# US 5,710,287 A · Taxanes having an amino substituted side-chain and pharmaceutical compositions containing them

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- Number: US 5,710,287 A
- Document ID: US5710287A
- Status: Granted
- Kind: A
- Application number: 08/462,122
- Filed: 1995-06-05
- Granted: 1998-01-20
- Earliest claimed: 1991-09-23
- Assignees: Florida State University
- Inventors: Robert A. Holton; Hossain Nadizadeh; Kasthuri Rengan; Chunlin Tao
- Web page: https://patentgrep.com/patent/US5710287A

## CPC

- C07D 407/12: linked by a chain containing hetero atoms as chain links
- C07C 227/22: from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
- C07C 231/12: by reactions not involving the formation of carboxamide groups
- C07C 233/87: of a carbon skeleton containing six-membered aromatic rings
- C07D 205/08: with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D 305/14: condensed with carbocyclic rings or ring systems
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07F 7/003: {without C-Metal linkages}
- C07F 7/1804: {Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896)}
- C07C 2601/14: The ring being saturated
- C07C 2601/16: the ring being unsaturated
- C07C 2603/62: containing three- or four-membered rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Taxane derivatives having an amino substituted C13 side chain.

## Claims

### Claim 1

A taxane having the formula ##STR47## wherein X.sub.1 is --OX.sub.6, --SX.sub.7, or --NX.sub.8 X.sub.9 ;
X.sub.2 is hydrogen; substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; or substituted or unsubstituted aryl or heteroaryl;
X.sub.3 and X.sub.4 are independently hydrogen; substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; or substituted or unsubstituted aryl or heteroaryl;
X.sub.5 is --CONX.sub.8 X.sub.10 ;
X.sub.6 is hydrogen; substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; substituted or unsubstituted aryl or heteroaryl; or hydroxy protecting group;
X.sub.7 is substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; substituted or unsubstituted aryl or heteroaryl; or sulfhydryl protecting group;
X.sub.8 is hydrogen; substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; or substituted or unsubstituted aryl or heteroaryl;
X.sub.9 is an amino protecting group;
X.sub.10 is substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; or substituted or unsubstituted aryl or heteroaryl;
R.sub.1 is hydroxy, protected hydroxy or together with R.sub.14 forms a carbonate;
R.sub.2 is hydroxy or --OCOR.sub.31 ;
R.sub.4a is hydrogen; substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; substituted or unsubstituted aryl or heteroaryl; cyano; hydroxy; or --OCOR.sub.30 ;
R.sub.7a is hydrogen, halogen, or --OR.sub.28 ;
R.sub.9 is hydrogen or together with R.sub.9a forms an oxo;
R.sub.9a is hydrogen, hydroxy, protected hydroxy, acyloxy, or together with R.sub.9 forms an oxo;
R.sub.10 is hydrogen or together with R.sub.10a forms an oxo,
R.sub.10a is hydrogen, --OCOR.sub.29, hydroxy, or protected hydroxy, or together with R.sub.10 forms an oxo;
R.sub.14 is hydrogen, hydroxy, protected hydroxy or together with R.sub.1 forms a carbonate;
R.sub.28 is hydrogen, acyl, or hydroxy protecting group; and
R.sub.29, R.sub.30, and R.sub.31 are independently hydrogen; substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; or substituted or unsubstituted monocyclic aryl or monocyclic heteroaryl.

### Claim 2 (depends on 1)

The taxane of claim 1 wherein R.sub.14 is hydroxy, protected hydroxy or together with R.sub.1 forms a carbonate; and R.sub.1 is as defined in claim 1.

### Claim 3 (depends on 1)

The taxane of claim 1 wherein R.sub.1 together with R.sub.14 forms a carbonate; and R.sub.14 is as defined in claim 1.

### Claim 4 (depends on 1)

The taxane of claim 1 wherein R.sub.9a is hydrogen, acyloxy, or together with R.sub.9 forms an oxo; and R.sub.9 is as defined in claim 1.

### Claim 5 (depends on 4)

The taxane of claim 4 wherein X.sub.8 is hydrogen and X.sub.10 is substituted, unsubstituted, straight, branch chained or cyclic alkyl.

