# US 5,352,669 A · O.sup.6 -benzylated guanine, guanosine and 2'-deoxyguanosine compounds possessing O.sup.6 -alkylguanine-DNA alkyltransferase depleting activity

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- Number: US 5,352,669 A
- Document ID: US5352669A
- Status: Granted
- Kind: A
- Application number: 07/616,913
- Filed: 1990-11-21
- Granted: 1994-10-04
- Earliest claimed: 1990-03-13
- Assignees: The United States of America as represented by the Department of Health and Human Services
- Inventors: Robert C. Moschel; M. Eileen Dolan; Anthony E. Pegg
- Web page: https://patentgrep.com/patent/US5352669A

## CPC

- C07H 19/16: Purine radicals
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

O.sup.6 -Benzylated guanine guanosine and 2'-deoxyguanosine compounds of the formula ##STR1## wherein Z is hydrogen, ##STR2## and R is a benzyl group or a substituted benzyl group, cause a depletion of O.sup.6 -alkylguanine-DNA alkyltransferase (AGT) activity in mammalian cells. These compounds may be administered to a host so as to reduce AGT levels in tumor cells of the host in order to increase host responsiveness to anti-neoplastic alkylating agents, including chloroethylating agents, such as chloroethylnitrosoureas, for chemotherapeutic treatment of a number of neoplasms.

## Claims

### Claim 1

A pharmaceutical composition which comprises compounds of the formula, ##STR7## wherein Z is ##STR8## and R is a benzyl group or a substituted benzyl group substituted at the ortho, meta or para position with a substituent selected from the group consisting of halogen, nitro, phenyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of up to 4 carbon atoms, alkynyl of up to 4 carbon atoms, amino, monoalkylamino, dialkylamino, trifluoromethyl, hydroxy, hydroxymethyl, and SO.sub.n R.sub.1 wherein n is 0, 1, 2 or 3 and R.sub.1 is hydrogen, alkyl of 1-4 carbon atoms, or phenyl; and a pharmaceutically acceptable excipient.

### Claim 2 (depends on 1)

The composition of claim 1, wherein R is a benzyl group.

### Claim 3 (depends on 1)

The composition of claim 1, wherein R is a p-chlorobenzyl group or a p-fluorobenzyl group.

### Claim 4 (depends on 1)

The composition of claim 1, wherein R is a p-methylbenzyl group.

### Claim 5 (depends on 1)

The composition of claim 1, further comprising an anti-neoplastic alkylating agent.

### Claim 6 (depends on 2)

The composition of claim 2, further comprising an anti-neoplastic alkylating agent.

### Claim 7 (depends on 3)

The composition of claim 3, further comprising an anti-neoplastic alkylating agent.

### Claim 8

The composition of claim , further comprising an anti-neoplastic alkylating agent.

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1, wherein Z is ##STR9## and R is a benzyl group or a substituted benzyl group substituted with a substituent selected from the group consisting of halogen, nitro, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, trifluoromethyl and hydroxymethyl.

### Claim 10 (depends on 9)

The pharmaceutical composition of claim 9, further comprising an anti-neoplastic alkylating agent.