (ii) the C-terminus of Xaa8 if Xaa9 is absent;
the side chain amino group of one residue selected from the group consisting of 2,4-diaminobutanoic acid at Xaa8, Orn at Xaa8, Lys at Xaa8, 2,4-diaminobutanoic acid at Xaa9, Orn at Xaa9, and Lys at Xaa9 forms an amide bond with the side chain carboxylic acid group of one residue selected from the group consisting of Glu at Xaa2, Asp at Xaa2, Glu at Xaa3, Asp at Xaa3, succinic acid at Xaa3, and Asp at Xaa4; and
the C-terminus of Xaa8 is optionally amidated if Xaa9 and P1 are absent, or the C-terminus of Xaa9 is optionally amidated if P1 is absent.

### Claim 2 (depends on 1)

The cyclic compound of claim 1, which is selected from the group consisting of:
‘NH’ is derived from the side chain amino group of a residue selected from the group consisting of 2,4-diaminobutanoic acid at Xaa8, Orn at Xaa8, Lys at Xaa8, 2,4-diaminobutanoic acid at Xaa9, Orn at Xaa9, and Lys at Xaa9, and
‘C═O’ is derived from the side chain carboxylic acid group of a residue selected from the group consisting of Glu at Xaa2, Asp at Xaa2, Glu at Xaa3, Asp at Xaa3, succinic acid at Xaa3, and Asp at Xaa4.

### Claim 3 (depends on 1)

The cyclic compound of claim 1, which is the cyclic compound of formula (II):
Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-P1 (II),
wherein in (II):
Xaa3 is selected from the group consisting of Asn, Asp, succinic acid, and Glu;
Xaa4 is Asn;
Xaa5 is Ile; and
Xaa7 is Trp.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Xaa5 is selected from the group consisting of Ile, Leu, norleucine (Nle), cyclopropylglycine, cyclobutylglycine, cyclopentylglycine, and cyclohexylglycine.

### Claim 5 (depends on 1)

The compound of claim 1, wherein RIII is a secondary or tertiary hydrocarbyl group.

### Claim 6 (depends on 5)

The compound of claim 5, wherein RIII is selected from the group consisting of cyclohexyl, —CH(CH3)(C1-C4 alkyl), and —C(CH3)2(C1-C3 alkyl).

### Claim 7 (depends on 1)

The compound of claim 1, wherein one of the following applies: (a) the C-terminus of Xaa8 is not amidated if Xaa9 and P1 are absent, or wherein the C-terminus of Xaa9 is not amidated if P1 is absent; (b) the C-terminus of Xaa8 is amidated if Xaa9 and P1 are absent, or wherein the C-terminus of Xaa9 is amidated if P1 is absent.

### Claim 8

(canceled)

### Claim 9 (depends on 1)

The compound of claim 1, wherein, if the carbon alpha to the carboxyl group of Xaa8 is chiral, the stereochemistry of the alpha carbon is S.

### Claim 10 (depends on 1)

The compound of claim 1, wherein in (IV) the heteroaryl is thiophene.

### Claim 11 (depends on 1)

The compound of claim 1, wherein RIV is selected from the group consisting of:
—(C0-C4 alkyl) phenyl, wherein the phenyl is substituted with 1-2 C1-C6 alkyl groups, wherein one of the C1-C6 alkyl groups is at the para position of the phenyl group;
wherein each occurrence of R1 is independently C1-C6 alkyl; m is 0, 1, or 2; and n is 0 or 1.

### Claim 12 (depends on 1)

The compound of claim 1, wherein P1 is not absent.

### Claim 13 (depends on 12)

The compound of claim 12, wherein P1 comprises at least one cysteine residue.

### Claim 14 (depends on 12)

The compound of claim 12, wherein P1 is selected from the group consisting of
β Ala Gln β Ala Cys-NH2, β Ala Gln β Ala Cys,
NH2(CH2CH2O)0-10CH2C(═O)NHCH(CH2SH)C(═O)OH,
NH2(CH2CH2O)0-10CH2C(═O)NHCH(CH2SH)C(═O)NH2,
NH2(CH2)0-12CH2C(═O)NHCH(CH2SH)C(═O)OH,
NH2(CH2)0-12CH2C(═O)NHCH(CH2SH)C(═O)NH2, and
NH2CH2CH2OCH2CH2OC(═O)NHCH(CH2SH)C(═O)NH2.

### Claim 15 (depends on 1)

The compound of claim 1, which is selected from the group consisting of:
29N-2 or 36 [also known as (3S,6S,14S, 17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-14-amino-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4, 7,10,13,18]hexaazacyclotricosine-6-carboxamide]
37 [also known as (3S,6S,14S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide]
38 [also known as (3S,6S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl) phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13, 18]hexaazacyclotricosine-6-carboxamide]
(3S,6S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide
(3S,6S,14S,17 S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-14-amino-7-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18] hexaazacyclotricosine-6-carboxamide
(3S,6S,14S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18] hexaazacyclotricosine-6-carboxamide
(3S,6S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-17-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide
(3S,6S,14S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-24-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-17-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide
(3S,6S,14 S,17 S,20 S,24 S,25 aS)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl) phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13, 18]hexaazacyclotricosine-6-carboxamide
(3S,6S,14S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide
(3S,6S,17S,20S,24S,25aS)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide
(3S,6S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide
(3S,6S,14S,17 S,20S,24S,25aS)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide
((3S,6S,14S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide
(3S,6S,17S,20S,24S,25aS)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide
(3S,6S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1l-yl)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide
or a salt or solvate thereof.

### Claim 16 (depends on 1)

The compound of claim 1, which is a compound of formula (V):
wherein:
Ra is NH2 or H;
Rb is cyclohexyl or sec-butyl;
Rc is selected from the group consisting of:
Rd is NH or S;
or a salt or solvate thereof.

### Claim 17 (depends on 1)

The compound of claim 1, wherein P1 is not absent and wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle.

### Claim 18

(canceled)

### Claim 19 (depends on 1)

A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one cyclic compound of claim 1.

### Claim 20 (depends on 19)

The composition of claim 19, wherein P1 in (I) is not absent and wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle.

### Claim at position 21

21-23. (canceled)

### Claim 24 (depends on 1)

A method of treating, reducing or preventing HIV-1 infection in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of claim 1.

### Claim at position 23

25-29. (canceled)

### Claim 30 (depends on 1)

A method of reducing the risk of HIV-1 infection in a mammal at risk of HIV-1 exposure, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of claim 1.

### Claim at position 25

31-35. (canceled)

### Claim 36 (depends on 1)

A method of promoting virolysis of HIV-1, the method comprising contacting the HIV-1 with an effective amount of at least one cyclic compound of claim 1, wherein P1 is not absent.

### Claim 37 (depends on 36)

The method of claim 36, wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle.

### Claim 38

(canceled)

### Claim 39 (depends on 1)

A method of reducing the rate of or preventing entry of HIV-1 into a cell of a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of claim 1.

### Claim at position 30

40-41. (canceled)

### Claim 42 (depends on 39)

The method of claim 39, wherein P1 is not absent and (I) is complexed through the at least one thiol group with at least one gold nanoparticle.

### Claim at position 32

43-44. (canceled)

### Claim 45 (depends on 1)

A method of preparing a derivatized gold nanoparticle, the method comprising contacting the nanoparticle with at least one cyclic compound of claim 1 to generate a reaction system; and isolating the derivatized gold nanoparticle from the reaction system.