# US 2014/0155336 A1 · Water-soluble camptothecin derivative, pharmaceutical composition and use thereof

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- Number: US 2014/0155336 A1
- Document ID: US20140155336A1
- Status: Published application
- Kind: A1
- Application number: 14/235,158
- Filed: 2011-07-27
- Published: 2014-06-05
- Earliest claimed: 2011-07-27
- Assignees: Hunan Fangshenghuamei Medical Tech. Co. Ltd.
- Inventors: Wenqiang Zhou; Jing Deng
- Web page: https://patentgrep.com/patent/US20140155336A1

## CPC

- C07H 15/26: Acyclic or carbocyclic radicals, substituted by hetero rings
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07F 9/6561: containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- 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 11/04: Phosphates; Phosphites; Polyphosphates
- C07H 19/10: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H 19/207: the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
- 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)
- 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
- 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

The present invention relates to a water soluble derivative of camptothecin and preparation method thereof, the derivative having a structure of formula I and being appropriate in water solubility, and having anti-cancer activity and stability of lactonic ring. The present invention also relates to a method for synthesizing the compound and medical use of the compound.

## Claims

### Claim 1

A water-soluble camptothecin derivative, comprising
a compound of Formula I
and pharmaceutically acceptable salts thereof:
wherein M represents hydroxyl or thiol, A represents ribose or deoxyribose or ribose derivative and is attached to a phosphorus atom via an oxygen of an hydroxyl group

### Claim 2 (depends on 1)

The camptothecin derivative of claim 1, wherein A is a nucleoside or nucleoside analog wherein one or more hydrogen atoms in carbon-hydrogen bonds, nitrogen-hydrogen bonds, or hydroxyl group of a pentose and/or a nucleobase are substituted; or A is a nucleoside analog that contains a nucleobase derivative, wherein the nucleobase derivative is a heteroaryl or heteroalicyclic group other than adenine, thymine, cytosine or guanine, having 1 to 3 mono-cyclic rings and 1 to 3 N, O or S atoms.

### Claim 3

A camptothecin derivative comprising a chemical structure of Formula II:
wherein R1 represents hydrogen, C1-C4 acyl, or an enzymatically reactive moiety;
R2 and R3 are the same or different, and independently represents hydrogen, halo, hydroxyl, alkoxy group, or an enzymatically reactive moiety;
B is hydrogen, optionally substituted thymine, optionally substituted adenine, optionally substituted cytosine, optionally substituted guanine, optionally substituted uracil, 5-fluorouricil, 5-aza-cytosine, 2-fluoroadenine, 2-chloroadenine, or 3,4,7,8-tetrahydroimidazo[1,3]-diazepin-8-ol; or
B is a heteroaromatic or heteroalicyclic group other than adenine, thymidine, cytosine or guanine and preferably has from 1 to 3 mono-cyclic or fused-rings and 1 to 3 N, O or S atoms.

### Claim 4 (depends on 3)

The camptothecin derivative of claim 3, wherein B is a substituted thymine, substituted adenine, substituted uracil, substituted cytosine, or substituted guanine, wherein the substitution group is alkyl, aryl, heteroaryl or heteroalicyclic group, wherein the heteroaryl or heteroalicyclic group has from 1 to 3 mono-cyclic or fused-rings and 1 to 3 N, O or S atoms.

### Claim 5 (depends on 3)

The camptothecin derivative of claim 3, wherein R1 is C1-C4 acyl.

### Claim 6 (depends on 5)

The camptothecin derivative of claim 5, wherein R1 is acetyl.

### Claim 7 (depends on 3)

The camptothecin derivative of claim 3, wherein R1=R3=H, R2=OH, B=hydrogen, thymine, adenine, cytosine, guanine, uracil, or 5-aza-cytosine.

### Claim 8 (depends on 3)

The camptothecin derivative of claim 3, wherein R1=Ac, R2=R3=H, B=hydrogen, thymine, adenine, cytosine, guanine, uracil, 5-aza-thymine, or 2-chloroadenine, wherein one hydrogen in an amino group is substituted with an acetyl group.

### Claim 9 (depends on 3)

The camptothecin derivative of claim 3, wherein R1=Ac, R2=F, R3=H, B=2-chloroadenine, wherein one hydrogen of an amino group is substituted with acetyl.

### Claim 10 (depends on 3)

The camptothecin derivative of claim 3, wherein R1=Ac, R2=H, R3=OAc, B=2-fluoadenine, wherein one hydrogen of an amino group is substituted with acetyl.