### Claim 6 (depends on 5)

The taxane of claim 5 wherein X.sub.2 is --OX.sub.6 ; X.sub.3 is substituted, unsubstituted, straight, branch chained or cyclic alkyl; substituted, unsubstituted, straight or branch chained alkenyl; or substituted or unsubstituted aryl or heteroaryl; X.sub.4 is hydrogen; and X.sub.6 is hydrogen or hydroxy protecting group.

### Claim 7 (depends on 6)

The taxane of claim 6 wherein
R.sub.2 is --OCOR.sub.31 ;
R.sub.4a is --OCOR.sub.30 ;
R.sub.10a is --OCOR.sub.29
R.sub.29 and R.sub.30 are substituted, unsubstituted, straight, branch chained or cyclic alkyl; and
R.sub.31 is substituted or unsubstituted monocyclic aryl or monocyclic heteroaryl.

### Claim 8 (depends on 4)

The taxane of claim 4 wherein X.sub.10 is substituted or unsubstituted ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, or cyclobutyl.

### Claim 9 (depends on 4)

The taxane of claim 4 wherein X.sub.5 is dimethylcarbamyl, diethylcarbamyl, diphenylcarbamyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, N-cyclohexylcarbamoyl, N-phenylcarbamoyl, N-methyl-N-phenylcarbamoyl, N,N-dimethylcarbamoyl, N-benzylcarbamoyl or 4-morpholinocarbonyl.

### Claim 10 (depends on 4)

The taxane of claim 4 wherein X.sub.5 is t-butylcarbamoyl.

### Claim 11 (depends on 1)

A pharmaceutical composition which contains the taxane of claim 1 and one or more pharmacologically acceptable, inert or physiologically active diluents or adjuvants.

### Claim 12

A taxane having the formula ##STR48## wherein X.sub.1 is --OX.sub.6, --SX.sub.7, or --NX.sub.8 X.sub.9 ;
X.sub.2 is hydrogen; substituted, unsubstituted, straight, branch chained or cyclic alkyl; substituted, unsubstituted, straight or branch chained alkenyl or alkynyl; or substituted or unsubstituted aryl or heteroaryl;
X.sub.3 and X.sub.4 are independently hydrogen; substituted, unsubstituted, straight, branch chained or cyclic alkyl; substituted, unsubstituted, straight or branch chained alkenyl or alkynyl; or substituted or unsubstituted aryl or heteroaryl;
X.sub.5 is --CONX.sub.8 X.sub.10 ;
X.sub.6 is hydrogen; substituted, unsubstituted, straight, branch chained or cyclic alkyl; substituted, unsubstituted, straight or branch chained alkenyl or alkynyl; substituted or unsubstituted aryl or heteroaryl; or hydroxy protecting group;
X.sub.7 is substituted, unsubstituted, straight, branch chained or cyclic alkyl; substituted, unsubstituted, straight or branch chained alkenyl or alkynyl; substituted or unsubstituted aryl or heteroaryl; or sulfhydryl protecting group;
X.sub.8 is hydrogen; substituted, unsubstituted, straight, branch chained or cyclic alkyl; substituted, unsubstituted, straight or branch chained alkenyl or alkynyl; or substituted or unsubstituted aryl or heteroaryl;
X.sub.9 is an amino protecting group;
X.sub.10 is substituted, unsubstituted, straight or branch chained alkenyl or alkynyl; substituted or unsubstituted aryl or heteroaryl; or alkyl, wherein said alkyl is substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, cyclobutyl, pentyl or hexyl;
R.sub.1 is hydroxy, protected hydroxy or together with R.sub.14 forms a carbonate;
R.sub.2 is hydroxy or --OCOR.sub.31 ;
R.sub.4a is hydrogen; substituted, unsubstituted, straight, branch chained or cyclic alkyl; substituted, unsubstituted, straight or branch chained alkenyl or alkynyl; substituted or unsubstituted aryl or heteroaryl; cyano; hydroxy; or --OCOR.sub.30 ;
R.sub.7a is hydrogen, halogen, or --OR.sub.28 ;
R.sub.9 is hydrogen or together with R.sub.9a forms an oxo;
R.sub.9a is hydrogen, hydroxy, protected hydroxy, acyloxy, or together with R.sub.9 forms an oxo;
R.sub.10 is hydrogen or together with R.sub.10a forms an oxo,
R.sub.10a is hydrogen, --OCOR.sub.29, hydroxy, or protected hydroxy, or together with R.sub.10 forms an oxo;
R.sub.14 is hydrogen, hydroxy, protected hydroxy or together with R.sub.1 forms a carbonate;
R.sub.28 is hydrogen, acyl, or hydroxy protecting group; and
R.sub.29, R.sub.30, and R.sub.31 are independently hydrogen; substituted, unsubstituted, straight, branch chained or cyclic alkyl; substituted, unsubstituted, straight or branch chained alkenyl or alkynyl; or substituted or unsubstituted monocyclic aryl or monocyclic heteroaryl.

