Therapeutic nucleosides

Details Therapeutic nucleosides Therapeutic nucleosides

1998-07-10

2002-05-21

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

Reexamination Certificate

active

06392085

ABSTRACT:

The present invention relates to purine nucleoside analogues containing a carbocyclic ring in place of the sugar residue, pharmaceutically acceptable derivatives thereof, and their use in medical therapy, particularly for the treatment of certain viral infections.
Hepatitis B virus (HBV) is a small DNA containing virus which infects humans. It is a member of the class of closely related viruses known as the hepadnaviruses, each member of which selectively infects either mammalian or avian hosts, such as the woodchuck and the duck.
Worldwide, HBV is a viral pathogen of major consequence. It is most common in Asian countries, and prevalent in sub-Saharan Africa. The virus is etiologically associated with primary hepatocellular carcinoma and is thought to cause 80% of the world's liver cancer. In the United States more than ten thousand people are hospitalized for HBV illness each year, an average of 250 die with fulminant disease.
The United States currently contains an estimated pool of 500,000-1 million infectious carriers. Chronic active hepatitis will develop in over 25% of carriers, and often progresses to cirrhosis. It is estimated that 5000 people die from HBV-related cirrhosis each year in the USA, and that perhaps 1000 die from HBV-related liver cancer. Even when a universal HBV vaccine is in place, the need for effective anti-HBV compounds will continue. The large reservoir of persistently infected carriers, estimated at 220 million worldwide, will receive no benefit from vaccination and will continue at high risk for HBV-induced liver disease. This carrier population serves as the source of infection of susceptible individuals perpetuating the instance of disease particularly in endemic areas or high risk groups such as IV drug abusers and homosexuals. Thus, there is a great need for effective antiviral agents, both to control the chronic infection and reduce progression to hepatocellular carcinoma.
Clinical effects of infection with HBV range from headache, fever, malaise, nausea, vomiting, anorexia and abdominal pains. Replication of the virus is usually controlled by the immune response, with a course of recovery lasting weeks or months in humans, but infection may be more severe leading to persistent chronic liver disease as outlined above. In “Viral Infections of Humans” (second edition, Ed., Evans, A. S. (1982) Plenum Publishing Corporation, New York), Chapter 12 describes in detail the etiology of viral hepatitis infections.
Of the DNA viruses, the herpes group is the source of many common viral illnesses in man. The group includes cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), herpes simplex virus (HSV) and human herpes virus 6 (HHV6).
In common with other herpes viruses, infection with CMV leads to a life-long association of virus and host and, following a primary infection, virus may be shed for a number of years. Clinical effects range from death and gross disease (microcephaly, hepatosplenemegaly, jaundice, mental retardation) through failure to thrive, susceptibility to chest and ear infections to a lack of any obvious ill effect. CMV infection in AIDS patients is a predominant cause of morbidity as, in 40 to 80% of the adult population, it is present in a latent form and can be reactivated in immunocompromised patients.
EBV causes infectious mononucleosis and isalso suggested as the causative agent of nasopharyngeal cancer, immunoblastic lymphoma, Burkitt's lymphoma and hairy leukoplakia.
VZV causes chicken pox and shingles. Chicken pox is the primary disease produced in a host without immunity. In young children, it is usually a mild illness characterized by a vesicular rash and fever. Shingles is the recurrent form of the disease which occurs in adults who were previously infected with varicella. The clinical manifestations of shingles include neuralgia and a vesicular skin rash that is unilateral and dermatomal in distribution. Spread of inflammation may lead to paralysis or convulsionsand coma can occur if the meninges becomes affected. In immunodeficient patients, VZV may disseminate causing serious or even fatal illness.
