WO1994000126A1

WO1994000126A1 - The use of bile acids as antiviral agents

Info

Publication number: WO1994000126A1
Application number: PCT/EP1993/001507
Authority: WO
Inventors: Fabio Berlati; Giancarlo Ceschel; Carlo Clerici; Roberto Pellicciari; Aldo Roda; Celestino Ronchi
Original assignee: Montefarmaco S.P.A.
Priority date: 1992-06-30
Filing date: 1993-06-15
Publication date: 1994-01-06
Also published as: IT1255450B; ITMI921602A0; ITMI921602A1

Abstract

The use of bile acids and the sulfate derivatives thereof as antiviral agents, and a method for the use thereof in the treatment of herpetic diseases.

Description

THE USE OF BILE ACIDS AS ANTIVIRAL AGENTS

The present invention relates to the use of bile acids as antiviral agents.

Particularly, the present invention relates to the use of bile acids having the following general formula

(I)

0

H q) OH H H H H OH, and R_? is always OH.

Said compounds are known and they respectively correspond to Cholic acid (I, a) ϋrsocholic acid (I, b)

Iocholic acid (I, c)

Chenodeoxycholic acid (I, d) ϋrsodeoxycholic acid (I, e) Iodeoxycholic acid (I, f)

12-Ketochenodeoxycholic acid (I, g)

12-Ketoursodeoxycholic acid (I, h)

23-Hydroxyursodeoxycholic acid (I, i)

Lithocholic acid (I, 1) 7-Ketolithocholic acid (I, m)

7-Ketodeoxycholic acid (I, n)

7 -Hydroxycholanoic acid (I, o)

7 -Hydroxycholansulfate acid (I, p)

23-Hydroxylithocholic acid (I, q) . The use of bile acids also comprises the derivatives thereof with a sulfate group in R. or R , two sulfate groups in R_χ, R₃ or R₄, a sulfate group in

R-. and an aminoethylsulfate group in R₇, the tauro- conjugated (aminoethanesulfonates) , the glyco- conjugated and the pharmaceutically acceptable salts thereof.

The viral infections remarkably increased in recent times.

These infectious agents are still nowadays a clinical-therapeutical problem. In fact, contrary to bacteria, viruses, as incomplete organisms, cannot exert a metabolic activity outside the host cell.

The virus classification thereof is still controversial and the most supported one is based on the kind of nucleic acid (DNA or RNA) contained, on the structural characteristics of the capside, on the envelope and on other chemical and structural properties.

--, Recently, more than 80 herpes viruses were recovered from different animal species [Nahmias A J. in: Viruses, Evolution and Cancer (Maramorosch K. , and Kurstak E.) Academic Press, New York, p. 605 (1974)].

The characteristics distinguishing them are the following: core, consisting of DNA - cubic symmetry of the capside^~ presence of an outer envelope deriving from the nuclear membrane of the host cell in which the virus multiplies.

Whereas the main part of viruses cause infections with a poor number of relapses which, in some cases, are due to antigenic variant of the same virus, on the contrary the herpes ones establish a latent infection with a subsequent reactivation time.

After the primary infection (first contact with the patient) in a peripheral site, the virus follows the ascendent way through nerves and localizes in the neurons of ganglia, srherein it remains all life long in a latent form.

With a still poorly known mechanism, the herpes virus, after being reactivated in the ganglial

(sensorial) cells, travels through the axons and localizes in a peripheral site.

In this step, the virus can appear clinically (latency-reactivation recurrence cycle) or not.

Only four of the large family of herpes virus are responsible for human infections:

- Herpes simplex type 1 and 2

- Varicella-Zoster

- Cytomegalovirus

- Epstein-Barr virus The virus, once come into contact with the cell membrane of the host cell wherein specific receptorial sites are located, penetrates inside the cell by means, of a phagocytosis mechanism.

Once the virus is inside, the viral genoma is released from the protein envelope with synthesis of the m-RNA necessary to form the precocious proteins, among which are some enzymes important for the duplication of the viral DNA.

Moreover, viral proteins are synthesized which constitute the capside and subsequently the assembly of the viral particles and the viral outer coating consisting of the cell membrane of the host cell takes place.

From what described above, it is evident the difficulty to obtain antiviral medicaments not interfering with the cell metabolism, since the virus for its replication uses enzymes mainly coming from the host cell.

At present, the therapeutical opportunities offered in the herpes simplex viral infections consist of antiviral medicaments either counteracting the absorption process of the viruses in the healthy cells or inhibiting the replication at the intracellular level, or in products with immunological activity in order to enhance the immune system. Now it has been found that bile acids, known therapeutical agents in the gastrointestinal and hepatic fields, have surprising antiviral properties in vivo.

Some bile acids are known to be active in vitro against the HIV-1 virus (G. LLoyd et al. , The Lancet, June, 25, 1988). Up to now, no antiviral activities have been described iri vivo for bile acids and the conjugated derivatives thereof.

According to the present invention, a clinical study was performed about the treatment of herpes affections with chenodeoxycholic acid.

A cream containing 5% active principle, consisting of chenodeoxycholic acid (CDCA) , was applied to mucocutaneous lesions of the erythematous (n^β 20) and vescicular (n° 57) kind caused by Herpes Simplex Type 1 (oro-labial) and only 5 by Herpes Simplex Type II.

The cream was applied on the lesion area about 4 times a day at 6 hour intervals.

The 20 patients at the erythematous step of the disease, after administration of the cream, showed no evolution of the disease, whereas the 50 patients with vescicular lesions showed formation of crust and healing of the lesion 2-3 days after the administration of the substance. The therapy caused no benefits in only 7 patients with herpetic lesions at the vescicular step and said lesions spontaneously healed after 10-14 days.

In about 50% of the patients, the recurrence time of the relapse markedly increased and in 10 patients no relapses appeared even after 1 year. The active principles will be formulated in topical preparations suitable for the envisaged therapeutic treatment. Particularly, creams, ointments, solutions, suspensions, dusting powders, labial sticks and the like are provided, containing 0.1 to 20% w/w, preferably 1 to 20%, of the active principle.

The topical compositions are prepared according to conventional techniques, for example as described in "Remington's Pharmaceutical Sciences Handbook" Mack Pub. Co. N.Y. USA XVII Ed. The following examples illustrate the invention.

EXAMPLE 1

Claims

1. The use of bile acids of general formula (I)

0

H

R₇ is OH, the derivatives thereof with a sulfate group in R.^ or R3, two sulfate groups in R-^, R₃ or R, , a sulfate group in R, and an or aminoethylsulfate group in R _t the tauro-conjugated (aminoethanesulfonates) , the glyco-conjugated and the pharmaceutically acceptable salts thereof, as antiviral agents.

2. The use of bile acids according to claim 1 as agents against Herpes simplex Type 1 and 2, Varicella- Zoster, Cytomegalovirus, Epstein-Barr virus.

3. The use of bile acids of the claim 1, for the preparation of a medicament having antiviral action.

4. The use of bile acids according to claim 3, for the preparation of a medicament useful for the treatment of diseases caused by Herpes simplex Type 1 and 2, Varicella-Zoster, Cytomegalovirus, Epstein-Barr virus.

5. Topical pharmaceutical compositions containing from 0.1 to 20% of a compound of claim 1 as the antiviral agent.

6. Pharmaceutical compositions of claim 5 in form of creams, ointments, solutions, suspensions, dusting powders, labial sticks.