### Claim 11 (depends on 3)

The camptothecin derivative of claim 3, wherein R1=Ac, R3=H, R2=OAc, B=hydrogen, thymine, adenine, cytosine, guanine, uracil, 5-aza-cytosine, wherein one hydrogen of an amino group is substituted with acetyl.

### Claim 12 (depends on 3)

The camptothecin derivative of claim 3, wherein a combination of R1, R2, R3, and B is selected from a group consisted of combinations 1 to 21 listed in the following table 6:
Combination #
R1
R2
R3
B
1
H
H
H
5-fluouracil
2
H
F
F
cytosine
3
H
H
H
5-aza-cytosine
4
H
H
H
2-chloroadenine
5
H
H
H
3,4,7,8-
tetrahydroimidazo[1,3]diazepin-
8-ol
6
H
H
H
adenine
7
H
H
H
thymine
8
H
H
H
cytosine
9
H
H
H
guanine
10
H
H
H
H
11
H
H
H
uracil
12
H
H
H
2-fluoroadenine
13
H
H
OH
2-fluoroadenine
14
H
F
H
2-chloroadenine
15
H
OH
H
thymine
16
H
OH
H
adenine
17
H
OH
H
cytosine
18
H
OH
H
guanine
19
H
OH
H
H
20
H
OH
H
5-aza-cytosine
21
Ac
H
H
5-fluouracil

### Claim 13 (depends on 3)

A method of preparing the compound of claim 3, comprising the following steps:
(1) reacting PCl3 with an azole of RH, producing a phosphine triamine reagent of Formula IV :
wherein, R is
(2) reacting the phosphine triamine reagent of Formula IV with a CPT, producing a CPT 20 (S)—O-phosphoramidite mono-ester intermediate of Formula V:
(3) reacting the CPT 20 (S)—O-phosphoramidite intermediate of Formula V with the suitably protected compound of Formula III, producing 20 (S)—O-phosphoramidite di-ester precursor of Formula VI:
wherein,
R1 represents H, C1-C4 acyl, or an enzymatically reactive moiety;
R2 and R3 are the same or different, and independently represents hydrogen, halo, hydroxyl, alkoxy, or an enzymatically reactive moiety;
B is hydrogen, an optionally substituted thymine, optionally substituted adenine, optionally substituted cytosine, optionally substituted guanine, optionally substituted uracil, 5-fluorouricil, 5-aza-cytosine, 2-fluoroadenine, 2-chloroadenine, or 3,4,7,8-tetrahydroimidazo[1,3]diazepin-8-ol; or a heteroaromatic or heteroalicyclic group other than adenine, thymidine, cytosine or guanine, and has from 1 to 3 mono- or fused-rings and 1 to 3 N, O or S atoms; and
(4) hydrolyzing the 20 (S)—O-phosphoramidite di-ester precursor of Formula VI, followed by oxidation and ammonolysis to remove the protecting group, producing the CPT 20 (S)—O-nucleotide CPT derivative of Formula II; and
(5) optionally, converting the compound of Formula II to a corresponding salt.

### Claim 14 (depends on 1)

A pharmaceutical formulation, comprising at least one camptothecin derivative of claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 15 (depends on 14)

The method of using the formulation of claim 14 for treatment of cancer, wherein said cancer is lung cancer, breast cancer, colon cancer, prostate cancer, melanoma, pancreas cancer, stomach cancer, liver cancer, brain cancer, kidney cancer, uterus cancer, cervix cancer, ovaries cancer, urinary track cancer, gastrointestinal cancer, leukemia, small cell lung cancer, solid tumor or blood borne tumor.

### Claim 16 (depends on 15)

The method of claim 15, wherein said cancer is small cell lung cancer.

### Claim 17 (depends on 15)

The method of claim 15, wherein said cancer is colon cancer.

### Claim 18 (depends on 13)

The method of claim 13, wherein during step (3), R1 in the CPT 20 (S)—O-phosphoramidite intermediate of Formula V is hydrogen, and the hydrogen is substituted with a suitable protecting group before reacting with the compound of Formula III.

### Claim 19 (depends on 13)

The method of claim 13, wherein during step (3), R2 or R3 in the CPT 20 (S)—O-phosphoramidite intermediate of Formula V is hydroxyl, and the hydroxyl group is suitably protected before reacting with the compound of Formula III.

### Claim 20 (depends on 13)

The method of claim 13, wherein during step (3), B in the CPT 20 (S)—O-phosphoramidite intermediate of Formula V contains amino, and the amino group is suitably protected before reacting with the compound of Formula III.