CA2108175A1 - Use of guanine derivative or a prodrug thereof in the treatment of hiv-1 infection - Google Patents
Use of guanine derivative or a prodrug thereof in the treatment of hiv-1 infectionInfo
- Publication number
- CA2108175A1 CA2108175A1 CA002108175A CA2108175A CA2108175A1 CA 2108175 A1 CA2108175 A1 CA 2108175A1 CA 002108175 A CA002108175 A CA 002108175A CA 2108175 A CA2108175 A CA 2108175A CA 2108175 A1 CA2108175 A1 CA 2108175A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- hiv
- treatment
- formula
- pro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
Abstract
A method of treatment of HIV-1 infections in mammals, which mammals are infected with herpesviruses, which method comprises the administration to the mammal in need of such treatment, an effective amount of a compound of formula (A) or a pro-drug, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.
Description
~o 92/18130 2 1 0 ~ ;1 7 5 PCI`/G892/00647 USE OF GU~NINE DERI\IATIvE OR A PRODRUG THEREOF IN THE TRE~TMENT OF
HIV-l INFECTION
This invention relates to a method of treatment of HIV-1 infection in humans and animals, and to the use of compounds s in the preparation of a medicament for use in the treatment of such infection.
EP-A-242482 ~Beecham Group p.l.c.) discloses BRL 44385, the compound of formula (A):
o N.~
HO(CH2)30 (A) and salts thereof, as antiviral agents.
Pro-drugs of the compound of formula ~A) disclosed EP-A-242482 are of formula (B):
X
<~ N~
HO(CH2 ) 30 - (B) and salts and derivatives thereof as defined under formula (A); wherein X is Cl_6 alkoxy, NH2 or hydrogen. Alternative pro-drugs are in the form of acetal derivatives of the side chain, described in EP-A-413544 (Beecham Group p.l.c.), 35 especially 2-amino-9-[3-(isopropoxymethoxy)propoxy)purine, which is ~L 557a^
.
WO92/18130 PCT/GB92/~K~7 ~,~a~ 2- ~`
The compound of formula (A~ and derivatives thereof have been described as useful i~ the treatment of infections caused by herpesviruses, such as herpes simplex type l, herpes simplex type 2, varicella-zoster and Epstein-Barr s viruses.
It has now been discovered that this compound has potential activity against the human immunodeficiency virus (HIV-l), in patients also infected with herpesviruses, and are O therefore of potential use in the treatment of HIV
infections in such patients.
This discovery is related to the ability oî the triphosphate derivative of BRL 44385 to inhibit the RNA-directed DNA
lS polymerase (reverse transcriptase) activity of human immunodeficiency virus type l ~HIV-l). The reverse transcriptase of HIV-l is a virus-encoded enzyme essential for the conversion of genomic RNA into proviral ds-DNA, and is therefore an excellent molecular target for antiviral 20 chemotherapy.
The ability of HIV to enter cells previously infected with herpesviruses is known (for example, B-lymphocytes infected with EBVl). The presence of both herpes and human 25 immunodeficiency viruses in the same cell has particular consequences.
1. BRL 44385 would be phosphorylated by herpes virus-encoded thymidine kinase leading to a high level of 30 BRL 44385 triphosphate. The triphosphate formed is not only an inhibitor of herpes DNA polymerase, but this work indicates that it also inhibits HIV reverse transcriptase.
HIV-l INFECTION
This invention relates to a method of treatment of HIV-1 infection in humans and animals, and to the use of compounds s in the preparation of a medicament for use in the treatment of such infection.
EP-A-242482 ~Beecham Group p.l.c.) discloses BRL 44385, the compound of formula (A):
o N.~
HO(CH2)30 (A) and salts thereof, as antiviral agents.
Pro-drugs of the compound of formula ~A) disclosed EP-A-242482 are of formula (B):
X
<~ N~
HO(CH2 ) 30 - (B) and salts and derivatives thereof as defined under formula (A); wherein X is Cl_6 alkoxy, NH2 or hydrogen. Alternative pro-drugs are in the form of acetal derivatives of the side chain, described in EP-A-413544 (Beecham Group p.l.c.), 35 especially 2-amino-9-[3-(isopropoxymethoxy)propoxy)purine, which is ~L 557a^
.