### Claim 13 (depends on 12)

The taxane of claim 12 wherein X.sub.8 is hydrogen and X.sub.10 is alkyl, said alkyl being substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, cyclobutyl, pentyl or hexyl.

### Claim 14 (depends on 13)

The taxane of claim 13 wherein X.sub.2 is --OX.sub.6 ; X.sub.3 is substituted, unsubstituted, straight, branch chained or cyclic alkyl; substituted, unsubstituted, straight or branch chained alkenyl; or substituted or unsubstituted aryl or heteroaryl; X.sub.4 is hydrogen; and X.sub.6 is hydrogen or hydroxy protecting group.

### Claim 15 (depends on 14)

The taxane of claim 14 wherein
R.sub.2 is --OCOR.sub.31 ;
R.sub.4a is --OCOR.sub.30 ;
R.sub.10a is --OCOR.sub.29
R.sub.29 and R.sub.30 are substituted, unsubstituted, straight, branch chained or cyclic alkyl; and
R.sub.31 is substituted or unsubstituted monocyclic aryl or monocyclic heteroaryl.

### Claim 16 (depends on 12)

The taxane of claim 12 wherein X.sub.10 is substituted or unsubstituted ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, or cyclobutyl.

### Claim 17 (depends on 12)

The taxane of claim 12 wherein X.sub.10 is substituted ethyl, n-propyl, isopropyl or cyclopropyl.

### Claim 18 (depends on 12)

The taxane of claim 12 wherein X.sub.5 is dimethylcarbamyl, diethylcarbamyl, diphenylcarbamyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, N-cyclohexylcarbamoyl, N-phenylcarbamoyl, N-methyl-N-phenylcarbamoyl, N,N-dimethylcarbamoyl, N-benzylcarbamoyl or 4-morpholinocarbonyl.

### Claim 19 (depends on 12)

A pharmaceutical composition which contains the taxane of claim 12 and one or more pharmacologically acceptable, inert or physiologically active diluents or adjuvants.

### Claim 20

A taxane having the formula ##STR49## wherein X.sub.1 is --OX.sub.6, --SX.sub.7, or --NX.sub.8 X.sub.9 ;
X.sub.2 is hydrogen; substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; or substituted or unsubstituted aryl or heteroaryl;
X.sub.3 and X.sub.4 are independently hydrogen; substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; substituted or unsubstituted heteroaryl; or substituted aryl;
X.sub.5 is --CONX.sub.8 X.sub.10 ;
X.sub.6 is hydrogen; substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; substituted or unsubstituted aryl or heteroaryl; or hydroxy protecting group;
X.sub.7 is substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; substituted or unsubstituted aryl or heteroaryl; or sulfhydryl protecting group;
X.sub.8 is hydrogen; substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; or substituted or unsubstituted aryl or heteroaryl;
X.sub.9 is an amino protecting group;
X.sub.10 is substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; or substituted or unsubstituted aryl or heteroaryl;
R.sub.1 is hydroxy, protected hydroxy or together with R.sub.14 forms a carbonate;
R.sub.2 is hydroxy or --OCOR.sub.31 ;
R.sub.4a is hydrogen; substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; substituted or unsubstituted aryl or heteroaryl; cyano; hydroxy; or --OCOR.sub.30 ;
R.sub.7a is hydrogen, halogen, or --OR.sub.28 ;
R.sub.9 is hydrogen or together with R.sub.9a forms an oxo;
R.sub.9a is hydrogen, hydroxy, protected hydroxy, acyloxy, or together with R.sub.9 forms an oxo;
R.sub.10 is hydrogen or together with R.sub.10a forms an oxo,
R.sub.10a is hydrogen, --OCOR.sub.29, hydroxy, or protected hydroxy, or together with R.sub.10 forms an oxo;
R.sub.14 is hydrogen, hydroxy, protected hydroxy or together with R.sub.1 forms a carbonate;
R.sub.28 is hydrogen, acyl, or hydroxy protecting group; and
R.sub.29, R.sub.30, and R.sub.31 are independently hydrogen; substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; or substituted or unsubstituted monocyclic aryl or monocyclic heteroaryl.

