# US 8,772,253 B2 · Aureolic acid derivatives, the method for preparation thereof and the uses

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- Number: US 8,772,253 B2
- Document ID: US8772253B2
- Status: Granted
- Kind: B2
- Application number: 13/384,816
- Filed: 2010-07-14
- Published: 2012-10-25
- Granted: 2014-07-08
- Earliest claimed: 2009-07-23
- Assignees: Entrechem, S.L.
- Applicants: Luz Elena Núñez González; Nuria Menéndez Sánchez; Javier González Sabin; Francisco Moris Varas; Beatriz García Fernández; Maria Pérez Solares; Alfredo Fernández Braña; Maria del Carmen Méndez Fernández; José Antonio Salas Fernández
- Inventors: Luz Elena Núñez González; Nuria Menéndez Sánchez; Javier González Sabin; Francisco Moris Varas; Beatriz García Fernández; Maria Pérez Solares; Alfredo Fernández Braña; Maria del Carmen Méndez Fernández; José Antonio Salas Fernández
- Web page: https://patentgrep.com/patent/US8772253B2

## CPC

- C07H 15/24: Condensed ring systems having three or more rings
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- 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

Aureolic acid derivatives, process for obtaining them and uses thereof. This invention provides a bacterial strain that produces compound belonging to the family of aureolic acids useful in the treatment of cancer or nervous system diseases.

## Claims

### Claim 1

Compound characterized by the formula VII:

### Claim 2 (depends on 1)

A method for treating a subject diagnosed with cancer, Paget's disease, neurological disorders, hypercalcemia or hypercalciuria, said method comprising administering to such subject a therapeutically effective amount of the compound of claim 1 or a salt or a pharmaceutically acceptable formulation thereof.

### Claim 3 (depends on 1)

A pharmaceutical composition comprising a compound according to the claim 1 or pharmaceutically acceptable salts thereof.

### Claim 4

The bacterial strain Streptomyces argillaceus ΔAH-W− (pMP3*BII), characterized by having the genes mtmA, mtmH y mtmW inactivated, and also by having an additional nucleic acid comprised in plasmid pMP3*BII, which encodes for enzymes involved in the biosynthesis of the sugar D-digitoxose.

### Claim 5 (depends on 4)

A process for obtaining the bacterial strain of claim 4, comprising the introduction of plasmid pMP3*BII in Streptomyces argillaceus ΔAH-W−.

### Claim 6 (depends on 4)

A process for obtaining an aureolic acid derivative characterized by the formula VII, said method comprising:
a. Incubating a bacterial strain of claim 4 in a suitable culture medium and
b. Isolating formula VII from the culture medium.

### Claim 7 (depends on 1)

A process for obtaining acylated derivatives of aureolic acid comprising a reaction of an aureolic acid according to claim 1 with an acylating agent in the presence of an enzyme.

### Claim 8 (depends on 7)

The process of claim 7, wherein the enzyme is a lipase.

### Claim 9 (depends on 8)

The process of claim 8, wherein the enzyme is the fraction A or B of the Candida antarctica lipase.

### Claim 10 (depends on 7)

The process of claim 7, wherein the enzyme is immobilized to a support.

### Claim 11 (depends on 10)

The process of claim 10, wherein the immobilizing support of lipase is an epoxyacrylic resin activated with decaoctyl groups.

### Claim 12 (depends on 7)

The process of claim 7, wherein the acylating agent is an ester, an anhydride or a carbonate.

### Claim 13 (depends on 12)

The process of claim 12, wherein the acylating agent is selected from a group consisting of vinyl acetate, trifluormethyl acetate, vinyl chloroacetate, vinyl propanoate, vinyl butanoate, acetonoxime levulinate, vinyl decanoate, vinyl dodecanoate, vinyl benzoate, vinyl crotonate, diallyl carbonate, allyl oxime carbonate, vinylene carbonate, succinic anhydride, vinyl adipate, and vinyl sorbate.

### Claim 14 (depends on 7)

The process of claim 7, wherein the reaction is carried out using the acylating agent itself as solvent.

### Claim 15 (depends on 7)

The process of claim 7, wherein the reaction is carried out using tetrahydrofuran as solvent if the acylating agent is a solid or the solubility of the aureolic acid in the acylating agent is low.