WO92/18130 PCT/GB92/~K~7 ~,~a~ 2- ~`
The compound of formula (A~ and derivatives thereof have been described as useful i~ the treatment of infections caused by herpesviruses, such as herpes simplex type l, herpes simplex type 2, varicella-zoster and Epstein-Barr s viruses.
It has now been discovered that this compound has potential activity against the human immunodeficiency virus (HIV-l), in patients also infected with herpesviruses, and are O therefore of potential use in the treatment of HIV
infections in such patients.
This discovery is related to the ability oî the triphosphate derivative of BRL 44385 to inhibit the RNA-directed DNA
lS polymerase (reverse transcriptase) activity of human immunodeficiency virus type l ~HIV-l). The reverse transcriptase of HIV-l is a virus-encoded enzyme essential for the conversion of genomic RNA into proviral ds-DNA, and is therefore an excellent molecular target for antiviral 20 chemotherapy.
The ability of HIV to enter cells previously infected with herpesviruses is known (for example, B-lymphocytes infected with EBVl). The presence of both herpes and human 25 immunodeficiency viruses in the same cell has particular consequences.
1. BRL 44385 would be phosphorylated by herpes virus-encoded thymidine kinase leading to a high level of 30 BRL 44385 triphosphate. The triphosphate formed is not only an inhibitor of herpes DNA polymerase, but this work indicates that it also inhibits HIV reverse transcriptase.
2. HIV replication may be enhanced by herpesvirus 35 transactivating factors. A product of HSV, ICP-4 (infected-cell protein) can increase the initiation of HIV
_ranscription.
. .
. . . ., .... ~ - .
. ' : :
.. ~, ~ ,. .. , . : , . . :
WO92/18130 ~ i PCT/GB92/~7 3. Double infection of herpesviruses and HIV may result in phenotypic mixing and the production of 'pseudotype' HIV
particles bearing herpesvirus envelope glycoproteins2. The packaging of HIV genomic RNA with HSV capsid proteins is 5 also believed to occur. Either situation may lead to the infection by HIV of CD4-negative, herpesvirus-permissible cells, previously not susceptible to entry of this virus.
This may also result in doubly-infected cells.
O Accordingly, the present invention provides a method of treatment of ~IV-l infections in mammals, including humans, which mammals are infected with herpesviruses, which method comprises the administration to the mammal in need of such treatment, an effective amount of a compound of formula (A):
~ N ~ N ~ ~H2 HO(cH2)3O
(A) 2s or a pro-drug, or a pharmaceutically acceptable salt, of either of the foregoing.
Examples of pro-drugs, pharmaceutically acceptable salts and derivatives are as described in the aforementioned European 30 Patent references, the subject matter of which are 0 incorporated herein by reference.
Particular pro-drugs of interest are as described in EP-A-413544.
3s WO92/18130 ~ PCT/GB92tOo~7 The compound of formula (A), pro-drugs, salts and derivatives may be prepared as described in the aforementioned European Patent references.
5 The compound may be administered by the oral route to humans and may be compounded in the form of syrup, tablets or capsule. When in the form of a tablet, any pharmaceutical carrier suitable for formulating such solid compositions may be used, for example magnesium stearate, starch, lactose, o glucose, rice, flour and chalk. The compound may also be in the form of an ingestible capsule, for example of gelatin, to contain the compound, or in the form of a syrup, a solution or a suspension. Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerine, saline and water 5 to which flavouring or colouring agents may be added to form syrups.
For parenteral administration, fluid unit dose forms are prepared containing the compound and a sterile vehicle. The 20 compound depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a 2s local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
30 Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is - ~
WO92/18130 '~ ~IQ~ 7 ~ PCT/GB92/00~7 ; -5-included in the composition to facilitate uniform distribution of the compound of the invention.
~referred parenteral formulatlons include aqueous s formulations uslng sterile water or normal saline.
