# US 5,703,117 A · Hydrolysis-promoting hydrophobic taxane derivatives

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- Number: US 5,703,117 A
- Document ID: US5703117A
- Status: Granted
- Kind: A
- Application number: 08/712,684
- Filed: 1996-09-12
- Granted: 1997-12-30
- Earliest claimed: 1996-09-12
- Assignees: The Liposome Company, Inc.
- Inventors: Eric Mayhew; Shaukat Ali; Andrew S. Janoff
- Web page: https://patentgrep.com/patent/US5703117A

## CPC

- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61P 35/00: Antineoplastic agents
- C07D 305/14: condensed with carbocyclic rings or ring systems
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided herein is a taxane having a hydrocarbon attached at the 2' and/or 7 positions, the hydrocarbon's alpha position being occupied by a "hydrolysis-promoting group" ("HPG"). Substitution of an HPG for the methylene unit ordinarily occupying the alpha position allows for enhanced in vivo hydrolysis of the hydrocarbon-taxane bond, and hence, for enhanced taxane therapeutic activity. Also provided herein are taxane-containing compositions, and methods of administering taxanes to animals, including those afflicted with cancers.

## Claims

### Claim 1

A taxane having the formula: ##STR5## wherein: A.sup.1 is H or a group having the formula Z--C(O)NHCH(C.sub.6 H.sub.5)CH(OR)--C(O)--, A.sup.2 is H or CH.sub.3 C(O)-- and;
Z is C.sub.6 H.sub.5 --, C.sub.6 H.sub.5 CH.sub.2 --O--, C(CH.sub.3).sub.3 --O-- or CH(CH.sub.3).dbd.C(CH.sub.3)--;
each of R and R.sup.1 is H or a group having the formula Y.sup.1 Y.sup.2, provided that at least one of R and R.sup.1 is not H and provided that when A.sup.3 is H, R.sup.1 is not H;
y.sup.1 is --O(O)OHX.sup.1 (CH.sub.2).sub.n1 (CH.dbd.CH).sub.n2 (CH.sub.2).sub.n3 (CH.dbd.CH).sub.n4 (CH.sub.2).sub.n5 (CH.dbd.CH).sub.n6 (CH.sub.2).sub.n7 (CH.dbd.CH).sub.n8 (CH.sub.2).sub.n9 --;
the sum of n1+2n2+n3+2n4+n5+2n6+n7+2n8+n9 is an integer of from 1 to 21, each of n2, n4, n6 and n8 is independently zero or 1, n1 is zero or an integer of from 1 to 21, n3 is zero or an integer of from 1 to 18, n5 is zero or an integer of from 1 to 15, n7 is zero or an integer of from 1 to 12, n9 is zero or an integer of from 1 to 9 and each of n1 to n9 can be the same or different at each occurrence;
X.sup.1 is an hydrolysis-promoting group; and
y.sup.2 is --CH.sub.3, --CO.sub.2 H or --CH.sub.2 OH.

### Claim 2 (depends on 1)

The taxane of claim 1, wherein A.sup.1 is a group having the formula Z--C(O)NHCH(C.sub.6 H.sub.5)CH(OR)C(O)--.

### Claim 3 (depends on 2)

The taxane of claim 2, wherein R.sup.1 is H.

### Claim 4 (depends on 3)

The taxane of claim 3, wherein R is a group having the formula Y.sup.1 CH.sub.3.

### Claim 5 (depends on 4)

The taxane of claim 4, wherein R is --C(O)CHX.sup.1 (CH.sub.2).sub.3 CH.sub.3, --C(O)CHX.sup.1 (CH.sub.2).sub.5 CH.sub.3, --C(O)CHX.sup.1 (CH.sub.2).sub.9 CH.sub.3, --C(O)CHX.sup.1 (CH.sub.2).sub.11 CH.sub.3, or--C(O)CHX.sup.1 (CH.sub.2).sub.13 CH.sub.3.

### Claim 6 (depends on 2)

The taxane of claim 2, wherein R is H.

### Claim 7 (depends on 6)

The taxane of claim 6, wherein R.sup.1 is a group having the formula Y.sup.1 CH.sub.3.

