CA2176392C - Use of 2-amino purine derivatives for the treatment and prophylaxis of human herpes virus 7 infection - Google Patents
Use of 2-amino purine derivatives for the treatment and prophylaxis of human herpes virus 7 infection Download PDFInfo
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- CA2176392C CA2176392C CA002176392A CA2176392A CA2176392C CA 2176392 C CA2176392 C CA 2176392C CA 002176392 A CA002176392 A CA 002176392A CA 2176392 A CA2176392 A CA 2176392A CA 2176392 C CA2176392 C CA 2176392C
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- 238000011282 treatment Methods 0.000 title claims abstract description 15
- 238000011321 prophylaxis Methods 0.000 title abstract description 3
- 150000005019 2-aminopurines Chemical class 0.000 title 1
- 206010063571 Human herpesvirus 7 infection Diseases 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 125000002252 acyl group Chemical group 0.000 claims abstract description 8
- 208000037773 HHV-7 infectious disease Diseases 0.000 claims abstract description 6
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 5
- 239000010452 phosphate Substances 0.000 claims abstract description 5
- -1 phosphate ester Chemical class 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 8
- 229960004396 famciclovir Drugs 0.000 claims description 7
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229910052739 hydrogen Chemical group 0.000 claims description 4
- 239000001257 hydrogen Chemical group 0.000 claims description 4
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 3
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical group [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 241000701041 Human betaherpesvirus 7 Species 0.000 description 8
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 6
- 229960001179 penciclovir Drugs 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 210000004700 fetal blood Anatomy 0.000 description 5
- 241000700605 Viruses Species 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 241001529453 unidentified herpesvirus Species 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000010166 immunofluorescence Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 241000700586 Herpesviridae Species 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002391 anti-complement effect Effects 0.000 description 1
- 108010008730 anticomplement Proteins 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000120 cytopathologic effect Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- BRPTUOYNOCSFRJ-FYZOBXCZSA-N sodium (2S)-4-(2-amino-6-oxo-1H-purin-9-yl)-2-(hydroxymethyl)butan-1-olate Chemical class [Na+].Nc1nc(=O)c2ncn(CC[C@H](CO)C[O-])c2[nH]1 BRPTUOYNOCSFRJ-FYZOBXCZSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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
-
- 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
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The use of a compound of formula (A), or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl deriva- tive of either of the foregoing in the manufacture of a medicament for use in the treatment (including prophylaxis) of HHV-7 infection.
Description
This invention relates to treatment of infection caused by human herpesvirus 7 (IiHV-7), and to the use of compounds in the preparation of a medicament for use in the treatment of such conditions.
When used herein, 'treatment' includes prophylaxis as appropriate.
EP-A-141927 (Beecham Group p.l.c.) discloses penciclovir, the compound of formula (A):
O
N NH
N N ~ NHz i ~ adz HO-CHa-CH-CHa-OH
(A) and salts, phosphate esters and acyl derivatives thereof, as antiviral agents.
The sodium salt hydrate of penciclovir is disclosed in EP-A-216459 (Beecham Group p.l.c.). Penciclovir and its antiviral activity is also disclosed in Abstract P.Vl l-5 p.193 of 'Abstracts of 14th Int. Congress of Microbiology', Manchester, England 7-13 September 1986 (Boyd et. al.).
Orally active bioprecursors of the compound of formula (A) are of formula (B):
X
HO -CEiz ~H -CH Z-0H
and salts and derivatives thereof as defined under formula (A); wherein X is Cl_6 alkoxy, NH2 or hydrogen. The compounds of formula (B) wherein X is C1_6 alkoxy or NH2 are disclosed in EP-A-141927 and the compounds of formula (B) wherein X is hydrogen, disclosed in EP-A-182024 (Beecham Gtroup p.l.c.) are WO 95!13074 2 I 7 6 3 9 2 PCT1GB94107A86 preferred prodrugs., A particularly preferred example of a compound of formula (t3) is that wherein X is hydrogen and wherein the two OH groups are in the form of the acetyl derivative, described in Example 2 of EP-A-182024, hereinafter referred to as famciclovir.
The compounds of formulae (A) and (B) and salts and derivatives thereof have been described as potentially effective in the treatment of infections caused by herpesviruses, such as herpes simplex type 1, herpes simplex type 2, variceIla-zoster, Epstein-Barr viruses, and cytomegalovirus.