As is common practice, the compositions will usually be accompanied by written or printed di~ections for use in the medical treatment concerned.
An amount effective to treat the virus infection depends on the nature and severity of the infection and the weight of the mammal.
l5 A suitable dosage unit might contain from 50mg to lg of active ingredient, for example lO0 to 500mg. Such doses may be administered l to 4 times a day or more usually 2 or 3 times a day. The effective dose of compound will, in general, be in the range of from 0.2 to 40mg per kilogram of 20 body wei~ht per day or, more usually, lO to 20 mg/kg per day.
The present invention also provides the use of a compound of formula (A) or a pro-drug, or a pharmaceutically acceptable 2s salt of either of the foregoing, in the preparation of a medicament for use in the treatment of HIV-l infections in mammals, including humans, which mammals are infected with herpesviruses.
30 Such treatment may be carried out in the manner as hereinbefore described.
The present invention further provides a pharmaceutical composition for use in the treatment of HIV-l infections ir.
3s mammals, including humans, infected with herpesviruses, WO92/18130 ~~ 6- PCT/GB92/~ ~7 which comprises an e~fective amount of a compound of formula (A) or a pro-drug, or a pharmaceutically acceptable salt of either of the foregoing, and a pharmaceutically acceptable carrier. Such compositions may be prepared in the manner as s hereinafter described.
The compound of formula (A~ and its prodrugs show a synergistic antiviral effect in conjunction with interferons; and treatment using combination products 0 comprising these two components for sequential or concomitant administration, by the same or different routes, are therefore within the ambit of the present invention.
It will be appreciated that the treatment of herpesvirus 5 infected patients may include prophylaxis of herpesvirus episode attacks (suppressive treatment). In patients with HSV infection only, suppressive treatment would probably only be given to those patients with frequent recurrences.
In contrast, the aforementioned finding in relation to HIV-20 1, indicates the need for continuous suppressive treatmentwith ~RL 44385 or a pro-drug to all HIV-1 infected patients with herpesvirus recurrences, particularly HSV-1, HSV-2 and VZV recurrences, even though these recurrences may be infrequent.
The compound of formula (A) and its prodrugs may also be administered in combination with other antiviral agents, especially anti-HIV agents such as AZT.
30 The following biochemical data illustrate the invention.
. . . .. , . .. :
.: .- : -- -:
. . .
` ~.
WO92~18130 ~ ~ ~ 7 3 PCT/GB92/~ ~7 BIOCHEMICAL DATA
Materials and Methods s Chemicals [3H]dGTP was purchased from Amersham International, Aylesbury, U.K. Template primers Poly (rC). p(dG)12 18 and Poly (dC)- P(dG)l2-l8 were obt from Pharmacia Ltd., Milton Xeynes, U.K. BRL 44385 triphosphate (BRL 44385-TP) was prepared in the laboratories o of SmithKline Beecham Pharmaceuticals, Great Burgh, United Kingdom.
Reverse transcriPtase Purified, E. coli expressed HIV-l reverse transcriptase (RT) was supplied by the Protein 15 Biochemistry Department of SmithKline Beecham Pharmaceuticals, Upper Merion, U.S.A. The enzyme was stored and diluted in a buffer containing 50mM Tris-HCl (pH 8.0), lOmM Hepes, llOmM NaCl, 5.7mM DTT, 0.3mM EDTA, 0.06% Triton X-100, 50% glycerol.
