# US 2019/0315784 A1 · Prodrugs of glutamine analogs

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- Number: US 2019/0315784 A1
- Document ID: US20190315784A1
- Status: Published application
- Kind: A1
- Application number: 16/454,880
- Filed: 2019-06-27
- Published: 2019-10-17
- Earliest claimed: 2015-07-31
- Assignees: The Johns Hopkins University; Ustav Organicke Chemie A Biochemie Av Cr, V.V.I.
- Applicants: The Johns Hopkins University; Ústav organické chemie a biochemie AV CR, v.v.i.
- Inventors: Barbara Slusher; Rana Rais; Lukas Tenora; Pavel Majer; Andrej Jancarik
- Web page: https://patentgrep.com/patent/US20190315784A1

## CPC

- C07F 9/2458: {of aliphatic amines}
- A61K 31/404: Indoles, e.g. pindolol
- A61P 35/00: Antineoplastic agents
- C07C 227/14: from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C 245/18: the carbon skeleton being further substituted by carboxyl groups
- C07C 271/22: to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
- C07D 209/18: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 209/20: substituted additionally by nitrogen atoms, e.g. tryptophane
- C07D 211/90: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 263/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 263/18: Oxygen atoms
- C07D 309/10: Oxygen atoms
- C07D 317/38: Ethylene carbonate
- C07D 317/40: Vinylene carbonate; Substituted vinylene carbonates
- C07D 473/34: attached in position 6, e.g. adenine
- C07F 9/65616: {containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs}
- C07H 15/203: Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
- C07H 19/207: the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
- C07K 5/06026: {the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala}
- C07K 5/06156: {and Trp-amino acid; Derivatives thereof}
- C07K 5/0808: {the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu}
- 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)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- 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)

## Abstract

The disclosure provides compounds having formula (I): and the pharmaceutically acceptable salts thereof, wherein R1, R2, R2′, and X are as defined as set forth in the specification. Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON). The disclosure also provides compounds having formula (I) for use in treating cancer.

## Claims

### Claim 1

A compound having formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is —(CH2)n—, wherein n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;
R1 is selected from the group consisting of H, C1-6 alkyl, substituted C1-6 alkyl, C3-C10 cycloalkyl, substituted C3-C10 cycloalkyl, C1-C6 alkenyl, and substituted C1-C6 alkenyl;
R2 is selected from the group consisting of —C(═O)—Ar, —C(═O)—Y—(CR3R4)m—Ar, —C(═O)—Y—(CR3R4)m—NR5R6, —P(═O)(OR7)(NHR9)o, —C(═O)—Y—(CR3R4)m—Ar—O—C(═O)—R8, —C(═O)—Y—(CR3R4)—Ar—O—R8, —C(═O)—O—R9, —C(═O)—Y—(CR3R4)m—Ar—O—C(═O)—Ar, and —C(═O)—Y—(CR3R4)m—Ar—NR5R6;
Y is —O— or a bond;
m is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8;
each n and o is an integer from 0 to 2 provided that the sum of n and o is 2;
each R3 and R4 is independently H, C1-C6 alkyl or substituted C1-C6 alkyl, aryl or substituted aryl, —(CR3R4)m—NR5R6, or
each R5 and R6 is independently H, alkyl, —C(═O)—(CR3R4)mH, —C(═O)—(NR5R6), or —C(═O)—(CR3R4)m—NR5R6;
each R7 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, —(CR3R4)m—Z, and —(CR3R4)m-Q-Z;
Q is a monosaccharide, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is
or R7 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;
each R9 is independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, —(CR3R4)m—Z, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and
provided that R1 is not H;
each R8 is independently alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosaccharide, acylated monosaccharide, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and
Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl
R2′ is selected from the group consisting of H, C1-C6 alkyl, and substituted C1-C6 alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein X is —CH2—.

### Claim 3

(canceled)

### Claim 4 (depends on 1)

The compound of claim 1, wherein R1 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopentyl, and cyclohexyl.

### Claim at position 5

5-16. (canceled)

### Claim 17

A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

### Claim 18 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.

### Claim 19 (depends on 1)

A method of treating cancer in a subject, the method comprising administering to the subject in need thereof a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of C1-6 straight-chain alkyl, a substituted C1-6 straight-chain alkyl, a C3-6 branched alkyl, and a substituted C3-6 branched alkyl.

### Claim 20

(canceled)

### Claim 21 (depends on 4)

The compound of claim 4, wherein R1 is selected from the group consisting of methyl, ethyl, and isopropyl.

### Claim 22 (depends on 1)

The compound of claim 1, wherein:
R2 is —C(═O)—Y—(CR3R4)m—NR5R6;
Y is a bond;
each m is independently 1, 2 or 3;
each R3 is independently H, C1-C6 alkyl, or —(CR3R4)m—NR5R6;
each R4 is H; and
each R5 is independently H, —C(═O)—(CR3R4)mH, —C(═O)—(NR5R6), or —C(═O)—(CR3R4)m—NR5R6;

### Claim 23 (depends on 22)

The compound of claim 22, wherein:
m is 1; and
R5 and R6 are each H.

### Claim 24 (depends on 1)

The compound of claim 1, wherein:
R2 is —C(═O)—Y—(CR3R4)m—NR5R6;
R5 is H;
R6 is —C(═O)—(CR3R4)mH.

### Claim 25 (depends on 1)

The compound of claim 1, wherein:
m is 1;
R5 is H;
R6 is —C(═O)—(CR3R4)m—NR5R6.

### Claim 26 (depends on 1)

The compound of claim 1, wherein:
R2 is —P(═O)(OR7)n(NHR9)o; and
n is 2 and o is 0;
n is 1 and o is 1; or
n is 0 and o is 2.

### Claim 27 (depends on 1)

The compound of claim 1, wherein:
R2 is —C(═O)—Y—(CR3R4)m—Ar—O—C(═O)—R8 or —C(═O)—Y—(CR3R4)m—Ar—O—R8;
Y is —O—; and
m is 0.

### Claim 28 (depends on 1)

The compound of claim 1, wherein:
R2 is —C(═O)—Y—(CR3R4)m—Ar—NR5R6;
Y is O;
each m is independently 0, 1, or 3;
each R3 is independently H, C1-C6 alkyl, or —(CR3R4)m—NR5R6;
each R4 is H;
each R5 is independently H, —C(═O)—(CR3R4)mH, —C(═O)—NR5R6, or —C(═O)—(CR3R4)m—NR5R6; and
each R6 is H.

### Claim 29 (depends on 1)

The compound of claim 1 of formula (IIA):
wherein:
R1 is selected from the group consisting of H and C1-6 alkyl;
R11 is:
R12 is selected from the group consisting of H, C1-4 alkyl, and —C(═O)R13; and
R13 is C1-4 alkyl.

### Claim 30 (depends on 1)

The compound of claim 1 of formula (IIB):
wherein:
R1 is selected from the group consisting of H and C1-6 alkyl;
R11 is:
R12 is selected from the group consisting of H, C1-4 alkyl, and —C(═O)R13; and
R13 is C1-4 alkyl.

### Claim 31 (depends on 29)

The compound of claim 29, wherein R1 is selected from the group consisting of methyl, ethyl, and isopropyl.

### Claim 32 (depends on 30)

The compound of claim 30, wherein R1 is selected from the group consisting of methyl, ethyl, and isopropyl.

### Claim 33 (depends on 29)

The compound of claim 29, wherein R12 is —C(═O)R13.

### Claim 34 (depends on 30)

The compound of claim 30, wherein R12 is —C(═O)R13.