Human hetpesvirus 7 (F~iV-7) is a recently discovered member of the family Herpesviridae. The virus was first isolated in 1989 from the peripheral blood lymphocytes (PBL) of a healthy individual that were being cultured under conditions that lead to T-cell activation.
Analysis of restriction endonuclease profiles of the viral DNA indicated that the new agent differed from the other known human herpesviruses. Since then, HHV-7 has been isolated from the saliva of as many as 75% of healthy adults.
Antibodies to HHV-7 can be detected in serum specimens from approximately 90~
of the normal population and seroconversion usually occurs during childhood after the age of 2.
It is possible that HHV-7 may play a role in the activation of human immunodeficiency virus (HIV-1).
It has now been discovered that the above compounds have potential activity against HHV-7.
Accordingly, the present invention provides a method of treatment of HHV-7 infection in humans, which method comprises the administration to the human in need of such treatment, an effective amount of a compound of formula (A):
N NH
N N' \NFiz I
(G-IZ)z HO~i2~~1-IZ-0H
(A) or a bioprecttrsor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.
The term 'acyl derivative' is used herein to include any derivative of the ' WO 95!13074 PCTlGB94/02486 compounds of forrr~ula (A) in which one or more acyl groups are present. Such derivatives are included as bioprecursors of the compounds of formula (A) in addition to those derivatives which are per se biologically active.
The compound of formula (A) may be in one of the forms disclosed in EP-A-216459 (Beecham Group p.l.c.).
Examples of bioprecursors, pharmaceutically acceptable salts and derivatives are as described in the aforementioned European Patent references .
A particular compound of formula (B) of interest is 9-(4-acetoxy-3-acetoxymethy!but-I-yl)-2-aminopurine, known as famciclovir (FCV), the well-absorbed oral form of penciclovir (PCV).
The compound of formula (A), bioprecursors, salts and derivatives may be prepared as described in the aforementioned European Patent references.
The compound, in particular, famciclovir, 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, 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 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 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 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.
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 included in the composition to facilitate uniform distribution of the compound of the invention.
Preferred parenteral formulations include aqueous formulations using sterile water or normal saline, at a pH of around 7.4 or greater, in particular, containing penciclovir sodium salt hydrate.
When used herein, 'treatment' includes prophylaxis as appropriate.
EP-A-141927 (Beecham Group p.l.c.) discloses penciclovir, the compound of formula (A):
O
N NH
N N ~ NHz i ~ adz HO-CHa-CH-CHa-OH
(A) and salts, phosphate esters and acyl derivatives thereof, as antiviral agents.
The sodium salt hydrate of penciclovir is disclosed in EP-A-216459 (Beecham Group p.l.c.). Penciclovir and its antiviral activity is also disclosed in Abstract P.Vl l-5 p.193 of 'Abstracts of 14th Int. Congress of Microbiology', Manchester, England 7-13 September 1986 (Boyd et. al.).
Orally active bioprecursors of the compound of formula (A) are of formula (B):
X
HO -CEiz ~H -CH Z-0H
and salts and derivatives thereof as defined under formula (A); wherein X is Cl_6 alkoxy, NH2 or hydrogen. The compounds of formula (B) wherein X is C1_6 alkoxy or NH2 are disclosed in EP-A-141927 and the compounds of formula (B) wherein X is hydrogen, disclosed in EP-A-182024 (Beecham Gtroup p.l.c.) are WO 95!13074 2 I 7 6 3 9 2 PCT1GB94107A86 preferred prodrugs., A particularly preferred example of a compound of formula (t3) is that wherein X is hydrogen and wherein the two OH groups are in the form of the acetyl derivative, described in Example 2 of EP-A-182024, hereinafter referred to as famciclovir.
The compounds of formulae (A) and (B) and salts and derivatives thereof have been described as potentially effective in the treatment of infections caused by herpesviruses, such as herpes simplex type 1, herpes simplex type 2, variceIla-zoster, Epstein-Barr viruses, and cytomegalovirus.
Human hetpesvirus 7 (F~iV-7) is a recently discovered member of the family Herpesviridae. The virus was first isolated in 1989 from the peripheral blood lymphocytes (PBL) of a healthy individual that were being cultured under conditions that lead to T-cell activation.
Analysis of restriction endonuclease profiles of the viral DNA indicated that the new agent differed from the other known human herpesviruses. Since then, HHV-7 has been isolated from the saliva of as many as 75% of healthy adults.
Antibodies to HHV-7 can be detected in serum specimens from approximately 90~
of the normal population and seroconversion usually occurs during childhood after the age of 2.