HSV 1 and HSV 2 are some of the most common infectious agents of man. Most of these viruses are able to persist in the host's neural cells. Once infected, individuals are at risk of recurrent clinical manifestation of infection which can be both physically and psychologically distressing. HSV infection is often characterized by extensive lesions of the skin, mouth and/or genitals. Primary infections may be subclinical although they tend to be more severe than infections in individuals previously exposed to the virus. Ocular infections by HSV can lead to keratitis or cataracts. Infection in the newborn, in immunocompromised patients or penetration of infection into the central nervous system can prove fatal. HHV6 is the causative agent of roseola infantum (exanthum subitum) in children which is characterized by fever and the appearance of a rash after the fever has dedined. HHV6 has also been implicated in syndromes of fever and/or rash and pneumonia or hapatitis in immunocompromised patients.
It has been reported thatthe carbocyclic anaiogue of 2′-deoxyguanosine (2′-CDG) i.e. (1R*, 3S*, 4R)-2-amino-1,9-dihydro-9-[3-hydroxy-4-hydroxymethyl)cyclopentyl]-6H-purine-6-one, is active against several viruses. Thus in Proc. Natl. Acad. Sci. USA 1989, Vol. 86, pp 8541-8544, it is disclosed that 2′-CDG inhibits hepatitis B viral replication. 1. Med. Chem (1987) 30, pp 746-749 and Biochemical Pharmacology (1990) Vol. 40, No. 7, pp 1515-1522, report 2′-CDG, especially the (+)-enantiomer, as active against herpes simplex virus type 1 (HSV-1). Furthermore 2′-CDG and general analogues thereof are disclosed together with a plurality of other compounds in the following patent publications: U.S. Pat. No. 4,543,255 (with reference to HSV 1 and 2), PCT 90/06671 (with reference to hepatitis B), EP 219838, PCT 91/13549 (with reference to cytomegalovirus (CMV)). Other publication relating to 2′-CDG and the preparation thereof are J. Med. Chem. (1984) 27, pp 1416-1421, and J. Chem. Soc. Chem. Commun. (1987) pp 1083-1084.
It has now been discovered that certain analogues of 2′-CDG as referred to below, are useful for the treatment or prophylaxis of certain viral infections. According to a first aspect of the present invention, novel compounds of the formula (I) are provided:
wherein R
1
represents
hydrogen;
C
3-8
alkenyloxy; C
3-8
cycloalkoxy (e.g. cyclopentoxy); C
4-8
cycloalkenyloxy (e.g. cyclopenten-3-yloxy); aryloxy (e.g. phenoxy) or arylalkoxy (e.g. benzyloxy) in which the aryl may be substituted with one or more C
1-4
alkyl, halogen, hydroxy, C
1-4
alkoxy, amino or nitro;
C
3-6
alkenylthio (e.g. allylthio); C
3-6
cycloalkenylthio; C
4-8
cycloalkenylthio; arylthio (e.g. phenyithio) or arylalkylthio (e.g. benzylthio) in which the aryl may be substituted with one or more C
1-4
alkyl, halogen, hydroxy, C
1-4
alkoxy, amino or nitro;
an amino group, —NR
2
R
3
, in wnich R
2
and R
3
may be the same or different and are independently selected from hydrogen; C
1-8
alkyl; C
1-6
alkoxy; C
1-6
hydroxyalkyl (e.g. hydroxyethyl); C
1-6
alkoxyalkyl (e.g. methoxyethyl); C
3-7
cycloalkyl (e.g. cyclopropyl, cyclobutyl or cyctopentyl) in which the cycloalkyl may be substituted by one or more C
1-6
alkyl or hydroxy; aryl (e.g. phenyl) or aralkyl (e.g. benzyl) in which the aryl may be substituted with one or more C
1-4
alkyl, halogen, hydroxy, C
1-4
alkoxy, amino or nitro; C
3-6
alkenyl (e.g. allyl); or R
2
and R
3
together form a 4- to 8-membered ring (e.g. azetidinyl or pyrrolidinyl); provided that R
2
and R
3
cannot both be hydrogen or both be C
1-8
alkyl;
4-morpholinyl, 1-piperazinyl or 1-pyrrallyl;
or a pharmaceutically acceptable derivative thereof.
It is to be understood that the present invention encompasses the particular enantiomers depicted in formula (I), including tautomers of the purine, alone and in combination with their mirr

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