Assav for reverse transCriPtase activity The reaction mixture for the HIV-l RT assay contained in a volume of 120~1: 33mM Tris HCl (pH 8.0), lOOmM KCl, 3.3mM MgC12, 3.3mM
dithiothreitol, 0.2mM glutathione, 0.33mM EGTA (ethylene 2s glycol-bis-(~-aminoethyl ether) N,N-tetra acetic acid), 0.033% Triton X-100, 4.0~M [3H]dGTP (4.16 Ci/mmol, 16.7~Ci/ml) 0-50~M BRL 44385-TP, 0-3 A260 units/ml Poly (rC). p(dG)12_18 or Poly (dC)- P(dG)12-18 and 167ng/ml RT
(equivalent to 1.43nM for an equimolar mixture of p66 and 30 pSl polypeptides). The reaction mixtures without RT were prepared in the microwells of a 96-well plate and preincubated at 37C before the reactions were started by the addition of 20~1 of the enzyme solution. The plates were then incubated for 95-100 minutes at 37C. The 3s reactions were terminated by the addition of 40~1 of EDTA
WO92/18130 PCT/GB92/~ ~7 ~ '?~ 5 -8- ~^
solution (0.2M, pH6.5). The individual reaction mixtures were transferred to a DEAE filter mat (1205-405, LKB Wallac, Finland), prewetted with 0.3M NaCl/0.03M Na citrate, using a cell harvester (1295-001, LKB Wallac). The filter mat was s washed three times in the NaCl/Na citrate buffer and then once in 95% ethanol. Scintillation fluid (Beta Plate Scint, LKB Wallac) was added to the dried filter, and the reaction mixtures assayed for incorporation of radioactive dGMP in an LKB 1205 Beta Plate Liquid Scintillation Counter.
Results From the plot of % inhibition against concentration of inhibitor approximate IC50 values were obtained for 15 BRL 44385-TP as follows.
Experiment 1 y ( C). P(dG)12-18 temPlate - primer used:-IC50 BRL 44385-TP - 3.7~M.
Experiment 2 25 Poly (rC). ptdG)12-18 template - primer used:-IC50 BRL 44385-TP = l.9~M.
y (dC). p(dG)12-18 template - primer used:-IC50 BRL 44385-TP = 1.2~M.
', ~ .: , ~
WO92~18130 ~-~J~ PCT/GB92/~ ~7 " ,:~
_9_ Conclusion These results indicate that the concentration of BRL 44385 triphosphate required to give 50% inhibition of HIV-1 5 reverse transcriptase using a RNA template is in the range 1.9 - 3.7~M. When DNA was used as the template for the reverse transcriptase, the IC50 was 1.2~M. These levels of BRL 44385-TP should be obtained in the herpes-infected cell.
References 1. Complement Receptor 2 Mediates Enhancement of Human Immunodeficiency virus infection in Epstein-Barr virus-carrying B cells.
Tremblay et al., J. Exp. Med. 171, 1791 (1990).
20 2. Phenotypic mixing between human immunodeficiency virus and vesicular stomatitis virus or herpes simplex virus.
Zhu et al., J. of AIDS, 3, 215 (1990).
_ranscription.
. .
. . . ., .... ~ - .
. ' : :
.. ~, ~ ,. .. , . : , . . :
WO92/18130 ~ i PCT/GB92/~7 3. Double infection of herpesviruses and HIV may result in phenotypic mixing and the production of 'pseudotype' HIV
particles bearing herpesvirus envelope glycoproteins2. The packaging of HIV genomic RNA with HSV capsid proteins is 5 also believed to occur. Either situation may lead to the infection by HIV of CD4-negative, herpesvirus-permissible cells, previously not susceptible to entry of this virus.
This may also result in doubly-infected cells.
O Accordingly, the present invention provides a method of treatment of ~IV-l infections in mammals, including humans, which mammals are infected with herpesviruses, which method comprises the administration to the mammal in need of such treatment, an effective amount of a compound of formula (A):
~ N ~ N ~ ~H2 HO(cH2)3O
(A) 2s or a pro-drug, or a pharmaceutically acceptable salt, of either of the foregoing.
Examples of pro-drugs, pharmaceutically acceptable salts and derivatives are as described in the aforementioned European 30 Patent references, the subject matter of which are 0 incorporated herein by reference.
Particular pro-drugs of interest are as described in EP-A-413544.
3s WO92/18130 ~ PCT/GB92tOo~7 The compound of formula (A), pro-drugs, salts and derivatives may be prepared as described in the aforementioned European Patent references.