### Claim 8 (depends on 7)

The taxane of claim 7, wherein R.sup.1 is --C(O)CHX.sup.1 (CH.sub.2).sub.3 CH.sub.3, --C(O)CHX.sup.1 (CH.sub.2).sub.5 CH.sub.3, --C(O)CHX.sup.1 (CH.sub.2).sub.9 CH.sub.3, or --C(O)CHX.sup.1 (CH.sub.2).sub.13 CH.sub.3.

### Claim 9 (depends on 1)

The taxane of claim 1, wherein X.sup.1 is F, Cl, Br, I, the group --OC.sub.6 H.sub.4 X.sup.2 or the group --C(O)X.sup.2 and wherein X.sup.2 is F, Cl, Br, I, CN, NO.sub.2 or NH.sub.3.sup.+.

### Claim 10 (depends on 2)

The taxane of claim 2, wherein Z is C.sub.6 H.sub.5.

### Claim 11 (depends on 10)

The taxane of claim 10, wherein A.sup.2 is CH.sub.3 C(O)--.

### Claim 12 (depends on 11)

The taxane of claim 11, wherein R.sup.1 is H and R is --C(O)CHX.sup.1 (CH.sub.2).sub.3 CH.sub.3, --C(O)CHX.sup.1 (CH.sub.2).sub.5 CH.sub.3, --C(O)CHX.sup.1 (CH.sub.2).sub.9 CH.sub.3, --C(O)CHX.sup.1 (CH.sub.2).sub.11 CH.sub.3, or --C(O)CHX.sup.1 (CH.sub.2).sub.13 CH.sub.3.

### Claim 13 (depends on 12)

The taxane of claim 12, wherein X.sup.1 is F, Cl, Br or I.

### Claim 14 (depends on 11)

The taxane of claim 11, wherein R.sup.1 is H and R is --C(O)CHX.sup.1 (CH.sub.2).sub.3 CH.sub.3, --C(O)CHX.sup.1 (CH.sub.2).sub.5 CH.sub.3, --C(O)CHX.sup.1 (CH.sub.2).sub.9 CH.sub.3, --C(O)CHX.sup.1 (CH.sub.2).sub.11 CH.sub.3, or --C(O)CHX.sup.1 (CH.sub.2).sub.13 CH.sub.3.

### Claim 15 (depends on 14)

The taxane of claim 14, wherein X.sup.1 is F, Cl, Br or I.

### Claim 16 (depends on 1)

A composition comprising the taxane of claim 1 and a pharmaceutically acceptable medium.

### Claim 17 (depends on 16)

The composition of claim 16, wherein the pharmaceutically acceptable medium comprises a lipid carrier and wherein the taxane is associated with the lipid carrier.

### Claim 18 (depends on 17)

The composition of claim 17, wherein the lipid carrier is a fatty acid, phospholipid, lipoprotein, micelle, lipid complex or liposome.

### Claim 19 (depends on 16)

A method of administering a taxane to an animal which comprises administering the composition of claim 16 to the animal.

### Claim 20 (depends on 19)

The method of claim 19, wherein the animal is afflicted with a cancer and wherein an anticancer effective amount of the taxane is administered.

### Claim 21 (depends on 20)

The method of claim 20, wherein the anticancer effective amount of the taxane is from about 0.1 mg per kg of body weight of the animal to about 1000 mg per kg.

### Claim 22 (depends on 20)

The method of claim 20, wherein the taxane is associated with a liposome.

### Claim 23 (depends on 20)

The method of claim 20, wherein A.sup.1 is a group having the formula C.sub.6 H.sub.5 C(O)NHCH(C.sub.6 H.sub.5)CH(OR)C(O)--, A.sup.2 is CH.sub.3 C(O)--, and one of R or R.sup.1 is --C(O)CHX.sup.1 (CH.sub.2).sub.3 CH.sub.3, --C(O)CHX.sup.1 (CH.sub.2).sub.5 CH.sub.3, --C(O)CHX.sup.1 (CH.sub.2).sub.9 CH.sub.3, --C(O)CHX.sup.1 (CH.sub.2).sub.11 CH.sub.3 or --C(O)CHX.sup.1 (CH.sub.2).sub.13 CH.sub.3.

### Claim 24 (depends on 20)

The method of claim 20, wherein the cancer is a lung, colon, brain, stomach, breast, ovarian cancer, prostate or stomach cancer, or a leukemia, lymphoma, sarcoma or carcinoma.

### Claim 25 (depends on 19)

The method of claim 19, comprising administering an additional bioactive agent to the animal.