It is possible that HHV-7 may play a role in the activation of human immunodeficiency virus (HIV-1).
It has now been discovered that the above compounds have potential activity against HHV-7.
Accordingly, the present invention provides a method of treatment of HHV-7 infection in humans, which method comprises the administration to the human in need of such treatment, an effective amount of a compound of formula (A):
N NH
N N' \NFiz I
(G-IZ)z HO~i2~~1-IZ-0H
(A) or a bioprecttrsor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.
The term 'acyl derivative' is used herein to include any derivative of the ' WO 95!13074 PCTlGB94/02486 compounds of forrr~ula (A) in which one or more acyl groups are present. Such derivatives are included as bioprecursors of the compounds of formula (A) in addition to those derivatives which are per se biologically active.
The compound of formula (A) may be in one of the forms disclosed in EP-A-216459 (Beecham Group p.l.c.).
Examples of bioprecursors, pharmaceutically acceptable salts and derivatives are as described in the aforementioned European Patent references .
A particular compound of formula (B) of interest is 9-(4-acetoxy-3-acetoxymethy!but-I-yl)-2-aminopurine, known as famciclovir (FCV), the well-absorbed oral form of penciclovir (PCV).
The compound of formula (A), bioprecursors, salts and derivatives may be prepared as described in the aforementioned European Patent references.
The compound, in particular, famciclovir, 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, 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 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 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 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.
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 included in the composition to facilitate uniform distribution of the compound of the invention.
Preferred parenteral formulations include aqueous formulations using sterile water or normal saline, at a pH of around 7.4 or greater, in particular, containing penciclovir sodium salt hydrate.
WO 95113074 217 6 3 9 2 PCT~GB94102486 As is common practice, the compositions will usually be accompanied' by written or printed directions 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.
A suitable dosage unit might contain from 50mg to lg of active ingredient, for example 100 to SOOmg. Such doses may be administered 1 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 body weight per day or, more usually, 10 to 20 mg/kg per day. In the case of famciclovir, the dosage unit would be 250 mg, 500 mg or 750 mg, preferably 250 mg or 500 mg.
The present invention also provides the use of a compound of formula (A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester andlor acyl derivative of either of the foregoing, in the preparation of a medicament for use in the treatment of HHV-7 infection. 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 HHV-7 infection, which comprises an effective amount of a compound of formula (A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester andlor acyl derivative of either of the foregoing, and a pharmaceutically acceptable carrier. Such compositions may be prepared in the manner as hereinafter described.
The compound of formula (A) and its prodrugs show a synergistic antiviral effect in conjunction with interferons; and treatment using combination products comprising these two components for sequential or concomitant administration, by the same or different routes, are therefore within the ambit of the present invention.
Such products are described in EP-A-271270 (Beecham Group p.l.c.).
An assay method involving the inhibition of a cytopathic effect in human cord blood cells is conducted at a dose range of O.O1N,M - 100uM. The general procedure is as described for HHV-7, in Chapter 23 of 'Human Herpesvirus;
Epidemiology, Molecular Biology and Clinical Pathology - Conference Proceedings, Ablashi D. V. (Ed).
An amount effective to treat the virus infection depends on the nature and severity of the infection and the weight of the mammal.
A suitable dosage unit might contain from 50mg to lg of active ingredient, for example 100 to SOOmg. Such doses may be administered 1 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 body weight per day or, more usually, 10 to 20 mg/kg per day. In the case of famciclovir, the dosage unit would be 250 mg, 500 mg or 750 mg, preferably 250 mg or 500 mg.
The present invention also provides the use of a compound of formula (A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester andlor acyl derivative of either of the foregoing, in the preparation of a medicament for use in the treatment of HHV-7 infection. 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 HHV-7 infection, which comprises an effective amount of a compound of formula (A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester andlor acyl derivative of either of the foregoing, and a pharmaceutically acceptable carrier. Such compositions may be prepared in the manner as hereinafter described.
The compound of formula (A) and its prodrugs show a synergistic antiviral effect in conjunction with interferons; and treatment using combination products comprising these two components for sequential or concomitant administration, by the same or different routes, are therefore within the ambit of the present invention.
Such products are described in EP-A-271270 (Beecham Group p.l.c.).
An assay method involving the inhibition of a cytopathic effect in human cord blood cells is conducted at a dose range of O.O1N,M - 100uM. The general procedure is as described for HHV-7, in Chapter 23 of 'Human Herpesvirus;
Epidemiology, Molecular Biology and Clinical Pathology - Conference Proceedings, Ablashi D. V. (Ed).
R'O 95113074 2 1 7 6 3 9 2 P~/GB94/02486 Evaluation of PCV against HHV-7 in Human Cord Blood Cellsa Human mononuclear cells were isolated from umbilical cord blood and inoculated in triplicate with the test virus. One hour later, duplicate dilutions of the compound were added, resulting in 0, 5, 10, 50, or 100 xM final concentrations. After 3 days, cellls were removed and tested for the presence of virus by indirect / immunofluorescence (IFA) using type specific monoclonal antibodies. Three fields of 100 cells each were read from each sample.
HHV-7 Strain SB
Compound Conc 'Y ~ Inf ~ Inhib Inf pM Day Day 7 Day 7 Uninfected 0 0 Infected 4 49 pCV 5 4 42 21 aDilutions of the compounds were added I hr after viral inoculation of human cord blood. The infected cells was measured by anti-complement immunofluorescence (ACIF). All numbers are averages of results of cord blood from 3 donors and triplicate readings were performed on each sample. Each reading represents actual counting of 3 fields.
-$-
HHV-7 Strain SB
Compound Conc 'Y ~ Inf ~ Inhib Inf pM Day Day 7 Day 7 Uninfected 0 0 Infected 4 49 pCV 5 4 42 21 aDilutions of the compounds were added I hr after viral inoculation of human cord blood. The infected cells was measured by anti-complement immunofluorescence (ACIF). All numbers are averages of results of cord blood from 3 donors and triplicate readings were performed on each sample. Each reading represents actual counting of 3 fields.
-$-
Claims (4)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical composition for use in the treatment of HHV-7 infection, which comprises a compound of formula (A):
or a bioprecursor of the formula (B) wherein X is C1-6alkoxy, NH2 or hydrogen, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either the foregoing; and a pharmaceutically acceptable carrier.
or a bioprecursor of the formula (B) wherein X is C1-6alkoxy, NH2 or hydrogen, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either the foregoing; and a pharmaceutically acceptable carrier.
2. A composition according to claim 1 wherein the treatment is for HHV-7 infection in patients infected with human immunodeficiency virus.
3. A composition according to claim 1 wherein the Compound is famciclovir.
4. A composition according to claim 3 wherein famciclovir is used at a dose of 250 mg, 500 mg or 750 mg, once, twice, or three times a day.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9323404.5 | 1993-11-12 | ||
| GB939323404A GB9323404D0 (en) | 1993-11-12 | 1993-11-12 | Pharmaceuticals |
| PCT/GB1994/002486 WO1995013074A1 (en) | 1993-11-12 | 1994-11-11 | Use of 2-amino purine derivatives for the treatment and prophylaxis of human herpes virus 7 infection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2176392A1 CA2176392A1 (en) | 1995-05-18 |
| CA2176392C true CA2176392C (en) | 2005-11-08 |
Family
ID=10745092
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002176392A Expired - Fee Related CA2176392C (en) | 1993-11-12 | 1994-11-11 | Use of 2-amino purine derivatives for the treatment and prophylaxis of human herpes virus 7 infection |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US6051579A (en) |
| EP (1) | EP0728002B1 (en) |
| JP (1) | JP3821840B2 (en) |
| KR (1) | KR100341736B1 (en) |
| CN (1) | CN1071572C (en) |
| AT (1) | ATE210445T1 (en) |
| AU (1) | AU696833B2 (en) |
| CA (1) | CA2176392C (en) |
| CY (1) | CY2337B1 (en) |
| DE (1) | DE69429447T2 (en) |
| DK (1) | DK0728002T3 (en) |
| ES (1) | ES2169117T3 (en) |
| GB (1) | GB9323404D0 (en) |
| PT (1) | PT728002E (en) |
| SI (1) | SI0728002T1 (en) |
| WO (1) | WO1995013074A1 (en) |
| ZA (1) | ZA948908B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6475253B2 (en) | 1996-09-11 | 2002-11-05 | 3M Innovative Properties Company | Abrasive article and method of making |
| WO2004018470A2 (en) * | 2002-08-26 | 2004-03-04 | Teva Pharmaceutical Industries Ltd. | Crystalline solid famciclovir forms i, ii, iii and preparation thereof |
| EP2434013A1 (en) * | 2005-09-08 | 2012-03-28 | The Research Foundation for Microbial Diseases of Osaka University | Promoter for introducing gene into lymphocyte or blood cell and application thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3485225D1 (en) * | 1983-08-18 | 1991-12-05 | Beecham Group Plc | ANTIVIRAL GUANINE DERIVATIVES. |
| EP0182024B1 (en) * | 1984-09-20 | 1991-04-03 | Beecham Group Plc | Purine derivatives and their pharmaceutical use |
| DE3671227D1 (en) * | 1985-07-27 | 1990-06-21 | Beecham Group Plc | 9-SUBSTITUTED GUANINE MONOHYDRATES. |
| GB8628826D0 (en) * | 1986-12-02 | 1987-01-07 | Beecham Group Plc | Pharmaceutical products |
| US4795799A (en) * | 1987-09-08 | 1989-01-03 | Phillips Petroleum Company | Production of aromatic sulfide/ketone polymers with alkali metal carbonate |
| AU635642B2 (en) * | 1990-05-24 | 1993-03-25 | E.R. Squibb & Sons, Inc. | Fluorinated bis(hydroxymethyl) cyclobutyl purines and pyrimidines |
| GB9015051D0 (en) * | 1990-07-07 | 1990-08-29 | Beecham Group Plc | Pharmaceutical treatment |
-
1993
- 1993-11-12 GB GB939323404A patent/GB9323404D0/en active Pending
-
1994
- 1994-11-10 ZA ZA948908A patent/ZA948908B/en unknown
- 1994-11-11 DE DE69429447T patent/DE69429447T2/en not_active Expired - Lifetime
- 1994-11-11 PT PT95900830T patent/PT728002E/en unknown
- 1994-11-11 JP JP51369795A patent/JP3821840B2/en not_active Expired - Fee Related
- 1994-11-11 CA CA002176392A patent/CA2176392C/en not_active Expired - Fee Related
- 1994-11-11 ES ES95900830T patent/ES2169117T3/en not_active Expired - Lifetime
- 1994-11-11 SI SI9430409T patent/SI0728002T1/en unknown
- 1994-11-11 EP EP95900830A patent/EP0728002B1/en not_active Expired - Lifetime
- 1994-11-11 DK DK95900830T patent/DK0728002T3/en active
- 1994-11-11 CN CN94194328A patent/CN1071572C/en not_active Expired - Fee Related
- 1994-11-11 WO PCT/GB1994/002486 patent/WO1995013074A1/en not_active Ceased
- 1994-11-11 KR KR1019960702484A patent/KR100341736B1/en not_active Expired - Fee Related
- 1994-11-11 AT AT95900830T patent/ATE210445T1/en active
- 1994-11-11 AU AU81491/94A patent/AU696833B2/en not_active Ceased
-
1998
- 1998-12-10 US US09/209,666 patent/US6051579A/en not_active Expired - Lifetime
-
2003
- 2003-03-11 CY CY0300023A patent/CY2337B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PT728002E (en) | 2002-05-31 |
| DE69429447D1 (en) | 2002-01-24 |
| CN1136277A (en) | 1996-11-20 |
| EP0728002A1 (en) | 1996-08-28 |
| CN1071572C (en) | 2001-09-26 |
| AU8149194A (en) | 1995-05-29 |
| JP3821840B2 (en) | 2006-09-13 |
| CA2176392A1 (en) | 1995-05-18 |
| DE69429447T2 (en) | 2002-07-25 |
| GB9323404D0 (en) | 1994-01-05 |
| ATE210445T1 (en) | 2001-12-15 |
| HK1012234A1 (en) | 1999-07-30 |
| US6051579A (en) | 2000-04-18 |
| KR100341736B1 (en) | 2002-11-23 |
| EP0728002B1 (en) | 2001-12-12 |
| ES2169117T3 (en) | 2002-07-01 |
| SI0728002T1 (en) | 2002-04-30 |
| ZA948908B (en) | 1995-08-17 |
| CY2337B1 (en) | 2004-02-06 |
| WO1995013074A1 (en) | 1995-05-18 |
| JPH09511218A (en) | 1997-11-11 |
| DK0728002T3 (en) | 2002-04-08 |
| AU696833B2 (en) | 1998-09-17 |
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Legal Events
| Date | Code | Title | Description |
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| EEER | Examination request | ||
| MKLA | Lapsed | ||
| MKLA | Lapsed |
Effective date: 20121113 |