5 The compound may be administered by the oral route to humans and may be compounded in the form of syrup, tablets or capsule. When in the form of a tablet, any pharmaceutical carrier suitable for formulating such solid compositions may be used, for example magnesium stearate, starch, lactose, o glucose, rice, flour and chalk. The compound may also be in the form of an ingestible capsule, for example of gelatin, to contain the compound, or in the form of a syrup, a solution or a suspension. Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerine, saline and water 5 to which flavouring or colouring agents may be added to form syrups.
For parenteral administration, fluid unit dose forms are prepared containing the compound and a sterile vehicle. The 20 compound depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a 2s local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
30 Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is - ~
WO92/18130 '~ ~IQ~ 7 ~ PCT/GB92/00~7 ; -5-included in the composition to facilitate uniform distribution of the compound of the invention.
~referred parenteral formulatlons include aqueous s formulations uslng sterile water or normal saline.
As is common practice, the compositions will usually be accompanied by written or printed di~ections for use in the medical treatment concerned.
An amount effective to treat the virus infection depends on the nature and severity of the infection and the weight of the mammal.
l5 A suitable dosage unit might contain from 50mg to lg of active ingredient, for example lO0 to 500mg. Such doses may be administered l to 4 times a day or more usually 2 or 3 times a day. The effective dose of compound will, in general, be in the range of from 0.2 to 40mg per kilogram of 20 body wei~ht per day or, more usually, lO to 20 mg/kg per day.
The present invention also provides the use of a compound of formula (A) or a pro-drug, or a pharmaceutically acceptable 2s salt of either of the foregoing, in the preparation of a medicament for use in the treatment of HIV-l infections in mammals, including humans, which mammals are infected with herpesviruses.
30 Such treatment may be carried out in the manner as hereinbefore described.
The present invention further provides a pharmaceutical composition for use in the treatment of HIV-l infections ir.
3s mammals, including humans, infected with herpesviruses, WO92/18130 ~~ 6- PCT/GB92/~ ~7 which comprises an e~fective amount of a compound of formula (A) or a pro-drug, or a pharmaceutically acceptable salt of either of the foregoing, and a pharmaceutically acceptable carrier. Such compositions may be prepared in the manner as s hereinafter described.
The compound of formula (A~ and its prodrugs show a synergistic antiviral effect in conjunction with interferons; and treatment using combination products 0 comprising these two components for sequential or concomitant administration, by the same or different routes, are therefore within the ambit of the present invention.
It will be appreciated that the treatment of herpesvirus 5 infected patients may include prophylaxis of herpesvirus episode attacks (suppressive treatment). In patients with HSV infection only, suppressive treatment would probably only be given to those patients with frequent recurrences.
In contrast, the aforementioned finding in relation to HIV-20 1, indicates the need for continuous suppressive treatmentwith ~RL 44385 or a pro-drug to all HIV-1 infected patients with herpesvirus recurrences, particularly HSV-1, HSV-2 and VZV recurrences, even though these recurrences may be infrequent.
The compound of formula (A) and its prodrugs may also be administered in combination with other antiviral agents, especially anti-HIV agents such as AZT.
30 The following biochemical data illustrate the invention.
. . . .. , . .. :
.: .- : -- -:
. . .
` ~.
WO92~18130 ~ ~ ~ 7 3 PCT/GB92/~ ~7 BIOCHEMICAL DATA
Materials and Methods s Chemicals [3H]dGTP was purchased from Amersham International, Aylesbury, U.K. Template primers Poly (rC). p(dG)12 18 and Poly (dC)- P(dG)l2-l8 were obt from Pharmacia Ltd., Milton Xeynes, U.K. BRL 44385 triphosphate (BRL 44385-TP) was prepared in the laboratories o of SmithKline Beecham Pharmaceuticals, Great Burgh, United Kingdom.
Reverse transcriPtase Purified, E. coli expressed HIV-l reverse transcriptase (RT) was supplied by the Protein 15 Biochemistry Department of SmithKline Beecham Pharmaceuticals, Upper Merion, U.S.A. The enzyme was stored and diluted in a buffer containing 50mM Tris-HCl (pH 8.0), lOmM Hepes, llOmM NaCl, 5.7mM DTT, 0.3mM EDTA, 0.06% Triton X-100, 50% glycerol.