### Claim 21 (depends on 20)

The taxane of claim 20 wherein X.sub.8 is hydrogen and X.sub.10 is substituted, unsubstituted, straight, branched chain or cyclic alkyl.

### Claim 22 (depends on 21)

The taxane of claim 21 wherein X.sub.2 is --OX.sub.6 ; X.sub.3 is substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl; substituted or unsubstituted heteroaryl; or substituted aryl; X.sub.4 is hydrogen; and X.sub.6 is hydrogen or hydroxy protecting group.

### Claim 23 (depends on 22)

The taxane of claim 22 wherein
R.sub.2 is --OCOR.sub.31 ;
R.sub.4a is --OCOR.sub.30 ;
R.sub.10a is --OCOR.sub.29
R.sub.29 and R.sub.30 are substituted, unsubstituted, straight, branched chain or cyclic alkyl; and
R.sub.31 is substituted or unsubstituted monocyclic aryl or monocyclic heteroaryl.

### Claim 24 (depends on 20)

The taxane of claim 20 wherein X.sub.10 is substituted or unsubstituted ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, sec-butyl or cyclobutyl.

### Claim 25 (depends on 20)

The taxane of claim 20 wherein X.sub.5 is dimethylcarbamyl, diethylcarbamyl, diphenylcarbamyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, N-cyclohexylcarbamoyl, N-phenylcarbamoyl, N-methyl-N-phenylcarbamoyl, N,N-dimethylcarbamoyl, N-benzylcarbamoyl or 4-morpholinocarbonyl.

### Claim 26 (depends on 20)

The taxane of claim 20 wherein X.sub.5 is t-butyl carbamoyl.

### Claim 27 (depends on 20)

A pharmaceutical composition which contains the taxane of claim 20 and one or more pharmacologically acceptable, inert or physiologically active diluents or adjuvants.

### Claim 28

A taxane having the formula ##STR50## wherein X.sub.3 is hydrogen; substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; substituted or unsubstituted aryl or heteroaryl;
X.sub.5 is --CONX.sub.8 X.sub.10 ;
X.sub.8 is hydrogen; substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; or substituted or unsubstituted aryl or heteroaryl;
X.sub.10 is substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl or alkynyl; or substituted or unsubstituted aryl or heteroaryl.

### Claim 29 (depends on 28)

The taxane of claim 28 wherein X.sub.8 is hydrogen and X.sub.10 is substituted, unsubstituted, straight, branched chain or cyclic alkyl.

### Claim 30 (depends on 29)

The taxane of claim 29 wherein X.sub.3 is substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl; substituted or unsubstituted heteroaryl; or substituted aryl.

### Claim 31 (depends on 28)

The taxane of claim 28 wherein X.sub.10 is substituted or unsubstituted ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, isobutyl, sec-butyl or cyclobutyl.

### Claim 32 (depends on 28)

The taxane of claim 28 wherein X.sub.5 is dimethylcarbamyl, diethylcarbamyl, diphenylcarbamyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, N-cyclohexylcarbamoyl, N-phenylcarbamoyl, N-methyl-N-phenylcarbamoyl, N,N-dimethylcarbamoyl, N-benzylcarbamoyl or 4-morpholinocarbonyl.

### Claim 33 (depends on 32)

The taxane of claim 32 wherein X.sub.3 is substituted, unsubstituted, straight, branched chain or cyclic alkyl; substituted, unsubstituted, straight or branched chain alkenyl; substituted or unsubstituted heteroaryl; or substituted aryl.

### Claim 34 (depends on 28)

The taxane of claim 28 wherein X.sub.5 is t-butylcarbamoyl.