Assav for reverse transCriPtase activity The reaction mixture for the HIV-l RT assay contained in a volume of 120~1: 33mM Tris HCl (pH 8.0), lOOmM KCl, 3.3mM MgC12, 3.3mM
dithiothreitol, 0.2mM glutathione, 0.33mM EGTA (ethylene 2s glycol-bis-(~-aminoethyl ether) N,N-tetra acetic acid), 0.033% Triton X-100, 4.0~M [3H]dGTP (4.16 Ci/mmol, 16.7~Ci/ml) 0-50~M BRL 44385-TP, 0-3 A260 units/ml Poly (rC). p(dG)12_18 or Poly (dC)- P(dG)12-18 and 167ng/ml RT
(equivalent to 1.43nM for an equimolar mixture of p66 and 30 pSl polypeptides). The reaction mixtures without RT were prepared in the microwells of a 96-well plate and preincubated at 37C before the reactions were started by the addition of 20~1 of the enzyme solution. The plates were then incubated for 95-100 minutes at 37C. The 3s reactions were terminated by the addition of 40~1 of EDTA
WO92/18130 PCT/GB92/~ ~7 ~ '?~ 5 -8- ~^
solution (0.2M, pH6.5). The individual reaction mixtures were transferred to a DEAE filter mat (1205-405, LKB Wallac, Finland), prewetted with 0.3M NaCl/0.03M Na citrate, using a cell harvester (1295-001, LKB Wallac). The filter mat was s washed three times in the NaCl/Na citrate buffer and then once in 95% ethanol. Scintillation fluid (Beta Plate Scint, LKB Wallac) was added to the dried filter, and the reaction mixtures assayed for incorporation of radioactive dGMP in an LKB 1205 Beta Plate Liquid Scintillation Counter.
Results From the plot of % inhibition against concentration of inhibitor approximate IC50 values were obtained for 15 BRL 44385-TP as follows.
Experiment 1 y ( C). P(dG)12-18 temPlate - primer used:-IC50 BRL 44385-TP - 3.7~M.
Experiment 2 25 Poly (rC). ptdG)12-18 template - primer used:-IC50 BRL 44385-TP = l.9~M.
y (dC). p(dG)12-18 template - primer used:-IC50 BRL 44385-TP = 1.2~M.
', ~ .: , ~
WO92~18130 ~-~J~ PCT/GB92/~ ~7 " ,:~
_9_ Conclusion These results indicate that the concentration of BRL 44385 triphosphate required to give 50% inhibition of HIV-1 5 reverse transcriptase using a RNA template is in the range 1.9 - 3.7~M. When DNA was used as the template for the reverse transcriptase, the IC50 was 1.2~M. These levels of BRL 44385-TP should be obtained in the herpes-infected cell.
References 1. Complement Receptor 2 Mediates Enhancement of Human Immunodeficiency virus infection in Epstein-Barr virus-carrying B cells.
Tremblay et al., J. Exp. Med. 171, 1791 (1990).
20 2. Phenotypic mixing between human immunodeficiency virus and vesicular stomatitis virus or herpes simplex virus.
Zhu et al., J. of AIDS, 3, 215 (1990).
Claims (9)
1. A method of treatment of HIV-1 infections in mammals, which mammals are infected with herpesviruses, which method comprises the administration to the mammal in need of such treatment, an effective amount of a compound of formula (A):
(A) or a pro-drug, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.
(A) or a pro-drug, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.
2. Use of a compound of formula (A):
(A) or a pro-drug, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing; in the manufacture of a medicament for use in the treatment of HIV-1 infections in mammals, which mammals are infected with herpesviruses.
(A) or a pro-drug, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing; in the manufacture of a medicament for use in the treatment of HIV-1 infections in mammals, which mammals are infected with herpesviruses.
3. A pharmaceutical composition for use in the treatment of HIV-1 infections in mammals, which mammals are infected with herpesviruses, comprising a compound of formula (A):
(A) or a pro-drug, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing; and a pharmaceutically acceptable carrier.
(A) or a pro-drug, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing; and a pharmaceutically acceptable carrier.
4. A method, use or composition according to claim 1, 2 or 3 wherein the compound is BRL 44385, of formula (A).
5. A method, use or composition according to claim 1, 2 or 3 wherein the compound is a pro-drug of the compound of formula (A), as described in EP-A-413544 (Beecham Group p.l.c.).
6. A method, use or composition according to claim 5 wherein the pro-drug of the compound of formula (A) is 2-amino-9-(3-(isopropoxymethoxy)propoxy)purine, known as BRL
55792.
55792.
7. A method, use or composition according to claim 5 or 6 wherein the medicament is adapted for oral administration.
8. A method, use or composition according to claim l, 2 or 3 wherein the compound administered is in a 50mg to 1g unit dose.
9. BRL 44385, or a pro-drug therefor, for use in continuous suppressive treatment of HIV patients with HSV or VZV recurrences.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9107896.4 | 1991-04-13 | ||
| GB919107896A GB9107896D0 (en) | 1991-04-13 | 1991-04-13 | Pharmaceuticals |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2108175A1 true CA2108175A1 (en) | 1992-10-14 |
Family
ID=10693221
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002108175A Abandoned CA2108175A1 (en) | 1991-04-13 | 1992-04-10 | Use of guanine derivative or a prodrug thereof in the treatment of hiv-1 infection |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0580657A1 (en) |
| JP (1) | JPH06506673A (en) |
| AU (1) | AU1541292A (en) |
| CA (1) | CA2108175A1 (en) |
| GB (1) | GB9107896D0 (en) |
| IE (1) | IE921156A1 (en) |
| MX (1) | MX9201665A (en) |
| PT (1) | PT100367A (en) |
| WO (1) | WO1992018130A1 (en) |
| ZA (1) | ZA922702B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5648211A (en) * | 1994-04-18 | 1997-07-15 | Becton, Dickinson And Company | Strand displacement amplification using thermophilic enzymes |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY101126A (en) * | 1985-12-13 | 1991-07-31 | Beecham Group Plc | Novel compounds |
| GB8713695D0 (en) * | 1987-06-11 | 1987-07-15 | Beecham Group Plc | Process |
| EP0353955A3 (en) * | 1988-08-02 | 1991-08-14 | Beecham Group Plc | Novel compounds |
| GB8918827D0 (en) * | 1989-08-17 | 1989-09-27 | Beecham Group Plc | Novel compounds |
-
1991
- 1991-04-13 GB GB919107896A patent/GB9107896D0/en active Pending
-
1992
- 1992-04-10 MX MX9201665A patent/MX9201665A/en unknown
- 1992-04-10 EP EP92908131A patent/EP0580657A1/en not_active Withdrawn
- 1992-04-10 PT PT100367A patent/PT100367A/en not_active Application Discontinuation
- 1992-04-10 AU AU15412/92A patent/AU1541292A/en not_active Abandoned
- 1992-04-10 CA CA002108175A patent/CA2108175A1/en not_active Abandoned
- 1992-04-10 JP JP4507714A patent/JPH06506673A/en active Pending
- 1992-04-10 IE IE115692A patent/IE921156A1/en not_active Application Discontinuation
- 1992-04-10 WO PCT/GB1992/000647 patent/WO1992018130A1/en not_active Application Discontinuation
- 1992-04-13 ZA ZA922702A patent/ZA922702B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MX9201665A (en) | 1992-10-01 |
| EP0580657A1 (en) | 1994-02-02 |
| IE921156A1 (en) | 1992-10-21 |
| WO1992018130A1 (en) | 1992-10-29 |
| PT100367A (en) | 1993-07-30 |
| GB9107896D0 (en) | 1991-05-29 |
| JPH06506673A (en) | 1994-07-28 |
| AU1541292A (en) | 1992-11-17 |
| ZA922702B (en) | 1992-12-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |