AU2013257951A1 - Use of compounds for the treatment of pain - Google Patents
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- AU2013257951A1 AU2013257951A1 AU2013257951A AU2013257951A AU2013257951A1 AU 2013257951 A1 AU2013257951 A1 AU 2013257951A1 AU 2013257951 A AU2013257951 A AU 2013257951A AU 2013257951 A AU2013257951 A AU 2013257951A AU 2013257951 A1 AU2013257951 A1 AU 2013257951A1
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- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- 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
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
- A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Pain & Pain Management (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
The present invention relates to new therapies to treat pain and related diseases, as well as pharmaceutical compounds for use in said therapies.
Description
WO 2013/167743 PCT/EP2013/059752 1 Use of compounds for the treatment of pain The present invention relates to the field of method of treatment of pain and the provision of pharmaceutical compounds suitable for such treatments. Acute and chronic pain affects millions of people after in jury or surgery and those suffering from diseases like arthri tis, cancer, and diabetes. Nociception (the detection of noxious or damaging stimuli) serves a crucial biological purpose: it alerts living organisms to environmental dangers, inducing the sensation of pain, reflex withdrawal and complex behavioural and emotional responses, which protect the organism from further damage. Noxious stimuli are detected by specialized high thresh old primary sensory neurons (nociceptors), which transfer sig nals to the spinal cord and then transmit them to the brain for higher level processing that results in the conscious awareness of the sensation called pain. The functional importance of pain perception is exemplified by individuals with defects in noci ception; patients with congenital insensitivity to pain do not survive past their twenties. Two basic types of pain can be distinguished - acute and chronic. Acute or nociceptive pain is generally self-limiting and serves a protective biological function by warning of on going tissue damage caused by noxious chemical, thermal and me chanical stimuli. Examples of nociceptive pain include: post operative pain, pain associated with trauma, and the pain asso ciated with arthritis. Chronic pain, on the other hand, serves no protective biological function, and reflects either poor res olution of the painful stimuli, or is itself a disease process. Chronic pain is unrelenting and not self-limiting and can per sist for years and even decades after the initial injury. Chron ic pain is predominantly neuropathic in nature and may involve damage either to the peripheral or central nervous systems. Chronic pain may, however, also be nociceptive, such as inflam matory in nature. Furthermore, chronic pain may also be mixed nociceptive and neuropathic. Finally, chronic pain may also be of a central origin, deriving from processes/conditions in the central or peripheral nervous system, such as e.g. post stroke pain or post-amputation pain/phantom limb pain, which may, how ever, also be considered neuropathic in nature.
WO 2013/167743 PCT/EP2013/059752 2 Currently available therapies for pain have a number of dis advantages, which warrant the development of new therapies for the treatment, prevention and/or reduction of pain. The disad vantages are different for the different classes of available drugs. Use of non-steroidal anti-inflammatory drugs (NSAIDs) in creases the risk of gastrointestinal (GI) bleeding and impaired renal function or renal failure as well as cardiovascular (CV) disease. p-opioid receptor agonists (opioids and opiates) carry the risk of addiction, as well as respiratory depression and constipation. Anti-depressants (e.g. tricyclic anti-depressants (TCAs), such as nortriptyline and desipramine, as well as the selective serotonin norepinephrine reuptake inhibitors (SSNRIs), including e.g. venlafaxaine) may have a negative impact on car diac function or, as in the case of the SSNRI duloxetine, may induce nausea. Anti-convulsants, such as pregabalin and gapa bentin, can induce somnolence. The disadvantage for any of the existing available drugs may also be related to limited efficacy in treating and/or preventing pain. It is a goal of the present invention to provide methods of preventing, treating, ameliorating or suppressing pain, in par ticular by the use of novel compounds for this purpose. The present invention therefore provides the use of new classes of compounds for the treatment, prevention or reduction of pain. The present invention also provides a method of treat ing pain in a subject comprising the administration of a thera peutic compound selected from the inventive compounds. In a re lated aspect the present invention provides the use of a com pound of the invention for the manufacture of an analgesic or a medicament for the treatment of pain in a subject. The invention is further defined by the subject matter of the claims. The com pounds of the invention are e.g. given in the claims and in the tables herein. The compounds according to the invention are contemplated to have advantages in that they have less side effects as deter mined by one or several of the side effects listed above for one or more of the available therapies. Less side effects can be as sessed e.g. either in terms of reduced severity and/or reduced frequency of side effects. Such reduced side effects can e.g. be less somnolence c.f. anti-convulsants, fewer or less frequent cardiovascular side effects c.f. anti-depressants, less addic- WO 2013/167743 PCT/EP2013/059752 3 tion potential c.f. p-opioid receptor agonists, less GI bleeding c.f. NSAIDs etc. Alternatively, the compounds according to the invention are contemplated to have improved efficacy c.f. the available thera pies. Improved efficacy can e.g. be determined as a greater num ber of responders or greater magnitude of efficacy c.f. one or several of the existing therapies. In a further embodiment, the compounds according to the in vention are contemplated to have both reduced side effects and improved efficacy c.f. available therapies. In particular, selected pain subtypes can be specifically treated by the inventive compounds. Example inventive compounds are selected from the groups of a) nucleotide analogues, b) nucleoside analogues, c) compounds that interact with DNA polymerase, or d) compounds that interact with DNA. In the following tables 1, 2 and 3 the inventive com pounds or salts thereof are identified by their unique CAS num ber (Chemical Abstracts Service, www.cas.org). The invention in cludes any salt form of the given compounds, but preferably re lates to the exact salt form as given in the tables. Table 3 re fers to both table 3a and 3b. Further inventive compounds are defined as derivatives of a given formula as described below the tables. Table 1: Adefovir and Tenofovir derivatives (CAS number) 1000271-66-8 1026368-64-8 118552-93-5 3768-14-7 1000271-70-4 1034684-26-8 182798-75-0 142341-05-7 1000272-10-5 1034684-27-9 184350-33-2 142341-04-6 1000272-12-7 1034684-29-1 184350-32-1 124076-74-0 1001254-18-7 1034684-30-4 182799-00-4 186345-42-6 1001254-20-1 1072095-06-7 113852-35-0 7292-42-4 1001254-60-9 1082741-23-8 147127-15-9 180587-75-1 1002339-71-0 1135389-73-9 441785-21-3 206646-04-0 1004956-31-3 1135389-75-1 182799-03-7 116384-53-3 1004956-37-9 1135389-79-5 135295-28-2 441785-25-7 1004956-38-0 1135389-83-1 182798-87-4 206184-49-8 1004956-39-1 1174936-58-3 147127-16-0 113852-37-2 1010415-54-9 1174936-59-4 402575-05-7 114088-58-3 WO 2013/167743 PCT/EP2013/059752 4 1016647-26-9 118553-04-1 147127-17-1 444805-28-1 1016647-27-0 118580-13-5 182798-94-3 149394-66-1 1016647-28-1 1204478-99-8 166403-66-3 1239618-19-9 1016968-33-4 1245542-30-6 182798-89-6 1239618-20-2 1029865-70-0 1245542-31-7 182415-40-3 1239618-22-4 1029865-73-3 1245542-32-8 182798-88-5 1239618-24-6 1030137-98-4 1245542-34-0 182798-76-1 1239618-25-7 1031705-73-3 1245542-37-3 182798-98-7 1239618-28-0 1031705-74-4 1252577-04-0 182799-08-2 1239618-29-1 1044748-23-3 1254203-56-9 160616-17-1 1239618-30-4 1044748-24-4 1258056-86-8 184349-94-8 210990-00-4 107021-20-5 1258056-91-5 141110-66-9 210990-01-5 1092383-86-2 1258056-93-7 184350-30-9 211037-62-6 1092383-87-3 1258056-95-9 182799-14-0 211038-08-3 1092383-88-4 1258056-97-1 160616-15-9 211038-09-4 1164197-08-3 1262544-94-4 182798-95-4 1082741-24-9 1164197-13-0 1262544-98-8 182798-83-0 201341-01-7 1164197-41-4 1296194-74-5 142341-08-0 201341-03-9 1164197-43-6 1296194-75-6 184350-34-3 441785-45-1 1164197-77-6 1296194-76-7 155629-69-9 1082741-33-0 1164197-85-6 1296194-77-8 343248-31-7 441785-47-3 1164197-87-8 1296194-78-9 160616-19-3 441785-43-9 1164197-92-5 1296850-87-7 182799-15-1 859210-03-0 1179503-61-7 1296851-05-2 911208-73-6 441785-84-8 1179503-63-9 1296851-08-5 184350-24-1 441786-20-5 118553-06-3 1296851-11-0 184350-26-3 956470-86-3 118553-07-4 1296851-12-1 849364-05-2 441786-21-6 1204479-00-4 1296851-13-2 160616-09-1 859209-85-1 1247809-34-2 1296851-15-4 182798-90-9 441786-01-2 1305351-60-3 1296851-16-5 441785-29-1 1004956-32-4 1305351-61-4 1296851-17-6 160616-20-6 1004956-33-5 1305351-62-5 1296851-18-7 849364-04-1 441785-94-0 1305351-63-6 1296851-19-8 160616-25-1 441786-03-4 1305351-64-7 1296851-20-1 402575-21-7 1004956-34-6 1305351-65-8 1309464-46-7 182798-97-6 441786-53-4 1305351-66-9 1309464-47-8 402575-22-8 1004956-35-7 1305351-67-0 1309464-48-9 156623-83-5 441786-22-7 1305351-68-1 1309464-50-3 402575-24-0 1004956-36-8 WO 2013/167743 PCT/EP2013/059752 5 1305351-69-2 1309464-53-6 182411-02-5 441786-28-3 1305351-70-5 1309464-54-7 160616-21-7 441786-02-3 1305351-71-6 1309464-55-8 142341-24-0 441785-88-2 1305351-72-7 1309464-56-9 142341-28-4 441786-52-3 1305351-73-8 1313815-26-7 160616-22-8 441785-93-9 1305351-74-9 1313815-31-4 113892-17-4 441785-92-8 1305351-79-4 1313815-36-9 160616-23-9 928651-97-2 160616-18-2 1313815-40-5 210989-65-4 928651-98-3 182798-92-1 1313815-45-0 210989-68-7 441786-05-6 182798-93-2 1313815-50-7 182411-03-6 441785-99-5 182799-02-6 1313815-55-2 201341-05-1 139972-59-1 182799-07-1 1313815-59-6 202138-50-9 183197-29-7 182799-12-8 1313815-63-2 1001848-80-1 229024-18-4 184349-96-0 1313815-69-8 731772-45-5 402575-02-4 184350-08-1 1313815-73-4 731772-50-2 643028-52-8 186345-31-3 1313815-78-9 160616-24-0 402575-00-2 186345-32-4 1313815-83-6 220351-03-1 169514-95-8 186345-33-5 1322510-88-2 1239618-23-5 169515-08-6 186345-34-6 1338605-26-7 220350-77-6 182799-10-6 186345-35-7 1338605-30-3 857498-25-0 643029-02-1 186345-37-9 1338605-34-7 1239618-21-3 643029-04-3 186345-38-0 1338606-04-4 211038-16-3 643029-05-4 186345-39-1 1338606-05-5 168537-52-8 402574-96-3 349660-23-7 1338606-06-6 201341-13-1 402574-97-4 349660-24-8 1338606-07-7 1077883-92-1 183197-34-4 349660-25-9 1338606-08-8 193207-56-6 402575-15-9 349660-26-0 1338606-09-9 625095-61-6 643029-06-5 349660-27-1 1338606-12-4 959141-98-1 183197-31-1 349660-28-2 1346265-18-6 441785-22-4 402575-43-3 349660-29-3 1346265-20-0 193207-55-5 183197-35-5 349660-41-9 1346265-22-2 207125-89-1 402575-14-8 349660-42-0 1352652-56-2 107021-21-6 873195-95-0 349660-43-1 1352820-25-7 128347-14-8 183197-27-5 349660-44-2 1352820-27-9 118552-94-6 183197-30-0 349660-45-3 1352820-30-4 126354-33-4 183197-43-5 349660-46-4 1362688-83-2 1072095-08-9 184349-92-6 402574-94-1 1362688-84-3 207125-90-4 184350-31-0 402574-95-2 1362688-85-4 182799-09-3 402575-17-1 WO 2013/167743 PCT/EP2013/059752 6 402574-98-5 1362688-86-5 352227-03-3 643029-01-0 402574-99-6 1362688-87-6 182799-11-7 183197-41-3 402575-01-3 1362688-88-7 184350-35-4 183197-39-9 402575-06-8 1362688-89-8 402575-03-5 184350-27-4 402575-07-9 1362688-90-1 402575-10-4 402575-23-9 402575-08-0 1362688-91-2 228874-55-3 643029-03-2 402575-09-1 1362688-92-3 184349-87-9 643028-59-5 402575-11-5 1362688-93-4 402575-12-6 182799-01-5 402575-13-7 1362688-94-5 184350-13-8 873195-83-6 402575-16-0 1362688-95-6 182799-05-9 169515-10-0 402575-18-2 165950-14-1 441785-35-9 183197-37-7 402575-19-3 165950-24-3 118553-03-0 402733-86-2 402575-29-5 165950-25-4 402575-20-6 182799-13-9 402575-31-9 165950-26-5 864068-62-2 228874-51-9 402575-32-0 165950-27-6 160616-16-0 402575-30-8 402575-33-1 165950-28-7 911208-75-8 183197-32-2 402575-34-2 165950-29-8 1301109-86-3 343248-32-8 402575-39-7 165950-30-1 911208-87-2 643028-68-6 402575-40-0 165950-31-2 182799-06-0 873195-84-7 402575-41-1 165950-34-5 441785-67-7 873195-86-9 402575-42-2 165950-39-0 882508-28-3 873195-93-8 402575-44-4 165950-40-3 182798-91-0 873195-94-9 402575-46-6 170874-69-8 182799-16-2 402575-62-6 402575-47-7 170874-70-1 441785-33-7 184350-01-4 402575-61-5 170874-71-2 441785-73-5 402575-25-1 402575-63-7 178918-37-1 184350-29-6 368430-79-9 402575-65-9 178918-38-2 956470-68-1 402575-27-3 527715-10-2 183197-44-6 859209-99-7 402575-28-4 528577-76-6 187472-38-4 441786-25-0 402575-45-5 627094-84-2 189999-49-3 184350-25-2 402575-26-2 653584-15-7 190453-99-7 441785-31-5 848944-69-4 653584-16-8 190454-00-3 402575-35-3 402575-36-4 653584-17-9 202138-51-0 138870-19-6 848944-47-8 653584-18-0 202138-52-1 201340-95-6 873195-90-5 653584-19-1 202138-53-2 441785-27-9 873195-91-6 653584-20-4 202138-54-3 211037-52-4 873195-92-7 653584-21-5 221005-90-9 211037-53-5 184350-03-6 653584-22-6 221005-91-0 184350-28-5 643028-61-9 WO 2013/167743 PCT/EP2013/059752 7 653584-23-7 221005-92-1 731772-46-6 873195-89-2 653584-24-8 221005-93-2 201340-97-8 848944-48-9 653584-25-9 228874-52-0 201340-99-0 873195-87-0 653584-26-0 228874-53-1 441785-49-5 184350-05-8 653584-27-1 228874-56-4 201341-07-3 873195-85-8 653584-28-2 342631-41-8 859210-23-4 848944-23-0 653584-29-3 372519-68-1 1239618-17-7 848944-66-1 653584-30-6 372519-70-5 147127-19-3 183197-33-3 653584-31-7 372519-73-8 107021-12-5 848944-24-1 653584-32-8 372519-74-9 113852-41-8 183107-09-7 653584-33-9 372519-75-0 92999-29-6 244229-68-3 653584-34-0 372519-81-8 92924-62-4 183107-19-9 653584-35-1 675875-50-0 115226-05-6 183107-20-2 653584-36-2 675875-51-1 92924-55-5 183107-10-0 653584-37-3 675875-64-6 129556-87-2 183107-11-1 653584-38-4 675875-65-7 147057-09-8 873195-88-1 653584-39-5 675875-68-0 147057-10-1 220350-52-7 653584-40-8 675875-73-7 402575-37-5 220350-60-7 653584-41-9 675875-74-8 156644-97-2 220350-68-5 653584-42-0 675875-80-6 135295-27-1 220350-73-2 653584-43-1 675875-84-0 145986-72-7 220351-10-0 653584-44-2 675875-85-1 145986-73-8 220351-17-7 653584-45-3 675880-36-1 1000271-88-4 183107-12-2 653584-46-4 675880-37-2 1000271-90-8 387356-18-5 653584-47-5 693223-05-1 1000271-92-0 625095-66-1 653584-48-6 855306-26-2 1000692-46-5 693222-97-8 653584-49-7 855306-27-3 1000692-47-6 693222-98-9 653584-50-0 869070-70-2 1001254-04-1 693222-99-0 653584-51-1 869070-71-3 1001254-05-2 201341-11-9 848944-09-2 873425-05-9 1001254-08-5 174579-85-2 848944-10-5 873425-06-0 1001254-09-6 201341-09-5 848944-11-6 873425-07-1 1001254-14-3 174579-59-0 848944-12-7 873425-08-2 1001254-15-4 449206-07-9 848944-13-8 873425-09-3 1001254-16-5 374678-43-0 848944-14-9 873425-10-6 1001254-17-6 389121-36-2 848944-15-0 873425-11-7 1016647-48-5 917381-96-5 848944-16-1 873425-12-8 1016647-50-9 917381-97-6 848944-17-2 873425-14-0 928651-89-2 917789-34-5 WO 2013/167743 PCT/EP2013/059752 8 848944-18-3 873425-16-2 928651-90-5 940933-82-4 848944-19-4 873425-17-3 928651-91-6 940933-83-5 848944-20-7 873425-19-5 928651-92-7 940933-84-6 848944-21-8 873425-20-8 928651-93-8 940933-85-7 848944-22-9 873425-22-0 928651-94-9 940933-86-8 848944-25-2 873425-23-1 928651-95-0 940933-87-9 848944-26-3 873425-24-2 928651-96-1 940933-88-0 848944-27-4 875282-62-5 928652-00-0 940933-89-1 848944-28-5 882508-27-2 928652-01-1 940933-90-4 848944-29-6 882508-29-4 928652-02-2 940933-91-5 848944-30-9 882508-30-7 940933-80-2 940933-92-6 848944-31-0 892145-75-4 940933-81-3 940933-93-7 848944-32-1 911208-67-8 943719-57-1 940933-94-8 848944-33-2 911208-77-0 944047-67-0 940933-95-9 848944-34-3 911208-81-6 944047-68-1 948592-15-2 848944-35-4 911208-84-9 944047-69-2 957768-99-9 848944-36-5 913356-64-6 944047-70-5 957769-02-7 848944-37-6 913356-66-8 944047-71-6 957769-05-0 848944-38-7 916313-27-4 944047-72-7 957769-09-4 848944-39-8 916313-29-6 944047-73-8 957769-36-7 848944-40-1 916313-30-9 944047-74-9 957769-37-8 848944-41-2 916313-31-0 944047-75-0 959433-59-1 848944-42-3 916313-32-1 944047-76-1 959780-16-6 848944-43-4 916313-33-2 944047-77-2 959780-17-7 848944-44-5 916313-34-3 944047-78-3 960316-04-5 848944-45-6 916313-35-4 944047-79-4 960316-05-6 848944-46-7 916313-40-1 944047-80-7 960316-06-7 848944-49-0 916313-55-8 944047-81-8 960316-07-8 848944-50-3 916313-56-9 944047-82-9 960316-08-9 848944-51-4 928651-79-0 944047-83-0 960316-09-0 848944-52-5 928651-80-3 944047-84-1 960316-10-3 848944-53-6 928651-81-4 946134-64-1 960316-11-4 848944-54-7 928651-82-5 946134-66-3 960316-12-5 848944-55-8 928651-83-6 946134-68-5 960316-13-6 848944-56-9 928651-84-7 946134-70-9 960316-14-7 848944-64-9 928651-85-8 946134-72-1 960316-15-8 848944-65-0 928651-86-9 946134-74-3 913356-68-0 848944-67-2 957769-35-6 948885-37-8 916313-41-2 WO 2013/167743 PCT/EP2013/059752 9 848944-68-3 957777-50-3 948885-38-9 916313-42-3 873195-96-1 957777-51-4 948885-39-0 917381-94-3 873425-13-9 957777-52-5 948885-40-3 957769-33-4 889885-97-6 957777-53-6 948885-47-0 957777-61-6 889885-98-7 957777-54-7 948885-48-1 957777-62-7 889886-03-7 957777-55-8 956470-89-6 959861-27-9 906348-04-7 957777-56-9 956471-16-2 959861-29-1 906348-05-8 957777-57-0 956471-18-4 957768-98-8 906348-06-9 957777-58-1 956471-40-2 957769-30-1 906348-07-0 957777-59-2 956471-44-6 957769-31-2 913356-67-9 957777-60-5 957768-96-6 957769-32-3 917381-95-4 957769-34-5 Table 2: Cidofovir derivatives (CAS number) 117087-39-5 849176-94-9 956471-22-0 144028-83-1 160616-05-7 168537-83-5 174579-44-3 138776-64-4 113852-44-1 856686-25-4 174579-70-5 151223-48-2 128347-13-7 856686-24-3 193207-65-7 169515-03-1 133868-60-7 168537-70-0 193207-66-8 169515-07-5 138870-18-5 163078-01-1 174579-57-8 1323394-16-6 228874-13-3 875271-47-9 174579-71-6 155629-77-9 169515-09-7 132336-35-7 100802-98-0 151223-51-7 898225-59-7 193207-69-1 174579-86-3 151223-53-9 130029-17-3 193207-70-4 193207-67-9 187472-50-0 113852-40-7 148873-52-3 897931-59-8 138307-68-3 228874-11-1 168537-77-7 193207-68-0 180074-55-9 142276-30-0 193207-71-5 278611-19-1 190903-47-0 120362-35-8 193207-72-6 193207-63-5 163077-96-1 718638-95-0 193207-75-9 193207-64-6 169514-99-2 193207-59-9 875271-49-1 174579-40-9 198282-38-1 142276-31-1 193207-73-7 897931-60-1 198282-44-9 718639-00-0 193207-74-8 897931-74-7 151223-49-3 718639-06-6 904297-28-5 174579-50-1 138886-80-3 849176-97-2 904297-27-4 1164197-16-3 138776-65-5 898225-55-3 904297-25-2 1164197-21-0 168750-94-5 718639-11-3 904297-26-3 1164197-18-5 168750-95-6 718639-15-7 174579-48-7 1164197-22-1 193207-60-2 718639-20-4 178918-36-0 897931-65-6 198282-37-0 WO 2013/167743 PCT/EP2013/059752 10 444805-26-9 130042-69-2 361552-84-3 198282-43-8 496765-78-7 138307-69-4 168537-75-5 194419-93-7 904297-22-9 643028-48-2 875271-48-0 126354-59-4 718638-78-9 151223-03-9 1192360-48-7 193207-43-1 496765-79-8 120362-31-4 202933-08-2 193207-41-9 718638-81-4 897931-61-2 897931-66-7 193207-44-2 142247-19-6 151222-99-0 1164197-24-3 141700-02-9 496765-80-1 151223-55-1 361552-80-9 141700-01-8 904297-21-8 897931-75-8 897931-62-3 1345665-10-2 693803-28-0 849176-95-0 202933-26-4 193207-45-3 904297-23-0 151223-01-7 202933-27-5 190903-45-8 693803-29-1 849176-96-1 864068-46-2 174579-76-1 898225-56-4 883867-85-4 897931-63-4 86404-89-9 898225-57-5 148873-53-4 202933-23-1 100778-62-9 120362-33-6 151223-52-8 202933-24-2 100940-71-4 210989-63-2 849176-98-3 897931-72-5 193207-42-0 127757-45-3 849176-99-4 911827-24-2 193207-39-5 210989-60-9 849177-00-0 174579-39-6 174579-77-2 210989-62-1 228874-12-2 897931-73-6 174579-68-1 132336-37-9 898225-60-0 904297-29-6 174579-69-2 904297-19-4 718638-71-2 174579-49-8 100778-83-4 904297-20-7 897931-70-3 174579-38-5 1322510-41-7 849177-04-4 911827-25-3 92924-59-9 1322510-43-9 718638-93-8 718638-90-5 138776-61-1 1322510-93-9 163077-95-0 956470-88-5 126354-60-7 1322510-96-2 210989-59-6 151223-23-3 187472-36-2 1192360-50-1 210989-61-0 916313-26-3 151223-05-1 193207-46-4 343248-30-6 757955-83-2 120362-37-0 168537-76-6 132336-36-8 177493-23-1 127749-27-3 193207-47-5 202933-07-1 897931-71-4 127852-83-9 1322510-47-3 718639-52-2 897931-67-8 132336-42-6 1322511-06-7 168537-72-2 916313-25-2 151597-69-2 193207-48-6 718639-54-4 151223-50-6 151284-15-0 202933-28-6 718639-56-6 757955-82-1 151284-16-1 115265-37-7 168537-74-4 177493-24-2 127757-44-2 1322510-51-9 168537-69-7 244229-74-1 151223-00-6 1322510-57-5 343248-29-3 177493-25-3 151223-56-2 1322510-74-6 343248-25-9 343248-24-8 141700-03-0 1322510-75-7 WO 2013/167743 PCT/EP2013/059752 11 343248-27-1 912635-37-1 178918-46-2 1322510-40-6 278611-17-9 897931-68-9 127749-30-8 1322510-76-8 163077-99-4 244229-73-0 127852-84-0 1322510-84-8 163078-00-0 1164197-15-2 168537-54-0 1322510-78-0 904297-24-1 849176-90-5 151223-02-8 132336-32-4 163077-98-3 849176-91-6 151223-04-0 141782-25-4 718639-46-4 718639-27-1 194419-95-9 115265-63-9 718639-41-9 718639-31-7 187472-52-2 115265-59-3 168537-73-3 174579-87-4 160616-50-2 115265-17-3 168537-71-1 174579-81-8 138320-03-3 115265-09-3 856686-20-9 174579-82-9 155629-63-3 151223-54-0 168537-68-6 956470-85-2 143452-52-2 956471-20-8 875271-46-8 Table 3a: active compounds (CAS number) 50-41-9 82410-32-0 9001-63-2 99390-76-8 50-55-5 103024-93-7 9005-25-8 99751-63-0 50-63-5 104227-87-4 9031-94-1 100241-46-1 50-91-9 118353-05-2 9032-43-3 100286-90-6 51-21-8 119567-79-2 9036-19-5 100643-71-8 51-24-1 124832-26-4 9042-14-2 100827-28-9 51-45-6 127759-89-1 9050-67-3 100986-85-4 53-19-0 136470-78-5 9054-89-1D 101347-05-1 53-43-0 142217-69-4 10083-24-6 102052-95-9 53-60-1 145514-04-1 10212-25-6 102674-90-8 54-42-2 175865-60-8 10347-81-6 102805-86-7 55-03-8 176161-24-3 10418-03-8 102830-69-3 55-86-7 193681-12-8 10605-21-7 103737-56-0 56-47-3 202138-50-9 11006-77-2 103745-39-7 56-53-1 121104-96-9 11072-93-8 103913-16-2 56-92-8 124436-59-5 11089-65-9 104624-98-8 58-18-4 136816-75-6 13392-28-4 104880-60-6 58-22-0 136817-59-9 13422-51-0 105637-50-1 58-61-7D 137332-54-8 13422-55-4 106362-32-7 60-56-0 139110-80-8 13870-90-1 106566-58-9 61-12-1 143224-34-4 14092-89-8 107421-16-9 61-19-8D 147362-57-0 14378-21-3 107489-37-2 61-73-4 149488-17-5 14534-61-3 107753-78-6 WO 2013/167743 PCT/EP2013/059752 12 61-82-5 149845-06-7 14882-18-9 107868-30-4 63-25-2 150378-17-9 15176-29-1 109091-47-6 65-49-6 154612-39-2 15541-60-3 109093-57-4 66-81-9 155213-67-5 16090-09-8 110042-95-0 67-92-5 159910-86-8 17035-90-4 110078-40-5 68-19-9 159989-65-8 17397-89-6 110078-46-1 68-88-2 161814-49-9 19542-67-7 110143-10-7 70-00-8 174484-41-4 19545-26-7 110942-02-4 83-70-5 178040-94-3 19750-45-9 111393-93-2 83-89-6 178979-85-6 20153-98-4 112190-24-6 84-17-3 192725-17-0 20350-15-6 112885-42-4 88-58-4 198904-31-3 20554-84-1 113852-41-8 94-09-7 206361-99-1 20559-55-1 114246-76-3 96-84-4 223537-30-2 21245-02-3 114627-30-4 97-00-7 226700-79-4 21535-47-7 114719-57-2 97-77-8 233254-24-5 21679-14-1 115344-47-3 103-16-2 244767-67-7 21967-41-9 115743-28-7 113-52-0 269055-15-4 22029-76-1 116249-65-1 118-42-3 300832-84-2 22139-77-1 116649-85-5 119-04-OD 330600-85-6 22199-08-2 116680-01-4 123-31-9 61-73-4 22260-51-1 117704-65-1 123-77-3 174022-42-5 22862-76-6 118390-30-0 126-07-8 196618-13-0 23205-42-7D 118409-57-7 127-07-1 376348-65-1 23210-58-4 118409-58-8 128-13-2 394730-60-0 23288-49-5 118409-60-2 128-62-1 402957-28-2 24280-93-1 119413-54-6 129-46-4 500287-72-9 24815-24-5 119644-22-3 132-17-2 111393-84-1 24936-38-7 120011-70-3 132-69-4 113852-37-2 24937-79-9 120210-48-2 136-40-3 124265-89-0 25526-93-6 120586-49-4 137-26-8 129618-40-2 25535-16-4 121154-51-6 137-53-1 137487-62-8 25775-90-0 122111-03-9 146-56-5 138660-96-5 27314-97-2 122320-73-4 147-94-4 138660-97-6 27686-84-6 122520-85-8 148-82-3 144245-52-3 27762-78-3 122970-35-8 150-76-5 148998-94-1 28507-02-0 122970-40-5 151-21-3 149950-60-7 29321-75-3 123027-56-5 152-43-2 151356-08-0 30220-45-2 123027-69-0 WO 2013/167743 PCT/EP2013/059752 13 152-62-5 153101-26-9 30303-65-2 123391-12-8 303-45-7 154598-52-4 30516-87-1D 123774-72-1 314-13-6 159519-65-0 30516-87-1D, 124351-85-5 321-64-2 163451-80-7 31430-15-6 124930-59-2 339-72-0 174391-92-5 32672-69-8 124937-52-6 362-07-2 175385-62-3 32828-81-2 125372-33-0 402-71-1 195157-34-7 32981-86-5 126103-94-4 404-86-4 251562-00-2 33069-62-4 126320-77-2 440-17-5 306296-47-9 33089-61-1 126347-69-1 458-37-7 313682-08-5 34031-32-8 126595-07-1 468-61-1 370893-06-4 34157-83-0 128075-79-6 481-49-2 461443-59-4 34620-78-5D 128794-94-5 517-89-5 857094-21-4 35404-50-3D 129297-22-9 518-28-5 136194-77-9 35943-35-2 129453-61-8 521-78-8 136279-32-8 36244-81-2 129467-45-4 524-12-9 136449-85-9 36703-88-5 129580-63-8 538-03-4D 136458-97-4 37019-68-4 130108-72-4 548-04-9 137893-48-2 37300-21-3 130112-42-4 562-09-4 138069-52-0 37339-90-5 130717-51-0 569-65-3 138483-63-3 38176-02-2 130729-68-9 616-91-1 139272-69-8 38640-92-5 131262-82-3 636-47-5 139694-65-8 38937-66-5 131707-23-8 637-58-1 139893-43-9 38966-21-1 133432-71-0 749-02-0 139981-26-3 39323-99-4 133550-30-8 749-13-3 140942-13-8 39475-64-4 133550-34-2 751-94-0 141497-12-3 41135-06-2 133550-35-3 768-94-5 141752-91-2 43210-67-9 133898-83-6 881-68-5 141790-23-0 47231-30-1 134379-77-4 909-13-7 141994-72-1 49620-13-5 134499-06-2 969-33-5 143070-01-3 51321-79-0 134523-00-5 1229-29-4 143205-42-9 51333-22-3 134633-29-7 1244-76-4 143338-12-9 51630-58-1 134678-17-4 1393-48-2 143390-74-3 53023-17-9 134678-17-4D 1405-86-3 143491-57-0 53066-26-5 134878-17-4 1405-97-6 144113-82-6 53123-88-9 135062-02-1 1424-00-6 144141-97-9 53716-50-0 135295-27-1 1621-55-2 144189-66-2 53783-83-8 135525-71-2 1910-68-5 144779-91-9 54965-21-8 135525-77-8 WO 2013/167743 PCT/EP2013/059752 14 2068-78-2 144875-48-9 54965-24-1 135525-78-9 2140-72-9 145258-61-3 55134-13-9 135812-04-3 2169-75-7 145417-33-0 55303-98-5 135812-34-9 2210-63-1 145512-85-2 55954-61-5 136194-77-9 2391-56-2 146426-40-6 55981-09-4 136279-32-8 2413-38-9 146739-86-8 58569-55-4 136449-85-9 2438-72-4 146794-68-5 58581-89-8 136458-97-4 2753-45-9 147318-81-8 58970-76-6 137893-48-2 3039-71-2 147362-54-7 59729-32-7 138069-52-0 3056-17-5 147658-54-6 59789-29-6 138483-63-3 3093-35-4 148314-61-8 59865-13-3 139272-69-8 3254-89-5 148465-45-6 60050-95-5 139694-65-8 3416-05-5 148473-16-9 60525-15-7 139893-43-9 3424-98-4 148550-96-3 60628-96-8 139981-26-3 3572-43-8 148692-46-0 60857-08-1 140942-13-8 3572-60-9 148982-38-1 61413-54-5 141497-12-3 3599-32-4 149249-32-1 61718-82-9 141752-91-2 3731-59-7 50-41-10 62304-98-7 141790-23-0 4097-22-7 50-55-6 62304-98-7D 141994-72-1 4291-63-8 50-63-6 63585-09-1 143070-01-3 4991-65-5 50-91-10 63659-19-8 143205-42-9 5154-02-9 51-21-9 63968-64-9 143338-12-9 5398-51-6 51-24-2 64224-21-1 143390-74-3 5466-77-3 51-45-7 65589-59-5 143491-57-0 5535-20-6 53-19-1 65646-68-6 144113-82-6 5536-17-4 53-43-1 66611-37-8 144141-97-9 5987-82-6 53-60-2 67526-95-8 144189-66-2 6190-39-2 54-42-3 67700-30-5 144779-91-9 6485-39-8 55-03-9 67915-31-5 144875-48-9 6493-05-6 55-86-8 68238-36-8 145258-61-3 6873-13-8 56-47-4 68345-70-0 145417-33-0 7059-23-6 56-53-2 69123-90-6 145512-85-2 7081-38-1 56-92-9 69123-98-4 146426-40-6 7083-71-8 58-18-5 69304-47-8 146739-86-8 7235-40-7 58-22-1 69655-05-6 146794-68-5 7481-89-2 60-56-1 69655-05-6D 147318-81-8 7481-89-2D 61-12-2 69839-83-4 147362-54-7 7689-03-4 61-73-5 70280-03-4 147658-54-6 WO 2013/167743 PCT/EP2013/059752 15 8067-24-1 61-82-6 70831-56-0 148314-61-8 8077-15-4 63-25-3 71160-24-2 148465-45-6 134379-77-4 65-49-7 71486-22-1 148473-16-9 134499-06-2 66-81-10 71939-50-9 148550-96-3 134523-00-5 67-92-6 71963-77-4 148692-46-0 134633-29-7 68-19-10 72324-18-6 148982-38-1 134678-17-4 68-88-3 72559-06-9 149249-32-1 134678-17-4D 70-00-9 72599-27-0 50-41-10 134878-17-4 83-70-6 73573-88-3 50-55-6 135062-02-1 83-89-7 74817-61-1 50-63-6 135295-27-1 84-17-4 75330-75-5 50-91-10 135525-71-2 88-58-5 75706-12-6 51-21-9 135525-77-8 94-09-8 77181-69-2 51-24-2 135525-78-9 96-84-5 77372-73-7 51-45-7 135812-04-3 97-00-8 77907-69-8 53-19-1 135812-34-9 97-77-9 78416-81-6 53-43-1 8067-24-2 103-16-3 78613-38-4 53-60-2 8077-15-5 113-52-1 78842-13-4 54-42-3 9001-63-3 118-42-4 79559-97-0 55-03-9 9005-25-9 123-31-10 79617-96-2 55-86-8 9031-94-2 123-77-4 79794-75-5 56-47-4 9032-43-4 126-07-9 79902-63-9 56-53-2 9036-19-6 127-07-2 80621-81-4 56-92-9 9042-14-3 128-13-3 81840-15-5 58-18-5 9050-67-4 128-62-2 82147-31-7 58-22-1 10083-24-7 129-46-5 82640-04-8 60-56-1 10212-25-7 132-17-3 82822-14-8 61-12-2 10347-81-7 132-69-5 83461-56-7 61-73-5 10418-03-9 136-40-4 83546-42-3 61-82-6 10605-21-8 137-26-9 83919-23-7 63-25-3 11006-77-3 137-53-2 83923-14-2 65-49-7 11072-93-9 146-56-6 84290-27-7 66-81-10 11089-65-10 147-94-5 84303-06-0 67-92-6 13392-28-5 148-82-4 84371-65-3 68-19-10 13422-51-1 150-76-6 84472-85-5 68-88-3 13422-55-5 151-21-4 85233-19-8 70-00-9 13870-90-2 152-43-3 85326-06-3 83-70-6 14092-89-9 152-62-6 85326-06-3D 83-89-7 WO 2013/167743 PCT/EP2013/059752 16 14378-21-4 303-45-8 85465-82-3 84-17-4 14534-61-4 314-13-7 86903-77-7 88-58-5 8077-15-5 321-64-3 87190-79-2 94-09-8 9001-63-3 339-72-1 87857-41-8 96-84-5 9005-25-9 362-07-3 88495-63-0 97-00-8 9031-94-2 402-71-2 88899-55-2 97-77-9 9032-43-4 404-86-5 89778-26-7 103-16-3 9036-19-6 440-17-6 89813-21-8 113-52-1 9042-14-3 458-37-8 90832-70-5 118-42-4 9050-67-4 468-61-2 91421-42-0 123-31-10 10083-24-7 481-49-3 92047-17-1 123-77-4 10212-25-7 517-89-6 92562-88-4 126-07-9 10347-81-7 518-28-6 93253-86-2 127-07-2 10418-03-9 521-78-9 93265-81-7 128-13-3 10605-21-8 524-12-10 93957-54-1 128-62-2 11006-77-3 548-04-10 93957-55-2 129-46-5 11072-93-9 562-09-5 94540-23-5 132-17-3 11089-65-10 569-65-4 95933-74-7 132-69-5 13392-28-5 616-91-2 96187-53-0 136-40-4 13422-51-1 636-47-6 97123-80-3 137-26-9 13422-55-5 637-58-2 98059-61-1 137-53-2 13870-90-2 749-02-1 98530-12-2 146-56-6 14092-89-9 749-13-4 99011-02-6 147-94-5 14378-21-4 751-94-1 99390-76-8 148-82-4 14534-61-4 768-94-6 99751-63-0 150-76-6 120210-48-2 881-68-6 100241-46-1 151-21-4 120586-49-4 909-13-8 100286-90-6 152-43-3 121154-51-6 969-33-6 100643-71-8 152-62-6 122111-03-9 1229-29-5 100827-28-9 303-45-8 122320-73-4 1244-76-5 100986-85-4 314-13-7 122520-85-8 1393-48-3 101347-05-1 321-64-3 122970-35-8 1405-86-4 102052-95-9 339-72-1 122970-40-5 1405-97-7 102674-90-8 362-07-3 123027-56-5 1424-00-7 102805-86-7 402-71-2 123027-69-0 1621-55-3 102830-69-3 404-86-5 123391-12-8 1910-68-6 103737-56-0 440-17-6 123774-72-1 2068-78-3 103745-39-7 458-37-8 124351-85-5 2140-72-10 103913-16-2 468-61-2 WO 2013/167743 PCT/EP2013/059752 17 124930-59-2 2169-75-8 104624-98-8 481-49-3 124937-52-6 2210-63-2 104880-60-6 517-89-6 125372-33-0 2391-56-3 105637-50-1 518-28-6 126103-94-4 2413-38-10 106362-32-7 521-78-9 126320-77-2 2438-72-5 106566-58-9 524-12-10 126347-69-1 2753-45-10 107421-16-9 548-04-10 126595-07-1 3039-71-3 107489-37-2 562-09-5 128075-79-6 3056-17-6 107753-78-6 569-65-4 128794-94-5 3093-35-5 107868-30-4 616-91-2 129297-22-9 3254-89-6 109091-47-6 636-47-6 129453-61-8 3416-05-6 109093-57-4 637-58-2 129467-45-4 3424-98-5 110042-95-0 749-02-1 129580-63-8 3572-43-9 110078-40-5 749-13-4 130108-72-4 3572-60-10 110078-46-1 751-94-1 130112-42-4 3599-32-5 110143-10-7 768-94-6 130717-51-0 3731-59-8 110942-02-4 881-68-6 130729-68-9 4097-22-8 111393-93-2 909-13-8 131262-82-3 4291-63-9 112190-24-6 969-33-6 131707-23-8 4991-65-6 112885-42-4 1229-29-5 133432-71-0 5154-02-10 113852-41-8 1244-76-5 133550-30-8 5398-51-7 114246-76-3 1393-48-3 133550-34-2 5466-77-4 114627-30-4 1405-86-4 133550-35-3 5535-20-7 114719-57-2 1405-97-7 133898-83-6 5536-17-5 115344-47-3 1424-00-7 3093-35-5 5987-82-7 115743-28-7 1621-55-3 3254-89-6 6190-39-3 116249-65-1 1910-68-6 3416-05-6 6485-39-9 116649-85-5 2068-78-3 3424-98-5 6493-05-7 116680-01-4 2140-72-10 3572-43-9 6873-13-9 117704-65-1 2169-75-8 3572-60-10 7059-23-7 118390-30-0 2210-63-2 3599-32-5 7081-38-2 118409-57-7 2391-56-3 3731-59-8 7083-71-9 118409-58-8 2413-38-10 4097-22-8 7235-40-8 118409-60-2 2438-72-5 4291-63-9 7481-89-3 119413-54-6 2753-45-10 4991-65-6 7689-03-5 119644-22-3 3039-71-3 5154-02-10 8067-24-2 120011-70-3 3056-17-6 5398-51-7 7081-38-2 6190-39-3 5987-82-7 5466-77-4 7083-71-9 6485-39-9 7689-03-5 WO 2013/167743 PCT/EP2013/059752 18 5535-20-7 7235-40-8 6493-05-7 7059-23-7 5536-17-5 7481-89-3 6873-13-9 Table 3b: active compounds (INN) compound IUPAC Name and synonyms Formulation CMX 157 hexadecyloxypropyl 9-(2- Tenofovir (phosphonomethoxy)propyl)adenine; or (Prodrug) 2-(Adenin-9-yl)-1(R) methylethoxymethylphosphonic acid 3 (hexadecyloxy)propyl ester; or HDP-(R)-PMPA; or HDP-PMPA Entecavir 2-Amino-9-[(1S,3R,4S)-4-hydroxy-3- Entecavir (hydroxymethyl)-2 methylidenecyclopentyl]-6,9-dihydro 3H-purin-6-one Lamivudine 4-amino-i-[(2R,5S)-2-(hydroxymethyl)- Lamivudine 1,3-oxathiolan-5-yl]-1,2 dihydropyrimidin-2-one Telbivudine 1-(2-deoxy-B-L-erythro- Telbivudine pentofuranosyl)-5-methylpyrimidine 2,4 (1H, 3H) -dione Clevudine 1-[(2S,3R,4S,5S)-3-fluoro-4-hydroxy- Clevudine 5-(hydroxymethyl)oxolan-2-yl]-5 methylpyrimidine-2,4-dione Cidofovir ({[(S)-1-(4-amino-2-oxo-1,2- Cidofovir dihydropyrimidin-1-yl)-3 hydroxypropan-2 yl]oxy}methyl)phosphonic acid Ribavirin 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5- Ribavirin (hydroxymethyl)oxolan-2-yl]-1H-1,2,4 triazole-3-carboxamide Taribavirin 1-[(2R,3R,4S,5S)- 3,4-dihydroxy-5- Taribavirin (hydroxymethyl)oxolan-2-yl]- 1,2,4- hydrochlo triazole-3-carboximidamide ride Moroxydine N-(Diaminomethylidene)morpholine-4- Moroxydine carboximidamide Hydrochlo ride WO 2013/167743 PCT/EP2013/059752 19 NOV-205 9-[(2R,3R,4S,5R)-3,4-dihydroxy-5- organic (hydroxymethyl)oxolan-2-yl]-6,9- salt of dihydro-3H-purin-6-one + bis (2S)-2-amino-4-{[(1R)-1- glycine-L [(carboxymethyl)carbamoyl]-2- cysteinyl sulfanylethyl]carbamoyl}butanoic ac- bis-(g -L id; or Molixan (Brand name); or gluta bis-glycine-L-cysteinyl-bis-(g -L- mate)*9-b glutamate) / 9-b -D- D ribofuranozilhypoxanthine (organic ribo salt); or furanozilhy BAM-205 poxanthine NOV-002 (2S,2'S)-5,5'-(((2R,2'R)- (bis disulfanediylbis (1- (gamma-L ((carboxymethyl)amino)-1-oxopropane- glutamyl) 3,2-diyl))bis(azanediyl))bis(2-amino- L 5-oxopentanoic acid); or Glutathione cisteinyl disulphide; or Oxiglutatione sodium; bis-glycin or Bis(gamma-glutamyl-cysteinyl- disodium glycine) S,S'-disulfide disodium salt) salt; or BAM-002 Aciclovir / 2-Amino-1,9-dihydro-9-((2- Acyclovir acyclovir hydroxyethoxy)methyl)-6H-Purin-6-one Valaciclo- (S)-2-[(2-amino-6-oxo-6,9-dihydro-3H- valacyclo vir / purin-9-yl)methoxy]ethyl-2-amino-3- vir hydro valacyclo- methylbutanoate chloride vir Ganciclovir 2-amino-9-{[(1,3-dihydroxypropan-2- Ganciclovir yl)oxy]methyl}-6,9-dihydro-3H-purin- sodium 6-one Val- 2-[(2-amino-6-oxo-6,9-dihydro-3H- val ganciclovir purin-9-yl)methoxy]-3-hydroxypropyl ganciclovir (2S)-2-amino-3-methylbutanoate hydrochlo ride Penciclovir 2-amino-9-[4-hydroxy-3- Penciclovir (hydroxymethyl)butyl]-6,9-dihydro-3H purin-6-one Famciclovir 2-[(acetyloxy)methyl]-4-(2-amino-9H- Famciclovir WO 2013/167743 PCT/EP2013/059752 20 purin-9-yl)butyl acetate Vidarabine (2R,3S,4S,5R)-2-(6-amino-9H-purin-9- Vidarabine / adenine yl)-5-(hydroxymethyl)oxolane-3,4-diol arabinoside hydrate Idoxuridine 1-[(2R,4S,5R)-4-hydroxy-5- Idoxuridine (hydroxymethyl)oxolan-2-yl]-5-iodo 1,2,3,4-tetrahydropyrimidine-2,4 dione Tri- 1-[4-hydroxy-5-(hydroxymethyl)oxolan- Tri fluridine / 2-yl]-5- (trifluoromethyl) pyrimi- fluridine trifluoro- dine-2,4-dione thymidine (TFT) Edoxudine / 5-ethyl-i-[4-hydroxy-5- Edoxudine Edoxudin (hydroxymethyl)oxolan-2 yl]pyrimidine-2,4-dione Brivudine 5-[(E)-2-bromoethenyl]-1-[(2R,4S,5R)- Brivudine 4-hydroxy-5-(hydroxymethyl)oxolan-2 yl]-1,2,3,4-tetrahydropyrimidine-2,4 dione Cytarabine 4-amino-1-[(2R,3S,4R,5R)-3,4- Cytarabine / cytosine dihydroxy-5- (hydroxymethyl)oxolan-2 arabinoside yl] pyrimidin-2-one (Ara - C) Foscarnet phosphonoformic acid Foscarnet Sodium Docosanol Docosan-1-ol Docosanol Fomivirsen fomivirsen sodium Troman- N-1-adamantyl-N-[2- troman tadine (dimethylamino)ethoxy]acetamide tadine hy drochloride Imiquimod/ 3-(2-methylpropyl)-3,5,8- Imiquimod R-837 triazatricyclo[7.4.0.02,6]trideca 1(9),2(6),4,7,10,12-hexaen-7-amine Resiquimod 1-[4-amino-2- Resiquimod (ethoxymethyl)imidazo[4,5-c]quinolin 1-yl]-2-methylpropan-2-ol WO 2013/167743 PCT/EP2013/059752 21 Podophyllo- (10R,11R,15R,16R)-16-hydroxy-10 toxin (PPT) (3,4,5-trimethoxyphenyl)-4,6,13 / podofilox trioxatetracy clo[7.7..0 3 ' 7.0 "' 1]hexadeca-1,3(7),8 trien-12-one Rifampicin (7S,9E,11S,12R,13S,14R,15R,16R,17S,18 rifampicin S,19E,21Z)-2,15,17,27,29- sodium pentahydroxy-11-methoxy 3,7,12,14,16,18,22-heptamethyl-26 {(E)-[(4-methylpiperazin-1 yl)imino]methyl}-6,23-dioxo-8,30 dioxa-24 azatetracy clo[23.3. 1. 14' 7. 05' 8] triaconta 1(28),2,4,9,19,21,25(29),26-octaen 13-yl acetate Methisazone [ (1-Methyl-2-oxoindol-3- Methisazone / Metisa- ylidene)amino]thiourea zone Enfuvirtide Acetyl-YTSLIHSLIEESQNQ Enfuvirtide QEKNEQELLELDKWASLWNWF-amide Maraviroc 4,4-difluoro-N-{ (1S)-3-[3-(3- Maraviroc isopropyl- 5-methyl-4H-1,2,4-triazol 4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1 phenylpropyl}cyclohexanecarboxamide Vicriviroc 6-dimethylpyrimidin-5-yl)-[4-[(3S)-4- Vicriviroc [(1R)-2-methoxy-1-[4- maleate (trifluoromethyl)phenyl]ethyl]-3 methylpiperazin-1-yl]-4 methylpiperidin-1-yl]methanone Cenicrivi- (5E)-8-[4-(2-butoxyethoxy)phenyl]-1- cenicrivi roc (2-methylpropyl)-N-[4-[(S)-(3- roc mesyl propylimidazol-4- ate yl)methylsulfinyl]phenyl]-3,4 dihydro-2H-1-benzazocine-5 carboxamide PRO 140 Humanized monoclonal IgG4 kappa anti body targeting human C-C chemokine receptor type 5 (CCR5); or HuPRO-140; WO 2013/167743 PCT/EP2013/059752 22 or PA-14 Ibalizumab Abacavir / { (1S,4R)-4-[2-amino-6- Abacavir ABC (cyclopropylamino)-9H-purin-9 yl]cyclopent-2-en-1-yl}methanol Emtricita- 4-amino-5-fluoro-1-[(2S,5R)-2- Emtricita bine / FTC (hydroxymethyl)-1,3-oxathiolan-5-yl]- bine 1,2-dihydropyrimidin-2-one Didanosine 9- ( (2R, 5S) -5- Didanosine (hydroxymethyl)tetrahydrofuran-2-yl) 3H-purin-6(9H)-one Zidovudine 1-[(2R,4S,5S)-4-azido-5- Zidovudine (ZDV) / az- (hydroxymethyl)oxolan-2-yl]-5 idothymi- methylpyrimidine-2,4-dione dine (AZT) Apricita- 4-amino-i-[(2R,4R)-2-(hydroxymethyl)- Apricita bine 1,3- oxathiolan-4-yl]pyrimidin-2(1H)- bine one Stampidine methyl N-((4-bromophenoxy) {[(2S,5R)- Apricita 5-(5-methyl-2,4-dioxo-3,4- bine dihydropyrimidin-1(2H)-yl)-2,5 dihydrofuran-2 yl]methoxy}phosphoryl)-D-alaninate Elvucita- 4-Amino-5-fluoro-1-[(2S,5R)-5- Elvucita bine (hydroxymethyl)-2,5-dihydrofuran-2- bine yl]pyrimidin-2-one Racivir 4-Amino-5-fluoro-1-[(2S,5R)-2- Racivir (hydroxymethyl)-1,3-oxathiolan-5 yl]pyrimidin-2(1H)-one Amdoxovir [(2R,4R)-4-(2,6-Diaminopurin-9-yl)- Amdoxovir 1,3-dioxolan-2-yl]methanol Stavudine 1-((2R,5S)-5-(hydroxymethyl)-2,5- Apricita dihydrofuran-2-yl)-5- bine methylpyrimidine-2,4(1H,3H)-dione Zalcitabine 4-amino-i-((2R,5S)-5- Zalcitabine (hydroxymethyl)tetrahydrofuran-2 yl)pyrimidin-2(1H)-one Festinavir Festinavir WO 2013/167743 PCT/EP2013/059752 23 GS 7340 (9-[(R)-2-[[[[(S)-1- Tenofovir (isopropoxycarbonyl)ethyl] amino] (Prodrug) phenoxy-phosphinyl]-methoxy] propyl] adenine); or Tenofovir alafenamide fumarate; or N-[[S(P)]-[2-(Adenin-9 yl)-1(R)-methylethoxymethyl] (phe noxy)phosphoryl]-L-alanine isopropyl ester hemifumarate; or TAF; or GS 7340-03 Efavirenz (4S)-6-chloro-4-(2- Efavirenz (EFV) cyclopropylethynyl)-4- (EFV) (trifluoromethyl)-2,4-dihydro-1H-3,1 benzoxazin-2-one Nevirapine 11-cyclopropyl-4-methyl-5,11-dihydro- Nevirapine 6H- dipyrido[3,2-b:2',3' e][1,4]diazepin-6-one Loviride / 2-[(2-Acetyl-5-methylphenyl)amino]-2- Loviride Loveride (2,6-dichlorophenyl)acetamide Delavirdine N-[2-({4-[3-(propan-2- Delavirdine (DLV) ylamino)pyridin-2-yl]piperazin-1- mesylate yl}carbonyl)-1H-indol-5 yl]methanesulfonamide Etravirine 4-[6-Amino-5-bromo-2- [(4 cyanophenyl)amino] pyrimidin-4 yl]oxy- 3,5-dimethylbenzonitrile Rilpivirine 4-{[4-({4-[(E)-2-cyanovinyl]-2,6- Rilpivirine dimethylphenyl}amino)pyrimidin-2 yl]amino}benzonitrile Lersivirine 5-{[3, 5-diethyl-1-(2-hydroxyethyl)- Lersivirine 1H-pyrazol-4-yl]oxy}benzene- 1, 3 dicarbonitrile Raltegravir N-(2-(4-(4-fluorobenzylcarbamoyl)-5- ralte hydroxy-1-methyl-6-oxo-1,6- gravir, dihydropyrimidin-2-yl)propan-2-yl) raltegravir potassium (pediatric) WO 2013/167743 PCT/EP2013/059752 24 Elvitegravi 6-[(3-Chloro-2-fluorophenyl)methyl]- Elvitegravi r 1-[(2S)-1-hydroxy-3-methylbutan-2- r yl]-7-methoxy-4-oxoquinoline-3 carboxylic acid Dolute- (4R,12aS)-N-(2,4-difluorobenzyl)-7- Dolute gravir hydroxy-4-methyl-6,8-dioxo- gravir 3,4,6,8,12,12a-hexahydro-2H pyrido[1',2':4,5]pyrazino[2,1 b][1,3]oxazine-9-carboxamide Globoidnan (2R)-(3,4-dihydroxyphenyl)-2-{[4 A (3,4-dihydroxyphenyl)-6,7-dihydroxy 2-naphthoyl]oxy}propanoic acid MK-2048 (6S)-2-(3-chloro-4-fluorobenzyl)-8 ethyl-10-hydroxy-N,6-dimethyl-1,9 dioxo-1,2,6,7,8,9 hexahydropyra zino[1',2':1,5]pyrrolo[2,3 dlpyridazine-4-carboxamide BI 224436 (2S)-[4-(3,4-Dihydro-2H-chromen-6 yl)-3-quinolinyl][(2-methyl-2 propanyl)oxy]acetic acid Bevirimat 3B- (3-carboxy-3-methyl -butanoyloxy) bevirimat lup-20(29)- en-28-oic acid dimeglumine Vivecon Fosampre- {[(2R,3S)-1-[N-(2-methylpropyl) (4- fosampre navir aminobenzene)sulfonamido]-3-({[(3S)- navir cal oxolan-3-yloxy]carbonyl}amino)-4- cium phenylbutan-2-yl]oxy}phosphonic acid Lopinavir (2S)-N-[(2S,4S,5S)-5-[2-(2,6- Lopinavir dimethylphenoxy)acetamido]-4-hydroxy 1,6-diphenylhexan-2-yl]-3-methyl-2 (2-oxo-1,3-diazinan-1-yl)butanamide Nelfinavir (3S,4aS,8aS)-N-tert-butyl-2-[(2R,3R)- Nelfinavir 2-hydroxy-3-[(3-hydroxy-2- mesylate methylphenyl)formamido]-4 (phenylsulfanyl)butyl] decahydroisoquinoline-3-carboxamide WO 2013/167743 PCT/EP2013/059752 25 Ritonavir 1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)- Ritonavir 3-hydroxy-5-[(2S)-3-methyl-2 {[methyl({[2-(propan-2-yl)-1,3 thiazol-4 yl]methyl})carbamoyl]amino}butanamido ]-1,6-diphenylhexan-2-yl]carbamate Saquinavir (2S)-N-[(2S,3R)-4-[(3S)-3-(tert- Saquinavir, butylcarbamoyl)-decahydroisoquinolin- Saquinavir 2-yl]-3-hydroxy-1-phenylbutan-2-yl]- mesylate 2-(quinolin-2 ylformamido)butanediamide Amprenavir (3S)-oxolan-3-yl N-[(2S,3R)-3- Amprenavir hydroxy-4-[N-(2-methylpropyl) (4 aminobenzene)sulfonamido]-1 phenylbutan-2-yl]carbamate Indinavir (2S)-1-[(2S,4R)-4-benzyl-2-hydroxy-4- Indinavir (IDV) {[(1S,2R)-2-hydroxy-2,3-dihydro-1H inden-1-yl]carbamoyl}butyl]-N-tert butyl-4-(pyridin-3 ylmethyl)piperazine-2-carboxamide Atazanavir methyl N-[(1S)-1-{[(2S,3S)-3-hydroxy- Atazanavir 4-[(2S)-2-[(methoxycarbonyl)amino] 3,3-dimethyl-N'-{[4-(pyridin-2 yl)phenyl]methyl}butanehydrazido]-1 phenylbutan-2-yl]carbamoyl}-2,2 dimethylpropyl]carbamate Darunavir [ (1R, 5S, 6R) -2,8- Darunavir dioxabicyclo[3.3.0]oct-6-yl] N [(2S,3R)-4- [(4-aminophenyl)sulfonyl (2-methylpropyl)amino]-3-hydroxy-1 phenyl- butan-2-yl] carbamate Tipranavir N-{3-[(1R)-1-[(2R)-6-hydroxy-4-oxo-2- tipranavir (2-phenylethyl)-2-propyl-3,4-dihydro- disodium 2H-pyran-5-yl]propyl]phenyl}-5 (trifluoromethyl)pyridine-2 sulfonamide Trichosan- Trichosan thin (TCS) thin WO 2013/167743 PCT/EP2013/059752 26 Calanolide (+)-[10R,11S,12S]-10,11-trans A dihydro-12-hydroxy-6,6,10,11 tetramethyl-4-propyl-2H,6H-benzo[1,2 b:3,4-b':5,6-b'']tripyran-2-one Ceragenin / cationic steroid an tibiotics (CSAs) Cyanovirin- cyanovirin N (CV-N) N (pegylat ed) Epigallo- (2R,3R)-5,7-dihydroxy-2-(3,4,5 catechin trihydroxyphenyl)-3,4-dihydro-2H-1 gallate benzopyran-3-yl 3,4,5 (EGCG) trihydroxybenzoate Griffithsin Hydroxycar- hydroxyurea hydroxyurea bamide / hydroxyurea Miltefosine 2-(hexadecoxy-oxido- Miltefosine phosphoryl)oxyethyl-trimethyl-azanium Seliciclib 2- (R) - (1-Ethyl-2-hydroxyethylamino) - Seliciclib 6-benzylamino-9-isopropylpurine Resveratrol (E)-5-(4-hydroxystyryl)benzene-1,3- Resveratrol diol Chloroquine (RS)-N'-(7-chloroquinolin-4-yl)-N,N- chloro diethyl-pentane-1,4-diamine quine, chloroquine phosphate Leflunomide 5-methyl-N-[4-(trifluoromethyl) phe- Leflunomide nyl]-isoxazole-4-carboxamide Mycophenol- (4E)-6-(4-Hydroxy-6-methoxy-7-methyl- mycopheno ic acid 3-oxo-1,3-dihydro-2-benzofuran-5-yl)- late mo 4-methylhex-4-enoic acid fetil, my cophenolate sodium WO 2013/167743 PCT/EP2013/059752 27 Cobicistat Thiazol-5-ylmethyl N-[1-benzyl-4-[[2- Cobicistat [[(2-isopropylthiazol-4-yl)methyl methyl-carbamoyl]amino]-4-morpholino butanoyl]amino]-5-phenyl pentyl]carbamate Dexelvu- 4-Amino-5-fluoro-1-[(2R,5S)-5- Dexelvu citabine (hydroxymethyl)-2,5-dihydrofuran-2- citabine yl]pyrimidin-2-one Capravirine [5-(3,5-Dichlorophenyl)sulfanyl-4- Capravirine propan-2-yl-1-(pyridin-4 ylmethyl)imidazol-2-yl]methyl carba mate Emivirine 1-(ethoxymethyl)-6-(phenylmethyl)-5- Emivirine propan-2-ylpyrimidine-2,4-dione Lodenosine [(2S,4S,5R)-5-(6-Aminopurin-9-yl)-4- Lodenosine fluorooxolan-2-yl]methanol Atevirdine [4-[3-(ethylamino)pyridin-2- Atevirdine yl]piperazin-1-yl]-(5-methoxy-1H- mesylate indol-2-yl)methanone Brecanavir [(3R,3aS,6aR)-2,3,3a,4,5,6a- Brecanavir Hexahydrofuro[5,4-b]furan-3-yl] N [(2S,3R)-4-(1,3-benzodioxol-5 ylsulfonyl-(2-methylpropyl)amino)-3 hydroxy-1-[4-[(2-methyl-1,3-thiazol 4-yl)methoxy]phenyl]butan-2 yl]carbamate Aplaviroc 4-(4-{[(3R)-1-butyl-3-[ (R)- Aplaviroc cyclohexylhydroxymethyl]-2,5-dioxo 1,4,9-triazaspiro[5.5]undecan-9 yl]methyl}phenoxy)benzoic acid Boceprevir (1R,2S,5S)-N-[(22)-4-amino-1- Boceprevir cyclobutyl-3,4-dioxobutan-2-yl)]- 3 {(2S)-2-[(tert-butylcarbamoyl)amino] 3,3-dimethylbutanoyl}- 6,6-dimethyl 3-azabicyclo[3.1.0]hexane-2 carboxamide WO 2013/167743 PCT/EP2013/059752 28 Telaprevir (1S,3aR,6aS)-2-[(2S)-2-[[(2S)-2- Telaprevir Cyclohexyl-2-(pyrazine-2 carbonylamino)acetyl]amino]-3,3 dimethylbutanoyl]-N-[(3S)-1 (cyclopropylamino)-1,2-dioxohexan-3 yl]-3,3a,4,5,6,6a-hexahydro-1H cyclopenta[cipyrrole-1-carboxamide Pleconaril 3-{3,5-dimethyl-4-[3-(3- Pleconaril methylisoxazol-5-yl)propoxy]phenyl} 5-(trifluoromethyl)-1,2,4-oxadiazole Arbidol 1-methyl-2-((phenylthio)methyl)-3- Arbidol carbethoxy-4-((dimethylamino)methyl) 5-hydroxy-6-bromindole Amantadine adamantan-1-amine Amantadine Rimantadine (RS)-1-(1-adamantyl)ethanamine Rimantadine Oseltamivir ethyl (3R,4R,5S)-5-amino-4-acetamido- Oseltamivir 3-(pentan-3-yloxy)-cyclohex-1-ene-1 carboxylate Zanamivir (2R,3R,4S)-4-guanidino-3-(prop-i-en- Zanamivir 2-ylamino)-2-((1R,2R)-1,2,3 trihydroxypropyl)-3,4-dihydro-2H pyran-6-carboxylic acid Peramivir (1S,2S,3S,4R)-3-[(1S)-1-acetamido-2- Peramivir ethyl-butyl]-4- (diaminomethylidene amino)-2-hydroxy-cyclopentane- 1 carboxylic acid Laninamivir (4S,5R,6R)-5-acetamido-4- Laninamivir carbamimidamido-6-[(1R,2R)-3-hydroxy 2-methoxypropyl]-5,6-dihydro-4H pyran-2-carboxylic acid PS17977 Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5- PS17977 (2,4-dioxopyrimidin-1-yl)-4-fluoro-3 hydroxy-4-methyl-tetrahydrofuran-2 yl methoxy-phenoxy phosphoryl]amino]propanoate; or Sofosbuvir; or P(S)]-N-(2'-Deoxy-2' fluoro-2'-methyluridin-5'-0 yl) (phenoxy)phosphoryl]-L-alanine WO 2013/167743 PCT/EP2013/059752 29 isopropyl ester; or GS-7977 INX189 6-0-Methyl-2'-C-methyl-5'-O-[O-(2,2- INX189 dimethylpropyl)-L alanino] (naphthalen-1 yloxy)phosphoryl]guanosine N-[(2'-C,6-0-Dimethylguanosin-5'-0 yl) (naphthalen-1-yloxy)phosphoryl]-L alanine 2,2-dimethylpropyl ester; or INX-08189; or BMS-986094 Alamifovir disoproxil fumarate Alamifovir disoproxil hemi fumarate Table 3c: active compounds (INN), List of Integrity Polymerase Inhibitors: Rifapentine, Fidaxomicin, 2'-Deoxy-2'-methylidencytidine; 4 Amino-i-(2'-deoxy-2'-methyliden-1'-beta-D-ribofuranosyl)-2(1H) pyrimidinone, Aphidicolin glycinate, Clofarabine, Tezacitabine, 1-(2-Cyano-2-deoxy-beta-D-arabinofuranosyl)cytosine, Sapacita bine, Alkasar-18, Ethynylcytidine, Troxacitabine, Actinomycin D / Dactinomycin, Bakuchiol; Drupanol, Torcitabine, Hexadecyloxy propyl-cidofovir, 7-Deaza-2'-C-methyladenosine, Bis(2,2 dimethylpropionic acid) 1-(2-amino-9H-purin-9 ylmethyl)cyclopropoxymethylphosphorylbis(oxymethylene) diester, 2-[4-[4'-Chloro-4-(2-oxopyrrolidin-1-yl)biphenyl-2-ylmethoxy]-2 fluorophenyl]-1-cyclohexyl-1H-benzimidazole-5-carboxylic acid hydrochloride, 4'-C-Azidocytidine, 4-Amino-i-[(2R,3R,4R,5R)-3,4 dihydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2 yl]pyrimidin-2(1H)-one; 2'-C-Methylcytidine, 2-[5-Cyano-8 methyl-1(R)-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1 yl]acetic acid, 2-(4-Fluorophenyl)-5-isopropoxy-N-methyl-6 (methylsulfonamido)-1-benzofuran-3-carboxamide, 2'-C Methylguanosine, Balapiravir hydrochloride, 1-(2'-Deoxy-2' fluoro-2'-C-methyl-beta-D-ribofuranosyl)cytosine, 8-[3(R)-[l-[N [1-[21(S)-Acetoxy-5,6,9,17(S),19(R)-pentahydroxy-23(S)-methoxy 2(S),4,12,16(S),18 (R),20(R),22(R)-heptamethyl-1,11-dioxo-1,2- WO 2013/167743 PCT/EP2013/059752 30 dihydro-2,7-(epoxy[1,11,13]pentadecatrienimino)naphtho[2,1 b]furan-8-ylmethylideneamino]piperidin-4-yl]-N methylamino]cyclopropyl]pyrrolidin-1-yl]-1-cyclopropyl-7-fluoro 9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid; 8-[4-[N-[1-[1 (3-Carboxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizin 8-yl)pyrrolidin-3(R)-yl]cyclopropyl]-N-methylamino]piperidin-1 yliminomethyl]rifamycin SV, 1-(4-tert-Butyl-3-methoxybenzoyl) 4(S)-(methoxymethyl)-2 (R)-(1H-pyrazol-1-ylmethyl)-5 (R)-(2 thiazolyl)pyrrolidine-2-carboxylic acid, Filibuvir Table 3d: active compounds (INN), List of Integrity RTIs: N-(2-Nitrobenzoyl)-N'-[4-(5-bromo-2-pyrimidinyloxy)-3 chlorophenyl]urea, Dioxolane T; Dioxolane thymine nucleoside, Berberine iodide, 3'-Azido-3'-deoxythymidylyl-(5',5')-2',3' dideoxy-5'-inosinic acid, Lipoic acid, 3-(4,7 Dichlorobenzoxazol-2-ylmethylamino)-5-ethyl-6-methylpyridin 2(1H)-one; (L-697661), 3-(4,7-Dimethylbenzoxazol-2 ylmethylamino)-5-ethyl-6-methylpyridin-2(1H)-one; (L-697639), 3 [2-(Benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridine-2(1H)-one (L-696229), 1-(2,6-Difluorophenyl)-1H,3H-thiazolo[3,4 a]benzimidazole (NSC-625487), 5-Ethyl-3-(5-ethyl-2-methoxy-6 methylpyridin-3-ylmethylamino)-6-methylpyridin-2 (1H)-one (L 702007), Apricitabine; (±)-cis-1-[2-(Hydroxymethyl)-1,3 oxathiolan-4-yl]cytosine; (±)-2'-Deoxy-3'-oxa-4'-thiocytidine (dOTC), (-)-(S)-6-Chloro-2-[1-(furo[2,3-c]pyridin-5 yl)ethylsulfanyl]pyrimidine-4-amine (PNU-142721), (-)-6-Chloro 4(S)-(2-cyclopropylethynyl)-4-(trifluoromethyl)-3,4-dihydro-1H quinazolin-2-one, 4(S)-(2-Cyclopropylethynyl)-5,6-difluoro-4 (trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-one, N-(5 Cyanopyridin-2-yl)-N'-[(1S,2S)-2-(6-fluoro-2-hydroxy-3 propionylphenyl)cyclopropyl]urea, Phosphonovir, (E)-6-Chloro 4(S)-(2-cyclopropylvinyl)-4-(trifluoromethyl)-3,4-dihydro-1H quinazolin-2-one, (E)-4(S)-(2-Cyclopropylvinyl)-5,6-difluoro-4 (trifluoromethyl)-3,4-dihydro-1H-quinazolin-2-one, (-)-(2R,4R) 4-[2-Amino-6-(cyclopropylamino)-9H-purin-9-yl]-1,3-dioxolane-2 methano, Lagociclovir valactate, (+)-2(R)-(3,4-Dihydroxyphenyl) 3(R),5,7-trihydroxy-2,3-dihydro-4H-1-benzopyran-4-one; (Dihy droquercetin); taxifolin, 32-Cascade:N-[(S) diphenylmethylacetamide][2-2,2]:[(S)-2-oxo-3-azapropylidene:2 oxo-3-azaheptylidene]4:[(S)-3-oxo-4-aza-1-oxabutyl:3-oxo-4-aza- WO 2013/167743 PCT/EP2013/059752 31 1-oxaoctylede]naphthalene-2,7-disulfonic acid disodium salt, 11 Ethyl-5-methyl-8-[2-(1-oxidoquinolin-4-yloxy)ethyl]-6,11 dihydro-5H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, Tenofovir alafenamide fumarate, N-[4-[2-[4-Chloro-2-(3-chloro-5 cyanobenzoyl)phenoxy]acetamido]-3 methylphenylsulfonyl]propionamide sodium salt, 2-[4-Chloro-2-(3 chloro-5-cyanobenzoyl)phenoxy]-N-(2-methyl-4 sulfamoylphenyl)acetamide; 4-[2-[4-Chloro-2-(3-chloro-5 cyanobenzoyl)phenoxy]acetamido]-3-methylbenzenesulfonamide, Ler sivirine, 5(S)-(Cyclopropylmethoxy)-7-fluoro-5 (trifluoromethyl)-5,10-dihydrobenzo[b]-1,8-naphthyridine 1 oxide, Festinavir, Niglizin, [S(P)]-[5(R)-(9H-Adenin-9-yl)-4 fluoro-2,5-dihydrofuran-2(R)-yloxymethyl]-N-[l(S) (ethoxycarbonyl)ethyl]phosphonamidic acid phenyl ester, 2-[4 Bromo-3-(3-chloro-5-cyanophenoxy)-2-fluorophenyl]-N-[2-chloro-4 (propionamidosulfonyl)phenyl]acetamide sodium salt, 4-[2-[5 Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3 ylsulfanyl]acetamido]-3-chlorobenzoic acid potassium salt, Fosdevirine, 2-[5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H 1,2,4-triazol-3-ylsulfanyl]-N-(2-chloro-4 sulfamoylphenyl)acetamide, 3-[5-(6-Amino-1H-pyrazolo[3,4 b]pyridin-3-ylmethoxy)-2-chlorophenoxy]-5-chlorobenzonitrile, 3 [4-[1-[3-Cyclopentyl-1-methyl-2-(2-pyridyl)-1H-indol-6 ylcarboxamido]cyclobutylcarboxamido]phenyl]-2-propenoic acid trifluoroacetate, Mericitabine, 5'-0-[(Benzylamino) [2-(3 hydroxy-2,2-dimethylpropionylsulfanyl)ethoxyiphosphoryl]-2'-C methylguanosine, 6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6 cyclopentyl-3-(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2 ylsulfanyl)-4-hydroxy-5,6-dihydropyran-2-one, Tegobuvir, 2-(4 Methyl-1,4-diazepan-1-yl)-N-(5-methylpyrazin-2-ylmethyl)-5-oxo 5H-benzothiazolo[3,2-a][1,8]naphthyridine-6-carboxamide, N-[6 [3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2 methoxyphenyl]naphthalen-2-yl]methanesulfonamide, 2-Hydroxy N,N,N-trimethylethanaminium (2S)-2-tert-butyl-1-(3,3 dimethylbutyl)-4-[1-ethoxy-7-[(methylsulfonyl)amino]-1-oxido 1,4-dihydro-2,4,1-benzodiazaphosphorin-3-yl]-5-oxo-2,5-dihydro 1H-pyrrol-3-olate, N-(4-[(E)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4 dihydropyrimidin-1(2H)-yl)-2 methoxyphenyl]ethenyl]phenyl)methanesulfonamide, Lomibuvir, Lurbinectedin, Deleobuvir, cis-4'-Azido-5'-O-[4(S)-(3- WO 2013/167743 PCT/EP2013/059752 32 chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-2',3'-0 bis(propionyl)uridine, 1-(2-Amino-6-ethoxy-9H-purin-9-yl)-2 fluoro-2-C-methyl-1,2-dideoxy-beta-D-ribofuranose 3,5-cyclic [P(R)]-isopropylphosphate, (laR,12bS)-8-Cyclohexyl-N (dimethylsulfamoyl)-11-methoxy-la-[(3-methyl-3,8 diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1,1a,2,12b tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5 carboxamide, 6-0-Methyl-2'-C-methyl-5'-0-[0-(2,2 dimethylpropyl)-L-alanino] (naphthalen-1 yloxy)phosphoryl]guanosine, Setrobuvir, Sofosbuvir, 13 Cyclohexyl-3-methoxy-17,23-dimethyl-7H-10,6 (methanoiminothioiminoethanooxyethanoiminomethano)indolo[2,1 a][2]benzazepine-14,24-dione 16,16-dioxide, (2R)-4-(5 Cyclopropyl[1,3]thiazolo[4,5-d]pyrimidin-2-yl)-N-[3-fluoro-4 (trifluoromethoxy)benzyl]-1-[[4 (trifluoromethyl)phenyl]sulfonyl]piperazine-2-carboxamide, (2R,3S,4S,5R)-5-(4-Amino-2-oxopyrimidin-1(2H)-yl)-2-azido-4 methyl-2-[[(2-methylpropanoyl)oxy]methyl]tetrahydrofuran-3-yl 2 methylpropanoate, 5-(3,3-Dimethylbut-1-yn-1-yl)-3-[[cis-4 hydroxy-4-[[(3S)-tetrahydrofuran-3 yloxy]methyl]cyclohexyl][[(1R)-4-methylcyclohex-3-en-1 yl]carbonyl]amino]thiophene-2-carboxylic acid, N-[(S)-[5(R)-(4 Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-4(R)-hydroxy 3 (R)-(isobutyryloxy)-4-methyltetrahydrofuran-2 (R) ylmethoxy] (phenoxy)phosphoryl]-L-alanine isopropyl ester, [4 [[[5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)-1 benzofuran-6-yl] (methylsulfonyl)amino]methyl]-2 fluorophenyliboronic acid Table 3 consists of table 3a, 3b, 3c and 3d. Preferred inventive compounds are Tomeglovir derivatives, Alamifovir or Alamifovir derivatives, Emtricitabine or Emtricit abine derivatives, Entecavir or Entecavir derivatives, Adefovir or Adefovir derivatives, Cidofovir or Cidofovir derivatives, Tenofovir or Tenofovir derivatives. In special inventive groups of active compounds Adefovir (PMEA) is included or excluded. In special inventive groups of active compounds Adefovir Dipivoxil (Bis-POM PMEA) is included or excluded. In special inventive groups of active compounds Tenofovir (PMPA) is included or ex- WO 2013/167743 PCT/EP2013/059752 33 cluded. In special inventive groups of active compounds Pradefo vir (Remofovir, CAS 625095-60-5) is included or excluded. In a preferment, the inventive compound is Tomeglovir (Syno nym: BAY-38-4766; Chemical name: N-[4-[5-(Dimethylamino)-1 naphthylsulfonamido]phenyl]-3-hydroxy-2,2-dimethylpropionamide; CAS number: 233254-24-5), or any derivatives, salts, prodrugs or metabolites of Tomeglovir. Tomeglovir is an antiviral compound that was originally developed against Cytomegalovirus infection, and its antiviral properties are effected by the inhibition of viral terminase enzyme. In a preferment , the Tomeglovir deriva tive is selected from the derivatives as described in EP 1049666 B1 (incorporated herein by reference), especially selected from the compounds, or intermediates thereof, of the formula (I): / NR4-CO-R 3 NR RSO N(I G in which R and R2 are identical or different and represent hydrogen, formyl, phenyl or benzyl optionally substituted by one to three halogen atoms, or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, where alkyl or acyl can optionally be substituted by one to three substituents selected from halo gen and hydroxyl, A, D, E and G are identical or different and represent hydro gen, halogen, nitro, cyano, hydroxyl, carboxyl, trifluoromethyl, trifluoromethoxy or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms,
R
3 represents straight-chain or branched alkenyl having up to 6 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms, which optionally carries an amino group which can optionally be substituted by alkyl having up to 4 carbon atoms or by an amino protective group, or the alkyl is optionally identically or differently substituted one to 3 times by hydroxyl, cyano, halogen, azido, nitro, trifluoromethyl, car boxyl or phenyl which, for its part, can be identically or dif ferently substituted up to 2 times by nitro, halogen, hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, or R 3 represents radicals of the formulae: WO 2013/167743 PCT/EP2013/059752 34
CH
3
CH
3 or -L-O-CO-Q in which L represents a straight-chain or branched alkanediyl group having up to 6 carbon atoms, Q represents alkyl having up to 6 carbon atoms, which is op tionally substituted by carboxyl, or represents radicals of the formulae: (H2C)'
R
5
R
6 or 7 NRR , N in which a denotes the number 1 or 2,
R
5 denotes hydrogen,
R
6 denotes cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms or hydrogen, or denotes straight-chain or branched alkyl having up to 8 carbon atoms, where the alkyl is optionally substituted by cyano, methylthio, hydroxyl, mercapto, guanidyl or by a group of the formula -NR 9 Rl 0 or -R"-OC-, in which
R
9 and R1 0 independently of one another denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, and R" denotes hydroxyl, benzyloxy, alkoxy having up to 6 carbon atoms or the abovementioned group -NR 9
R'
0 , or the alkyl is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which, for its part, is substituted by hydroxyl, halogen, nitro, alkoxy having up to 8 carbon atoms or by the group -NR 9
R'
0 , in which
R
9 and R1 0 have the meaning indicated above, or the alkyl is optionally substituted by a 5- to 6-membered ni trogen-containing heterocycle or by indolyl, in which the corre sponding -NH functions are optionally substituted by alkyl hav ing up to 6 carbon atoms or protected by an amino protective group, WO 2013/167743 PCT/EP2013/059752 35 R7 and R8 are identical or different and denote hydrogen or an amino protective group,
R
4 denotes hydrogen or a radical of the formula
R
5 ' R 6 -CO NR R in which 5' 6' 7' 8' 6 7 R R', R and R8' have the meaning of R , R , R and R8 indicated above and are identical to or different from this, X has the meaning of R 4 indicated above and can be identical to or different from this meaning, and their stereoisomers, stereoisomeric mixtures and salts. N-[4-[[[5-(dimethylamino)-1-naphthalenyl]sulphonyl] amino]phenyl]acetamide may be included or excepted from these compounds. Preferably said compounds or intermediates or derivatives thereof are of the general formula (I), in which R and R2 are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl or acyl each having up to 6 carbon atoms, A, D, E and G are identical or different and represent hydro gen, halogen, nitro, cyano, hydroxyl, carboxyl, trifluoromethyl, trifluoromethoxy or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 5 carbon atoms,
R
3 represents straight-chain or branched alkenyl having up to 6 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms, which optionally carries an amino group which can be substituted by alkyl having up to 4 carbon atoms or by an amino protective group, or the alkyl is optional ly identically or differently substituted one to 3 times by hy droxyl, cyano, halogen, azido, nitro, trifluoromethyl, carboxyl or phenyl which, for its part, can be identically or differently substituted up to 2 times by nitro, halogen, hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, or
R
3 represents radicals of the formulae WO 2013/167743 PCT/EP2013/059752 36
CH
3 H3 or -L-O-CO-Q o o in which L represents a straight-chain or branched alkanediyl group having up to 6 carbon atoms, Q represents alkyl having up to 6 carbon atoms, which is op tionally substituted by carboxyl, or represents radicals of the formulae (HC) ao R 5 R 6 or 7N8~ NN -"XNR R in which a denotes the number 1 or 2,
R
5 denotes hydrogen,
R
6 denotes cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms or hydrogen, or denotes straight-chain or branched alkyl having up to 8 carbon atoms, where the alkyl is optionally substituted by cyano, methylthio, hydroxyl, mercapto, guanidyl or by a group of the formula NR 9 Ri 0 or -R"-OC-, in which
R
9 and Ri 0 independently of one another denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, and R" denotes hydroxyl, benzyloxy, alkoxy having up to 6 carbon atoms or the abovementioned group -NR 9
R'
0 , or the alkyl is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms which, for its part, is substituted by hydroxyl, halogen, nitro, alkoxy having up to 8 carbon atoms or by the group -NR 9
R'
0 , in which
R
9 and R1 0 have the meaning indicated above, or the alkyl is optionally substituted by a 5- to 6-membered ni trogen-containing heterocycle or by indolyl, in which the corre sponding -NH functions are optionally substituted by alkyl hav ing up to 6 carbon atoms or protected by an amino protective group, WO 2013/167743 PCT/EP2013/059752 37 R7 and R8 are identical or different and denote hydrogen or an amino protective group,
R
4 represents hydrogen or a radical of the formula
R
5 R' -CO NR R in which 5' 6' 7'8 5 6 78 R R', R and R8' have the meaning of R , R , R and R8 indi cated above and are identical to or different from these, and X represents hydrogen, and their stereoisomers, stereoisomer mixtures and salts. Preferably said compounds or intermediates or derivatives thereof are of the general formula (I), in which
R
3 represents straight-chain or branched alkenyl having up to 6 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms, in which the alkyl carries an amino group which can be substituted by alkyl having up to 4 carbon atoms or by an amino protective group, or the alkyl is identi cally or differently substituted one to 3 times by hydroxyl, cy ano, halogen, azido, nitro, trifluoromethyl, carboxyl or phenyl which, for its part, can be identically or differently substi tuted up to 2 times by nitro, halogen or hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 4 carbon atoms, or
R
3 represent radicals of the formulae CH CH 3 0 O) j+ or -L-O-CO-Q in which L and Q are as defined above. Preferably said compounds or intermediates or derivatives thereof are of the general formula (I) above, in which R and R2 are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl or acyl each having up to 5 carbon atoms, WO 2013/167743 PCT/EP2013/059752 38 A, D, E and G are identical or different and represent hydro gen, fluorine, chlorine, bromine, nitro, cyano, hydroxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,
R
3 represents straight-chain or branched alkenyl having up to 5 carbon atoms, or represents straight-chain or branched alkyl having up to 7 car bon atoms which optionally carries an amino group which can be substituted by alkyl having up to 3 carbon atoms, tert- bu tyloxycarbonyl or benzyloxycarbonyl, or the alkyl is optionally identically or differently substituted one to 3 times by hydrox yl, cyano, fluorine, chlorine, azido, nitro, trifluoromethyl or phenyl which, for its part, can be identically or differently substituted up to 2 times by nitro, fluorine, chlorine or hy droxyl or by straight-chain or branched alkyl or alkoxy having up to 3 carbon atoms, or
R
3 represent radicals of the formulae:
CH
3 CHa 0 O or -L-O-CO-Q in which L represents a straight-chain or branched alkanediyl group having up to 4 carbon atoms, Q represents alkyl having up to 4 carbon atoms, which is op tionally substituted by carboxyl, or represents radicals of the formulae: (H C)a R5 R6 or78 N NR'R' in which a denotes the number 1 or 2,
R
5 denotes hydrogen,
R
6 denotes cyclopentyl, cyclohexyl, phenyl or hydrogen, or de notes straight-chain or branched alkyl having up to 6 carbon at oms, WO 2013/167743 PCT/EP2013/059752 39 where the alkyl can optionally be substituted by cyano, methyl thio, hydroxyl, mercapto, guanidyl, amino, carboxyl or H 2 N-CO-, or the alkyl is substituted by cyclohexyl, naphthyl or phenyl which, for its part, can be substituted by fluorine, hydroxyl, nitro or alkoxy having up to 4 carbon atoms, or the alkyl is substituted by indolyl, imidazolyl, pyridyl, triazolyl or pyrazolyl, where the corresponding -NH functions are optionally substituted by alkyl having up to 4 carbon atoms or protected by tert-butyloxycarbonyl or benzyloxycarbonyl, R7 and R8 are identical or different and denote hydrogen, tert butyloxycarbonyl or benzyloxycarbonyl,
R
4 represents hydrogen or a radical of the formula: R' R 6 X 7r 8s CO NR R in which 5 6 78 RE' Rs' R' and R8' have the meaning of R , R , R7 and R8 indicated above and are identical to or different from these, and their stereoisomers, stereoisomer mixtures and salts. Preferably said compounds or intermediates or derivatives thereof are of the general formula (I) above, in which
R
3 represents straight-chain or branched alkenyl having up to 5 carbon atoms, or represents straight-chain or branched alkyl having up to 7 car bon atoms, in which the alkyl carries an amino group which can be substituted by alkyl having up to 3 carbon atoms, tert butyloxycarbonyl or benzyloxycarbonyl, or the alkyl is identi cally or differently substituted one to 3 times by hydroxyl, cy ano, fluorine, chlorine, azido, nitro, trifluoromethyl or phenyl which, for its part, can be identically or differently substi tuted up to 2 times by nitro, fluorine, chlorine or hydroxyl or by straight-chain or branched alkyl or alkoxy having up to 3 carbon atoms, or
R
3 represents radicals of the formulae WO 2013/167743 PCT/EP2013/059752 40
CH
3 CHa 03 O or -L--CO-Q in which L and Q are as defined above. Preferably said compounds or intermediates or derivatives thereof are of the general formula (I), above in which R and R2 are identical or different and represent hydrogen, phenyl or straight-chain or branched alkyl or acyl each having up to 4 carbon atoms, A, D, E and G are identical or different and represent hydro gen, fluorine, chlorine, bromine, hydroxyl, methyl or methoxy,
R
3 represents straight-chain or branched alkenyl having up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 5 car bon atoms, which optionally carries an amino group which can be substituted by tert-butyloxycarbonyl or benzyloxycarbonyl, or which is optionally identically or differently substituted one to 3 times by hydroxyl, cyano, fluorine, chlorine, nitro, azido, trifluoromethyl or phenyl which, for its part, can be identical ly or differently substituted up to 2 times by nitro, fluorine, chlorine, hydroxyl, methyl, ethyl, methoxy or ethoxy, or
R
3 represents radicals of the formulae
CH
3 . 0 ) + or L-O-CO-Q in which L represents a straight-chain or branched alkanediyl group having up to 4 carbon atoms, Q represents alkyl having up to 3 carbon atoms, which is op tionally substituted by carboxyl, or represents a radical of the formula NR'R' , in which WO 2013/167743 PCT/EP2013/059752 41
R
5 denotes hydrogen,
R
6 denotes cyclopentyl, cyclohexyl or hydrogen, or denotes straight-chain or branched alkyl having up to 4 carbon atoms, where the alkyl can optionally be substituted by cyano, methyl thio, hydroxyl, mercapto, guanidyl, amino, carboxyl or H 2 N-CO-, or the alkyl is substituted by cyclohexyl, naphthyl or phenyl which, for its part, can be substituted by fluorine, chlorine or alkoxy having up to 4 carbon atoms, or the alkyl is substituted by indolyl, imidazolyl, triazolyl, pyridyl or pyrazolyl, where the corresponding -NH functions are optionally substituted by methyl or protected by benzyloxymeth ylene or tert-butyloxy-carbonyl (BOC), R7 and R8 are identical or different and denote hydrogen or tert-butyloxycarbonyl,
R
4 represents hydrogen or a radical of the formula
R
5
R
6 "K 7 8 CO NR R in which 5' 6' 7'8 5 6 7 R R', R and R8' have the meaning of R , R , R and R8 indicated above and are identical to or different from these, and their stereoisomers, stereoisomer mixtures and salts. Preferably said compounds or intermediates or derivatives thereof are of the general formula (I) above, in which
R
3 represents straight-chain or branched alkenyl having up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 5 car bon atoms, in which the alkyl carries an amino group which can be substituted by tert-butyloxycarbonyl or benzyloxycarbonyl, or the alkyl is identically or differently substituted one to 3 times by hydroxyl, cyano, fluorine, chlorine, nitro, azido, tri fluoromethyl or phenyl which, for its part, can be identically or differently substituted up to 2 times by nitro, fluorine, chlorine, hydroxyl, methyl; ethyl, methoxy or ethoxy, or
R
3 represents radicals of the formulae WO 2013/167743 PCT/EP2013/059752 42
CH
3
CH
3 -0 ) or -L-0-CO-Q in which L or Q are as defined above, and their stereoisomers, stereoisomeric mixtures and salts. Preferably said compounds or intermediates or derivatives thereof are of the general formula (I) above, in which R and R2 represent straight-chain or branched alkyl having up to 4 carbon atoms, A, D, E and G represent hydrogen,
R
3 represents straight-chain or branched alkyl having up to 5 carbon atoms, which is substituted by hydroxyl, or
R
3 represents a radical of the formula -L-0-CO-Q in which L represents a straight-chain or branched alkanediyl group having up to 4 carbon atoms, Q represents a radical of the formula
R
5
R
6 RS RR - NR 7 R> in which
R
5 and R 6 denote hydrogen, and R7 and R8 denote hydrogen, and
R
4 represents hydrogen and their stereoisomers, stereoisomeric mixtures and salts. Preferably said compounds or intermediates or derivatives thereof are of the general formula (I) above, which are selected from the group of the following compounds H3C N CH 3 O SoqO -' C OH
H
3 C 3 and WO 2013/167743 PCT/EP2013/059752 43
H
3 C' NCH3 x 2 HCI O- 0 0NH2 The compound may be provided in a composition in association with a pharmaceutically acceptable substantially nontoxic carri er or excipient. In a preferment, the inventive compound is Alamifovir (Syno nym: LY-582563, MCC-478; Chemical name: Bis(2,2,2 trifluoroethyl) ((2-(2-amino-6-((4-methoxyphenyl)sulfanyl)-9H purin-9-yl)ethoxy)methyl)phosphonate;Bis(2,2,2-trifluoroethyl) ((2-{2-amino-6-((4-methoxyphenyl)sulfanyl)-9H-purin-9 yl}ethoxy)methyl)phosphonate; CAS number: 193681-12-8), or any derivatives, salts, prodrugs, metabolites of Alamifovir, includ ing but not restricted to the prodrugs Alamifovir disoproxil fumarate and Alamifovir disoproxil hemifumarate, or 'related compounds' of Alamifovir. Alamifovir is a purine nucleotide ana logue antiviral compound that was originally developed against Hepatitis B virus infection, and its antiviral properties are effected by the inhibition of viral DNA polymerase enzyme. Ala mifovir disoproxil hemifumarate is a prodrug of Alamifovir, that has been in the preclinical phase of development in rodents, as an anti-Hepatitis B antiviral. In a preferment, the derivative or salt or prodrug or metab olite of Alamifovir is selected from the compounds as described in EP 0785208 B1 and EP 2511281 Al (all incorporated herein by reference), especially selected from the compounds, or their salts or hydrates or solvates or intermediates thereof, of the formula (I): N N:NN N N
NH
2 0 2
CH
2
CHOCH
2 - OR 2 I 4
R
4
OR
3 WO 2013/167743 PCT/EP2013/059752 44 wherein R1 represents hydrogen atom, a C1-C6 alkoxy group, a Ci
C
4 alkoxy group substituted with one or more halogen atoms, a hal ogen atom, amino group, or nitro group; R2 and R independently represent hydrogen atom, a C1-C22 alkyl group, an acyloxymethyl group, an acylthioethyl group, or an ethyl group substituted with one or more halogen atoms; R 4 represents hydrogen atom, a Ci C4 alkyl group, a Ci-C4 hydroxyalkyl group, or a Ci-C4 alkyl group substituted with one or more halogen atoms; and X represents a carbon atom or a nitrogen atom. Preferably, R1 represents hydrogen atom or a C1-C6 alkoxy group. Preferably, R1 represents hydrogen atom or a Ci-C4 alkoxy group; and R2 and R independently represent hydrogen atom, a Ci C22 alkyl group, or an ethyl group substituted with one or more halogen atoms. Preferably, R' represents hydrogen atom or a Ci-C4 alkoxy group; R2 and R independently represent hydrogen atom, a C1-C22 alkyl group, or 2,2,2-trifluoroethyl group; and R 4 represents hydrogen atom or methyl group. Preferably, R' represents hydrogen atom or a Ci-C4 alkoxy group; R2 and R independently represent hydrogen atom or 2,2,2 trifluoroethyl group; and R 4 represents hydrogen atom or methyl group. Preferably, the compound is selected from the group consisting of: 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-phenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-methoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-m-methoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-o-methoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-ethoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2 trifluoroethyl)phosphonylmethoxy]propyl]-6-phenylthiopurine; 2-amino-9-[2-[bis(2,2,2 trifluoroethyl)phosphonylmethoxy]propyl]-6-p methoxyphenylthiopurine; WO 2013/167743 PCT/EP2013/059752 45 2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6 phenylthiopurine; 2-amino-9-[2-[(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6 p-methoxyphenylthiopurine; 2-amino-9-[2-[phosphonylmethoxy]ethyl]-6-phenylthiopurine; 2-amino-9-[2-[phosphonylmethoxy]ethyl]-6-p methoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-butoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-propoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-isopropoxyphenylthiopurine; and 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-isobutoxyphenylthiopurine. Preferably, R1 is hydrogen atom or a Ci-C4 alkoxy group; R 2 and
R
3 represent 2,2,2-trifluoroethyl group; and R 4 represents hydro gen atom or methyl group. Preferably, the compound is selected from the group consisting of: 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-phenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-methoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-m-methoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-o-methoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-ethoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2 trifluoroethyl)phosphonylmethoxy]propyl]-6-phenylthiopurine; 2-amino-9-[2-[bis(2,2,2 trifluoroethyl)phosphonylmethoxy]propyl]-6-p methoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-butoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-propoxyphenylthiopurine; WO 2013/167743 PCT/EP2013/059752 46 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-isopropoxyphenylthiopurine; and 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-isobutoxyphenylthiopurine. Preferably, R1 is hydrogen atom or a Ci-C4 alkoxy group; R 2 and
R
3 represent 2,2,2-trifluoroethyl group; and R 4 represents hydro gen atom. Preferably, the compound is selected from the group consisting of: 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-phenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-methoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-m-methoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-o-methoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-ethoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-butoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-propoxyphenylthiopurine; 2-amino-9-[2-[bis(2,2,2 trifluoroethyl)phosphonylmethoxy]ethyl]-6-p isopropoxyphenylthiopurine; and 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl] 6-p-isobutoxyphenylthiopurine. Preferably, R1 represents hydrogen atom or a C1-C2 alkoxy group; R2 and R represent 2,2,2-trifluoroethyl group; and R4 represents hydrogen atom. Preferably, the compound is 2-amino-9-[2-[bis(2,2,2 trifluoroethyl)phosphonylmethoxy]ethyl]-6-phenylthiopurine, 2 amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6 p-methoxyphenylthiopurine, 2-amino-9-[2-[bis(2,2,2 trifluoroethyl)phosphonylmethoxy]ethyl]-6-m methoxyphenylthiopurine, 2-amino-9-[2-[bis(2,2,2 trifluoroethyl)phosphonylmethoxy]ethyl]-6-o methoxyphenylthiopurine, or 2-amino-9-[2-[bis(2,2,2 trifluoroethyl)phosphonylmethoxy]ethyl]-6-p ethoxyphenylthiopurine.
WO 2013/167743 PCT/EP2013/059752 47 Preferably the said the derivative or salt or prodrug or me tabolite of Alamifovir is selected from the compounds, or their salts or hydrates or solvates or intermediates thereof (esp. acyclic nucleoside phosphonate derivatives), of the formula I: OMe S N N HR 0 O R2 0 wherein, Ri is selected from H or methyl; each R 2 is independently selected from -R3 or -OR 3 ; each R3 is independently selected from C-C8 alkyl, or C3
C
8 cycloalkyl; or a pharmaceutically acceptable salt, isomer, hydrate or solv ate thereof. Preferably the two R 2 are same; or wherein the two R 2 are differ ent. Preferably the acyclic nucleoside phosphonate derivative or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof having any one or more of the following: i) R 2 is -R 3 ; ii) R 2 is -OR 3 ; iii) one R 2 is -R 3 , and the other R 2 is -OR3. Preferably each R3 for each occurrence is independently selected from C1-C6 alkyl or C3-C 6 cycloalkyl; preferably, each R 3 for each occurrence is independently selected from C2-C6 alkyl or C4 C6 cycloalkyl. Preferably each R3 for each occurrence is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, t-butyl, n-pentyl, isopentyl, neopentyl, cyclopropyl, cy clobutyl, cyclopentyl, cyclohexyl, or -CH(CH 2
CH
3
)
2 , etc.; prefer ably, each R3 for each occurrence is independently selected from ethyl, propyl, isopropyl, butyl, isobutyl, isopentyl, neopentyl, cyclopentyl, cyclohexyl, or -CH(CH 2
CH
3
)
2 , etc.
WO 2013/167743 PCT/EP2013/059752 48 Preferably the acyclic nucleoside phosphonate derivative is se lected from the group consisting of: 2-amino-6-(4-methoxyphenylthio)-9-{2-[bis(acetoxy meth oxy)phosphonomethoxy]-ethyl}-purine; 2-amino-6-(4-methoxyphenylthio)-9-{2-[bis(propionyloxy meth oxy)phosphonomethoxy]-ethyl}-purine; 2-amino-6-(4-methoxyphenylthio)-9-{2-[bis(butanoyloxy meth oxy)phosphonomethoxy]-ethyl}-purine; 2-amino-6-(4-methoxyphenylthio)-9-{2-[bis(isobutanoyloxymethoxy) phosphonomethoxy]-ethyl}-purine; 2-amino-6-(4-methoxyphenylthio)-9-{2-[bis(pivaloyloxy meth oxy)phosphonomethoxy]-ethyl}-purine; 2-amino-6-(4-methoxyphenylthio)-9-{2-[bis(cyclopentyl formyloxymethoxy)phosphonomethoxy]-ethyl}-purine; 2-amino-6-(4-methoxyphenylthio)-9-{2-[bis(cyclohexyl formyloxymethoxy)phosphonomethoxy]-ethyl}-purine; 2-amino-6-(4-methoxyphenylthio)-9-{2-[bis(ethyloxy carbon yloxymethoxy)phosphonomethoxy]-ethyl}-purine; 2-amino-6-(4-methoxyphenylthio)-9-{2-[bis(propyloxy carbon yloxymethoxy)phosphonomethoxy]-ethyl}-purine; 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(isopropyloxycarbonyloxymethoxy)phosphonomethoxy]-ethyl} purine; 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(cyclopentyloxycarbonyloxymethoxy)phosphonomethoxy]-ethyl} purine; 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(cyclohexyloxycarbonyloxymethoxy)phosphonomethoxy]-ethyl} purine; 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(acetoxymethoxy)phosphonomethoxy]-propyl}-purine; 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(propionyloxymethoxy)phosphonomethoxy]-propyl}-purine; 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(butanoyloxymethoxy)phosphonomethoxy]-propyl}-purine; 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(isobutanoyloxymethoxy)phosphonomethoxy]-propyl}-purine; 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(pivaloyloxymethoxy)phosphonomethoxy]-propyl}-purine; WO 2013/167743 PCT/EP2013/059752 49 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(cyclopentylformyloxymethoxy)phosphonomethoxy]-propyl} purine; 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(cyclohexylformyloxymethoxy)phosphonomethoxy]-propyl} purine; 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(propyloxycarbonyloxymethoxy)phosphonomethoxy]-propyl} purine; 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(propyloxycarbonyloxymethoxy)phosphonomethoxy]-propyl} purine; 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(isopropyloxycarbonyloxymethoxy)phosphonomethoxy]-propyl} purine; 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(isobutyloxycarbonyloxymethoxy)phosphonomethoxy]-ethyl} purine; 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(neopentyloxycarbonyloxymethoxy)phosphonomethoxy]-ethyl} purine; 2-amino-6-(4-methoxyphenylthio)-9-{2-[bis(pentyl-3 oxycarbonyloxymethoxy)phosphonomethoxy]-ethyl}-purine; 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(cyclopentyloxycarbonyloxymethoxy)phosphonomethoxy]-propyl} purine; and 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(cyclohexyloxycarbonyloxymethoxy)phosphonomethoxy]-propyl} purine; or a pharmaceutically acceptable salt, isomer, hydrate or solv ate thereof. Preferably the acyclic nucleoside phosphonate derivative is se lected from the group consisting of: 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis (propionyloxymethoxy)phosphonomethoxy]-ethyl}-purine (Ii); 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis (isobutanoyloxymethoxy)phosphonomethoxy]-ethyl}-purine (12); 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis (pivaloyloxymethoxy)phosphonomethoxy]-ethyl}-purine (I3); WO 2013/167743 PCT/EP2013/059752 50 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(cyclohexylformyloxymethoxy)phosphonomethoxy]-ethyl}-purine ('4); (R)-2-amino-6-(4-methoxyphenylthio)-9-{2 [bis (pivaloyloxymethoxy)phosphonomethoxy]-propyl}-purine (15); 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(ethyloxycarbonyloxymethoxy)phosphonomethoxy]-ethyl}-purine (Is); 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(propyloxycarbonyloxymethoxy)phosphonomethoxy]-ethyl}-purine ('7); 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(isopropyloxycarbonyloxymethoxy)phosphonomethoxy]-ethyl} purine (18); 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(isobutyloxycarbonyloxymethoxy)phosphonomethoxy]-ethyl} purine (I); 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(neopentyloxycarbonyloxymethoxy)phosphonomethoxy]-ethyl} purine (Iro); 2-amino-6-(4-methoxyphenylthio)-9-{2-[bis(pentyl-3 oxycarbonyloxymethoxy)phosphonomethoxy]-ethyl}-purine (I,,); 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(cyclohexyloxycarbonyloxymethoxy)phosphonomethoxy]-ethyl} purine (112) ; (R)-2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(isopropyloxycarbonyloxymethoxy)phosphonomethoxy]-propyl} purine (11); and 2-amino-6-(4-methoxyphenylthio)-9-{2 [bis(cyclohexyloxycarbonyloxymethoxy)phosphonomethoxy]-propyl} purine (Ii4); or a pharmaceutically acceptable salt, isomer, hydrate or solv ate thereof. In a preferment, the 'related compound' of Alamifovir is se lected from compounds which bear one or more structural features in common with Alamifovir, which may point to potential analge sic activity similar to Alamifovir in these compounds. These common structural features which would define a 'related com pound' of Alamifovir would include the compound being a: WO 2013/167743 PCT/EP2013/059752 51 a) Purine analogue or derivative, b) Nucleotide analogue, c) Acyclic nucleotide. The compound may be provided in a composition in association with a pharmaceutically acceptable substantially nontoxic carri er or excipient. In a preferment, the inventive compound is Emtricitabine (Synonym: (-)-FTC, BW-524W91; Chemical name: (-)-(2R-cis)-4 Amino-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H) pyrimidinone / (-)-(2R,5S)-5-Fluoro-1-[2-(hydroxymethyl)-1,3 oxathiolan-5-yl]cytosine / (-)-2',3'-Dideoxy-5-fluoro-3' thiacytidine; CAS number: 143491-57-0), or any derivatives, salts, prodrugs or metabolites of Emtricitabine, including but not restricted to the salts (-)-Emtricitabine Triphosphate Tetrasodium (CAS number: 1188407-46-6), Emtricitabine 5' monophosphate, Emtricitabine 5'-monophosphate diammonium, (-)-B L-2',3'-Dideoxy-5-fluoro-3'-thiacytidine-5'-diphosphate, (-)-B L-2',3'-Dideoxy-5-fluoro-3'-thiacytidine-5'-diphosphate triammo nium, (-)-fB-L-2',3'-Dideoxy-5-fluoro-3'-thiacytidine-5' triphosphate, (-)-B-L-2',3'-Dideoxy-5-fluoro-3'-thiacytidine-5' triphosphate tetraammonium, or 'related compounds' of Emtricita bine. Emtricitabine is a pyrimidine nucleoside analogue antivi ral compound that was originally developed against Human Immuno deficiency Virus (HIV) and Hepatitis B virus infections, and its antiviral properties are effected by the inhibition of the viral reverse transcriptase enzyme (in HIV) and viral DNA polymerase enzyme (in Hepatitis B). In a preferment, the derivative or salt or prodrug or metab olite of Emtricitabine is selected from the compounds as de scribed in EP 0513200 B2 or EP 1439177 B1 (all incorporated herein by reference), especially selected from the compounds, or intermediates thereof , of the formula:
NH
2 ROSOj or WO 2013/167743 PCT/EP2013/059752 52 N H OjN9 RO ,O wherein R is selected from the group consisting of hydrogen, alkyl, silyl, and acyl; and wherein Y is selected from the group consisting of hydrogen, methyl, chloro, fluoro, iodo, bromo, alkyl, alkenyl, alkynyl, hydroxyalkyl, carboxyalkyl, thioalkyl, selenoalkyl, phenyl, cy cloalkyl, cycloalkenyl, thioaryl, and selenoaryl. Preferably the compound is 2-hydroxymethyl-5-oxol-1,3 oxathiolane, 2-acyloxymethyl-5-acyloxy-1,3-oxathiolane, 2 acetoxymethyl-5-acetoxy-1,3-oxathiolane. Preferred is a nucleoside having the formula: NH2 Y N S wherein R is selected from the group consisting of hydro gen, alkyl, silyl, and acyl; and wherein Y is selected from the group consisting of chloro, bromo, fluoro, and iodo; or wherein R is selected from the group consisting of hydro gen, alkyl, silyl, and acyl, and wherein Y is fluorine; or wherein R is selected from the group consisting of alkyl, silyl, and acyl, and wherein Y is selected from the group con sisting of chloro, bromo, fluoro, and iodo; or wherein R is H and wherein Y is fluoro or H. Preferably the said derivative or salt or prodrug or metabo lite of Emtricitabine is selected from the compounds, or their salts or hydrates or solvates or intermediates thereof, corre sponding to the (-)-enantiomer of cis-4-ammo-5-fluoro-1-(2 hydroxymethyl-1,3-oxathiolane-5-yl)-(1H)-pyrimidin-2-one, or its pharmaceutically acceptable salt or the 5'-O-alkyl derivative, WO 2013/167743 PCT/EP2013/059752 53 a 5'-O-alkylC(O) derivative, a monophosphate, a diphosphate, or a triphosphate of the (-)-enantiomer of cis-4-ammo-5-fluoro-1 (2-hydroxymethyl-1,3-oxathiolane-5-yl)-(1H)-pyrimidin-2-one. In a preferment, the 'related compound' of Emtricitabine is selected from compounds which bear one or more structural fea tures in common with Emtricitabine, which may point to potential analgesic activity similar to Emtricitabine in these compounds. These common structural features which would define a 'related compound' of Emtricitabine would include the compound being a: a) Pyrimidine analogue or derivative or b) Nucleoside analogue. The compound may be provided in a composition in association with a pharmaceutically acceptable substantially nontoxic carri er or excipient. In a preferment, the inventive compound is Entecavir (Syno nym: BMS-200475, ETV, SQ-34676; Chemical name: 2-Amino-9 [(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2 methylidenecyclopentyl]-6,9-dihydro-3H-purin-6-one / (1S,3R,4S)-9-[4-Hydroxy-3-(hydroxymethyl)-2 methylenecyclopentyl]guanine; CAS number: 142217-69-4), or any derivatives, salts, prodrugs or metabolites of Entecavir, in cluding but not restricted to the salts Entecavir monohydrate (CAS: 209216-23-9), Entecavir hydrochloride, Entecavir bromate, Entecavir sulphate, Entecavir phosphate, Entecavir sulfonate, Entecavir benzenesulfonate, Entecavir 4-methylbenzene sulfonate (Entecavir tosylate) Entecavir toluene sulfonic acid, Entecavir toluene sulfonic acid hydrate, Entecavir (1S)-champhor-10 sulfonate, Entecavir (1S)-champhor-10-sulfonate hydrate, Entecavir p-toluenesulfonate, Entecavir p-toluenesulfonate hy drate and the Entecavir intermediates (1s-trans)-2 [(phenylmethoxy)methyl]-3-cyclopenten-1-ol (CAS number: 11056 21-0), (1S,2R,3S,5R)-2-(Benzyloxymethyl)-6 oxabicyclo[3.1.0]hexan-3-ol (CAS number.: 117641-39-1), (1S,2R,3S,5R)-3-(Phenymethyloxy)-2-(phenylmethoxy)methyl-6 oxabicyclo[3.1.0]hexane (CAS number: 110567-22-1), (1S,2S,3S,5S)-5-(2-Amino-6-(benzyloxy)-9H-purin-9-yl)-3 (benzyloxy)-2-(benzyloxymethyl)cyclopentanol (CAS number: 142217-77-4), (2R,3S,5S)-3-(Benzyloxy)-5-[2-[[(4 methoxyphenyl)diphenylmethyl]amino]-6-(phenylmethoxy)-9H-purin 9-yl]-2-(benzyloxymethyl)cyclopentanol (CAS number: 142217-78 5), 6-(Benzyloxy)-9-((1S,3R,3S)-4-(benzyloxy)-3- WO 2013/167743 PCT/EP2013/059752 54 (benzyloxymethyl)-2-methylenecyclopentyl)-N-((4 methoxyphenyl)diphenylmethyl)-9H-purin-2-amine (CAS number: 142217-80-9), 2-Amino-1,9-dihydro-9-[(1S,3R,4S)-4-(benzyloxy)-3 (benzyloxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one (CAS number: 142217-81-0), or 'related compounds' of Entecavir. Entecavir is a purine nucleoside analogue antiviral compound with a pentose ring moiety, that was originally developed against Herpes Simplex Virus (HSV) and Hepatitis B virus infec tions, and its antiviral properties are effected by the inhibi tion of the respective viral DNA polymerase enzymes. In a preferment, the derivative or salt or prodrug or metab olite of Entecavir is selected from the compounds as described in EP 0481754 B1 or US 20100210669 Al (all incorporated herein by reference), especially selected from the compounds, or inter mediates thereof, of the formula: a H
R
9
OCH
2 O#R HH
R
7 -O H H or such a compound in pharmaceutically acceptable salt form wherein Ri is NN9 N N N N N J HZ N NH 2 NIf A N NH 2 N N NE N Null
NE
WO 2013/167743 PCT/EP2013/059752 55
R
2 is fluoro, chloro, bromo, iodo, hydrogen, methyl, trifluorome thyl, ethyl, n-propyl, 2-fluoroethyl, 2-chloroethyl, ethynyl or H /R 3 C C ; (trans) H
R
3 is chloro, bromo, iodo, hydrogen, methyl or trifluoromethyl;
R
4 is alkyl;
R
5 is hydrogen, alkyl, substituted alkyl, or aryl; and
R
6 and R 7 are independently hydrogen, -PO3H 2 , or 0 11 -OC-R Preferably, the said derivative or salt or prodrug or metab olite of Entecavir refers to the crystalline form of entecavir having the following general formula (I): NNH HO N NH2 HH In a preferment, the 'related compound' of Entecavir is se lected from compounds which bear one or more structural features in common with Entecavir, which may point to potential analgesic activity similar to Entecavir in these compounds. These common structural features which would define a 'related compound' of Entecavir would include the compound being a: a) Purine analogue or derivative, b) Pentose ring containing molecule, c) Nucleo side analogue. The compound may be provided in a composition in association with a pharmaceutically acceptable substantially nontoxic carri er or excipient. In a preferment, the inventive compound is Famciclovir (Syn onym: AK-120, BRL-42810, M-5210; Chemical name: 9-[4-Acetoxy-3 (acetoxymethyl)butyl]-2-aminopurine; CAS number: 104227-87-4), or any analogues, derivatives, salts, prodrugs, bioprecursors or metabolites of Famciclovir including but not restricted to the salts Famciclovir monohydrate or any phosphate ester and/or acyl derivatives of Famciclovir, or its metabolic active princi- WO 2013/167743 PCT/EP2013/059752 56 ple compound Penciclovir (Synonym: BRL-39123; Chemical name: 9 [4-Hydroxy-3-(hydroxymethyl)butyl]guanine; CAS number: 39809-25 1),or any analogues, derivatives, salts, prodrugs, bioprecursors or metabolites of Penciclovir, including but not restricted to the salts Penciclovir sodium (CAS number: 97845-62-0), Penciclo vir monohydrate, Penciclovir sodium hydrate, (R)-Penciclovir Triphosphate, or 'related compounds' of Famciclovir or Penciclo vir. Famciclovir and Penciclovir are purine nucleoside analogue antiviral compounds, that were originally developed against Her pes Simplex Virus (HSV) and Varicella Zoster Virus (VZV) infec tions, and their antiviral properties are effected by the inhi bition of the respective viral DNA polymerase enzymes. In a preferment, the analogue or derivative or salt or prodrug or bioprecursor or metabolite of Famciclovir is selected from the compounds as described in US 5246937 A and EP 0302644 B1 (incorporated herein by reference), especially selected from the compounds, or intermediates thereof , of the formula:
NNH
2 (CHNH
R
1 0-CHg.CH-CH gORa or a pharmaceutically acceptable salt thereof, where Ri and R 2 are each independently hydrogen, or a carboxylic acyl provided that Ri and R 2 are not both hydrogen; or Riand R 2 are joined to gether to form a cyclic acetal group or a cyclic carbonate group. Preferably Ri and/or R 2 is a carboxylic acyl group such that the group R 1 0- and/or R 2 0- is a pharmaceutically acceptable ester group. Preferably the carboxylic acyl group Ri and/or R 2 is a group 0
R-.C
wherein R 3 is C1-6 alkyl, C1-6 alkoxy or aryl optionally substitut ed with one or two groups selected from C1-6 alkyl, C1-6 alkoxy and halo. Preferably Ri and R 2 are joined together to form a group WO 2013/167743 PCT/EP2013/059752 57 C=0, or Preferably Ri and R 2 are joined together as a C(CH 3
)
2 group. Preferably the compound is selected from 2-amino-9-(4-acetoxy-3-acetoxymethylbut-1-yl)purine; 2-amino-9-(4-acetoxy-3-hydroxymethylbut-1-yl)purine; 2-amino-9-(3-hydroxymethyl-4-methoxycarbonyloxybut-1-yl)purine; 2-amino-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethylipurine; 2-amino-9-(4-propionyloxy-3-propionyloxymethylbut-1-yl)purine; 2-amino-9-(4-butyryloxyl-3-hydroxymethylbut-1-yl)purine; 2-amino-9-(4-benzoyloxyl-3-hydroxymethylbut-1-yl)purine; and pharmaceutically acceptable salts thereof. Further preferred Famciclovir derivatives and related com pounds are buciclovir, desciclovir, detiviciclovir, lagociclo vir, lagociclovir valactate, rociclovir as well as their pharma ceutically acceptable salts, esters and prodrugs. In a preferment, the analogue or derivative or salt or pro drug or bioprecursor or metabolite of Penciclovir is selected from the compounds as described in EP 0141927 B1, EP 0152316 B1 or EP 0388049 B1 (all incorporated herein by reference), espe cially selected from the compounds, or intermediates thereof of the formula (I): x N
NH
2
(CH
2 ) 2 HO-CH CH 2-OH WO 2013/167743 PCT/EP2013/059752 58 or a salt, phosphate ester or acyl derivative thereof (as here inafter defined), in which X represents chlorine, straight or branched chain C1-6 alkoxy, phenoxy, phenyl C1-6 alkoxy, -NH 2 , -OH or -SH, an acyl derivative is wherein one or both of the hydro gens in the acyclic -OH groups, and/or one of the hydrogen atoms in the -NH 2 group, are replaced by
R-C
O 0 groups, wherein R is hydrogen, Cl18 alkyl, phenyl, phenyl Ci_ 6 alkyl or imidazolyl; with the provisos that, i) when X is -OH, the compound of formula (I) is in a purity state of greater than 50% by weight of pure compound with respect to the mono- and di benzyl ethers thereof; and ii) the compound of formula (I) is other than a compound selected from the group consisting of: 9-[4'-hydroxy-3'-(hydroxymethyl)butyl]guanine cyclic phosphate; 9-[4'-hydroxy-3'-(hydroxymethyl)butyl]guanine cyclic pyrophos phate; 9-[4'-hydroxy-3'-(hydroxymethyl)butyl]-2,6-diaminopurine; 9-[4'-hydroxy 3'-(hydroxymethyl)butyl]-2,6-diaminopurine cyclic phosphosphate; 9-[4'-hydroxy-3'-(hydroxymethyl)butyl]-2,6-diaminopurine cyclic pyrophosphate; 9-[4'-hydroxy-3'-(hydroxymethyl)butyl]-2-amino-6-chloropurine; 9-[4'-hydroxy-3'-(hydroxymethyl)butyl]-2-amino-6-chloropurine cyclic phosphate; 9-[4'-hydroxy-3'-(hydroxymethyl)butyl]-2-amino-6-chloropurine cyclic pyrophosphate; 9-[4'-hydroxy-3'-(hydroxymethyl)butyl]guanine monophosphate mon osodium salt; 9-[4'-hydroxy-3'-(hydroxymethyl)butyl]-2,6-diaminopurine mono phosphate monosodium salt; and 9-[4'-hydroxy-3'-(hydroxymethyl)butyl]-2-amino-6-chloropurine monophosphate monosodium salt. Preferably R is C1-6 alkyl, phenyl or benzyl. Preferably the compound is of formula (II) WO 2013/167743 PCT/EP2013/059752 59 x N N N NH3 (II
(CH
2 ) 2 R 2 -CH- CH 2OR 2 or a pharmaceutically acceptable salt thereof, in which X is as defined in formula (I), and each of R , R2 and R represents hy drogen or an acyl group of formula R4-C-, O 0 in which R4 is C-18 alkyl or imidazolyl, or R or R2 represents a phosphate ester group of formula
(HO)
2 -P-, 0 or R and R2 together represent a bridging group: o o- HO 0 Preferably X is -OH, or a tautomer thereof. Preferably the compound is of formula (A) 0 N K' (A) N N NH2
(CH
2 ) 2 HO-CH2--CH-CH2-OH in a purity state of greater than 60% by weight of pure com pound, or a pharmaceutically acceptable salt thereof.
WO 2013/167743 PCT/EP2013/059752 60 A further compound is of formula (VII): x NNR (VII) N )"NHR (CH 2)2 CH 2 H2
CH
3 3 in which X is as defined in claim 1 and R' is hydrogen or acyl. A further compound is of formula: R 0 -CH 2 x CH-(CH2 ) 2 -Z R
O-CH
2 wherein Z' is hydroxy, chloro, bromo or iodo; Ra and Rb are
R-C
if 0 groups, as defined in claim 1; or Ra and Rb' together are
C(CH
3
)
2 ' 5-(2-Hydroxyethyl)-2,2-dimethyl-1,3-dioxan, 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxan, 2-acetoxymethyl-4-hydroxybut-1-yl acetate, or 2-acetoxymethyl-4-bromobut-1-yl acetate. Preferably the said analogue or derivative or salt or pro drug or bioprecursor or metabolite of Penciclovir is selected from the compounds, or intermediates thereof, of the formula: WO 2013/167743 PCT/EP2013/059752 61 R1 NYKN H 2 wherein R is hydroxy, amino or halogen; and R2 and R3 are inde pendently selected from hydrogen and a phosphate group having the formula: 0 II
-P-OR
4
OR
5 or R2 and R taken together form a phosphate group having the formula: I -P-OR4 or a pyrophosphate group having the formula
OR
4 -P-0-P-OR 5 II II o o wherein R4 and R are independently selected from hydrogen, a pharmaceutically acceptable cation, alkyl having 1 to 6 carbon atoms, phenyl, phenylalkyl wherein the alkyl moiety has 1 to 6 carbon atoms, with the proviso that R 2 and R3 are not both hydro gen. Preferably R2 and R3 taken together form a phosphate group having the formula:
-P-OR
4 || wherein R 4 is defined as above. Preferably R4 and R are the same. Preferred compounds are 9-[4'-Hydroxy-3' (hydroxymethyl)butyl]guanine cyclic phosphate and 9-[4'-Hydroxy 3'-(hydroxymethyl)butyl]-2,6-diaminopurine cyclic phosphate.
WO 2013/167743 PCT/EP2013/059752 62 Preferably the said analogue or derivative or salt or pro drug or bioprecursor or metabolite of Penciclovir is selected from the compounds, or intermediates thereof, of the formula (A): 0 N (~ H N N NH I 2 (CH 2)2 HO-CH -CH-CH 2-OH (A) or a pro-drug, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing. Preferably the compound is the sodium salt hydrate of the com pound of formula (A). Preferably the compound is a pro-drug of the compound of formula (A), is of formula (B): x N. / 2 N H (CH ) 2 22 HO-CH -CH-CH 2-OH (B) or a salt or derivative thereof, as defined in respect of formu la (A) above; wherein X is C1-6 alkoxy, NH 2 or hydrogen. Preferably the pro-drug compound of formula (B) is famciclovir, wherein X is hydrogen and wherein the two OH groups are in the form of the acetyl derivative. In a preferment, the 'related compound' of Famciclovir or its active principle Penciclovir is selected from compounds which bear one or more structural features in common with Famciclovir or Penciclovir, which may point to potential analgesic activity WO 2013/167743 PCT/EP2013/059752 63 similar to Famciclovir in these compounds. These common struc tural features which would define a 'related compound' of Entecavir would include the compound being a: a) Purine analogue or derivative, b) Nucleoside analogue or a c) Acyclic nucleoside analogue. The compound may be provided in a composition in association with a pharmaceutically acceptable substantially nontoxic carri er or excipient. In a further preferment the compound comprises Alamifovir or a derivative thereof, ester, hydrates or pharmaceutically ac ceptable salt form thereof, such as in Alamifovir disoproxil fumarate or Alamifovir disoproxil hemifumarate. In a further preferment the compound comprises Entecavir or a derivative thereof, ester, hydrates or pharmaceutically ac ceptable salt form thereof, such as in Entecavir monohydrate (CAS: 209216-23-9), Entecavir hydrochloride, Entecavir bromate, Entecavir sulphate, Entecavir phosphate, Entecavir sulfonate, Entecavir benzenesulfonate, Entecavir toluene sulfonic acid Entecavir toluene sulfonic acid hydrate, Entecavir (15) champhor-10-sulfonate, Entecavir (1S)-champhor-10-sulfonate hy drate, Entecavir p-toluenesulfonate, Entecavir p toluenesulfonate hydrate, (1s-trans)-2-[(phenylmethoxy)methyl] 3-cyclopenten-1-ol (CAS No.: 11056-21-0), (1S,2R,3S,5R)-2 (Benzyloxymethyl)-6-oxabicyclo[3.1.0]hexan-3-ol (CAS No.: 117641-39-1), (1S,2R,3S,5R)-3-(Phenymethyloxy)-2 (phenylmethoxy)methyl-6-oxabicyclo[3.1.0]hexane (CAS No.: 110567-22-1), (1S,2S,3S,5S)-5-(2-Amino-6-(benzyloxy)-9H-purin-9 yl)-3-(benzyloxy)-2-(benzyloxymethyl)cyclopentanol (CAS No.: 142217-77-4), (2R,3S,5S)-3-(Benzyloxy)-5-[2-[[(4 methoxyphenyl)diphenylmethyl]amino]-6-(phenylmethoxy)-9H-purin 9-yl]-2-(benzyloxymethyl)cyclopentanol (CAS No.: 142217-78-5) 6-(Benzyloxy)-9-((iS,3R,3S)-4-(benzyloxy)-3-(benzyloxymethyl)-2 methylenecyclopentyl)-N-((4-methoxyphenyl)diphenylmethyl)-9H purin-2-amine (CAS No.: 142217-80-9), 2-Amino-1,9-dihydro-9 [(1S,3R,4S)-4-(benzyloxy)-3-(benzyloxymethyl)-2 methylenecyclopentyl]-6H-purin-6-one (CAS No.: 142217-81-0). In a further preferment the compound comprises Emtricitabine or a derivative thereof, ester, hydrates or pharmaceutically ac ceptable salt form thereof, such as in (-)-Emtricitabine Tri phosphate Tetrasodium (CAS#: 1188407-46-6), Emtricitabine 5'- WO 2013/167743 PCT/EP2013/059752 64 monophosphate, Emtricitabine 5'-monophosphate diammonium, (-) -B-L-2',3'-Dideoxy-5-fluoro-3'-thiacytidine-5'-diphosphate, (-) -B-L-2',3'-Dideoxy-5-fluoro-3'-thiacytidine-5'-diphosphate triammonium, (-)-B-L-2',3'-Dideoxy-5-fluoro-3'-thiacytidine-5' triphosphate, (-)-B-L-2',3'-Dideoxy-5-fluoro-3'-thiacytidine-5' triphosphate tetraammonium. In a preferment the Adefovir derivative is selected from the derivatives as described in US 5,663,159 (incorporated herein by reference), especially selected from the compounds, or interme diates thereof, of the formula I or V 0 Formula I 11
R
2
-P-CH
2 -0-R 3 -B B Formula V 0 O=P 4RO. 0 *Stereochemistry R, S or RS wherein B represents adenyl (A), guanyl (G), or 2,6-diaminopurinyl (DAP); R and R2 are independently each OR4
R
3 represents
R
3 represents B x X represents hydrogen, methyl or hydroxymethyl; R4 represents a physiologically hydrolyzable group selected from the group con sisting of CH 2 0C (0) R' and CH (R') OC (O) R 5 (R, S, or RS stereochemis try); and R represents Ci-C20 alkyl, aryl or aryl-alkyl which may be substituted or unsubstituted by hydroxy or halogen. Preferably said compounds or intermediates thereof are of Formula III WO 2013/167743 PCT/EP2013/059752 65 0 B Formula HI It
R
7 -P O R1 X wherein B represents adenyl (A), guanyl (G), or diaminopurinyl (DAP);
R
7 is OH; X represents hydrogen, methyl or hydroxymethyl; R is OR';
R
4 represents a physiologically hydrolyzable group selected from the group consisting of CH 2 0C(O)R 5 and CH(R 5
)OC(O)R
5 (R, S, or RS stereochemistry); and
R
5 represents Ci-C2o alkyl, aryl or aryl-alkyl which may be sub stituted or unsubstituted by hydroxy or halogen. Preferably X is H and R 5 is Ci-C20 alkyl. Preferably X is H or hydroxymethyl. Preferably X is H. Preferably X is hydroxymethyl or methyl. Preferably B is adenyl. Preferably X is H and R 4 is CH 2 0C(O)R. Preferably the compound is 9-(2-phosphonylmethoxy) ethylade nine di(pivaloyloxymethyl)ester, 9-(2-phosphonylmethoxy) ethyl adenine di(propionyloxymethyl)ester, 9-(2-phosphonylmethoxy) ethyladenine di(isobutyryloxymethyl)ester, 9-(2 phosphonylmethoxy) ethyladenine di(benzoyloxymethyl)ester, or 9 (2-phosphonylmethoxy) ethyladenine mono(pivaloyloxymethyl)ester. Adefovir comprising substance may refer to ester or salt forms and variants thereof such as in Adefovir Dipivoxil, Adefo vir monophosphate, Adefovir diphosphate, Adefovir-d4 Diphosphate Triethylamine (CAS No.: 129532-77-0). The compound may be provided in a composition in association with a pharmaceutically acceptable substantially nontoxic carri er or excipient. In a preferment the Tenofovir derivative is selected from the derivatives as described in US 5,922,695, US 5,935,946 or US 5,977,089 (all incorporated herein by reference), especially se lected from a compound having formula (la) WO 2013/167743 PCT/EP2013/059752 66 O (1a)
A-OCH
2
P(Z)
2 wherein Z is independently -OC(R2) 2 0C0()X(R)a, an ester, an amidate or H, but at least one Z is -OC(R2 ) 2 0C(O)X(R)a; A is the residue of an antiviral phosphonomethoxy nucleotide an alog; X is N or 0; R2 independently is -H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkynyl, C7-C12 alkenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or -OR 3 in which R 3 is Ci C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl or C5-C12 aryl; R is independently -H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkynyl, C7-C12 alkyenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro, -N(R 4 )2 or -OR, where R 4 independently is -H or Ci-C8 alkyl, provided that at least one R is not H; and a is 1 when X is 0, or 1 or 2 when X is N; with the proviso that when a is 2 and X is N, (a) two N-linked R groups can be taken together to form a carbocycle or oxygen containing heterocycle, (b) one N-linked R additionally can be OR 3 or (c) both N-linked R groups can be -H; and the salts, hydrates, tautomers and solvates thereof. Preferably said compound has formula (1) R2 (1) O 0 OR
OR
8 RI wherein B is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2 aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza analogs, or WO 2013/167743 PCT/EP2013/059752 67 B is cytosin-1-yl; R is independently -H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkynyl, C7-C12 alkenylaryl, C7-C12 alkynylaryl, or C6 -C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or -OR 3 in which R 3 is C1 C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl or C-C12 aryl;
R
1 is hydrogen, -CH3, -CH 2 OH, -CH 2 F, -CH=CH 2 , or -CH 2
N
3 , or R 1 and R are joined to form -CH 2 -; R2 independently is hydrogen or C1-C6 alkyl; and R8 is hydrogen or -CHR2 -0-C(O)-OR, or R8 is joined with R to form -CH 2 -; and the salts, hydrates, tautomers and solvates thereof. Preferably R2 is -H. Preferably R is -CH3. Preferably one R2 is -CH3 and the other R2 is H. Preferably R3 is C1-C6 alkyl or phenyl. Preferably R 3 is -CH3 or -C 2
H
5 . Preferably X is 0. Prefer ably X is N and one R 3 is H. Preferably the compound is enriched or resolved at the car bon atom chiral center linked to R. Preferably at least about 90% of the compound is in the (R) configuration at the R site. Preferably B is adenin-9-yl. Preferably each R is ethyl. Preferably each R is isopropyl. Preferably each R is 3-pentyl or neopentyl. Preferably each R is t-butyl or isobutyl. Preferably B is 2,6-diaminopurin-9-yl. Preferably R is H. Preferably B is adenin-9-yl. Preferably R is Ci-C12 alkyl. Preferably R is -CH 2 OH. Preferably B is cytosin-1-yl. Preferably at least about 90% of the compound is in the (S) configuration at the R site. Preferably the compound is for oral administration. The Tenofovir derivative may also be a compound of formula WO 2013/167743 PCT/EP2013/059752 68 B 0 II 0 O P IOR*HO1 OR OH
CH
3 ) wherein B is adenin-9-yl and R independently is -H or -CH 2 -0 C(0)-0-CH(CH 3
)
2 , but at least one R is -CH 2 -0-C(0)-0-CH(CH 3
)
2 . Preferably both R are -CH 2 -0-C(0)-0-CH(CH 3
)
2 . Preferably the compound is a crystalline solid. Preferably the compound is enriched or resolved at the car bon atom chiral center (*). Preferably the compound has an X-ray powder diffraction spectrum peak using Cu-Ka radiation, expressed in degrees 20 at about 25.0. Preferably the compound is in a composition with an accepta ble excipient. Preferably the compound is in a composition comprising a lithium alkoxide and a 9-(2-hydroxypropyl)adenine solution. Preferably the compound is in a composition comprising an (R,S)-PMPA solution at a pH of about 2.7-3.5 wherein the solu tion has less than about 0.1 g/mL (R,S)-PMPA and wherein about 90-94% of the PMPA is in the (R) configuration. Preferably the compound is for oral administration to a pa tient. Preferably the compound is in a tablet containing 9-[2 (R) - [ [bis [ [(isopropoxycarbonyl)oxy]methoxy]phosphinoyl]methoxy] propyl]-adenine.fumaric acid (1:1), pregelatinized starch, croscarmellose sodium, lactose monohydrate and magnesium stea rate. Preferably the 9-[2-(R)-[ [bis[ [ (isopropoxycarbonyl)oxy] methoxy]phosphinoyl]methoxy]propyl]-adenine.fumaric acid (1:1) is crystalline. Preferably the tablet contains 75 mg 9-[2-(R) [[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinoyl]methoxy]propy 1 ]-adenine.fumaric acid (1:1), 11 mg pregelatinized starch, 8.8 mg croscarmellose sodium, 123.6 mg lactose monohydrate and 2.2 mg magnesium stearate. Tenofovir comprising substance may refer to ester or salt forms and variants thereof such as in Tenofovir Disoproxil, Tenofovir Disoproxil Fumarate, Tenofovir alafenamide, Tenofovir WO 2013/167743 PCT/EP2013/059752 69 alafenamide fumarate, Tenofovir hydrate (CASNO.: 206184-49-8), Tenofovir Diphosphate Triethylamine (CAS Number: 166403-66-3) The Tenofovir derivative may also be (R)-bis(POC)PMPA, espe cially preferred in a composition together with a pharmaceuti cally acceptable carrier. Preferably the compound is for oral administration to a patient. In a preferment the Cidofovir derivative is selected from the derivatives as described in US 5,142,051 (incorporated here in by reference), especially selected from a compound of the formula
B-CH
2 -CH-0-CH 2
-P(O)(OH)
2
CH
2 -OH wherein B is selected from the group consisting of uracil-1-yl, cytosin-1-yl, 5-methylcytosin-1-yl, thymin-1-yl, 5-fluoruracil 1-yl, guanin-9-yl, guanin-7-yl, adenin-3-yl, hypoxanthin-9-yl, 2-methyladenin-9-yl, 2-methylthioadenin-9-yl, 2-aminoadenin-9 yl, 2-aminopurin-9-yl, N 6 -dimethyladenin-9-yl, 8-bromoadenin-9 yl, 8-hydroxyadenin-9-yl, 6-hydroxylaminopurin-9-yl, 6 hydrazinopurin-9-yl, 6-thiopurin-9-yl, purin-9-yl, and xanthin 9-yl. Preferably B in the above selected compound is selected from the group consisting of uracil-1-yl, cytosin-1-yl, 5 methylcytosin-1-yl, thymin-1-yl, and 5-fluorouracil-1-yl, espe cially preferred wherein B is cytosin-1-yl. The present invention also relates to any pharmaceutically active salt of any one of the inventive compounds as given in the tables or further described above. The salt may be selected from the group consisting of a hydrochloride, embonate, teo clate, mesilate, acistrate, estolate, ethylsuccinate, gluco heptonate, lactobionate, propionate, stearate, stinoprate, lac tate, mesylate, acetate, diacetate hydrate, dihydrochloride, chlorhexidine, digluconate, gluconate, benzoate, phosphate, hy clate, hydrate, sulfate, bishydrogensulfate, tartrate, L tartrate, fumarate, malonate, maleate, acefyllinate, citrate, disulfide, -0-dinicotinate, hydrobromide, nitrate, gluconate; hydrogen-sulfate 4-water, succinate, nitrite, polygalacturonate, sulfate 2-water, dihydrogencitrate, calcium, hemi-calcium, hemi- WO 2013/167743 PCT/EP2013/059752 70 fumarate, sodium, or potassium salt and mixtures thereof. Pre ferred salts are Adefovir Dipivoxil, Tenofovir Disoproxil Fumarate (TDF), Pradefovir mesylate. The present invention also relates to any pharmaceutically active ester of any one of the inventive compounds as given in the tables or further described above. The ester may preferably be the hexadecyloxypropyl ester of the compounds according to the invention. The subject to be treated according to the present invention can be any non-human animal or a human. Preferably the subject is a mammal, in particular preferred embodiments a human. A non human-animal is preferably a non-human mammal or bird, especial ly preferred the the animal is a dog, cat, horse, cow, pig. According to the present invention pain and conditions asso ciated with pain, e.g. itching or depression, can be treated or prevented, in particular in the meaning of a prophylactic admin istration. "Preventing" or "prevention" herein does not require absolute success in the sense of an absolute prevention of pain but indicates a reduced risk of developing a disease or painful condition, or developing pain with reduced severity. Likewise, "treatment" shall not be construed as an absolute cure, but may also relate to amelioration or suppression of pain or pain asso ciated conditions. Pain and pain associated conditions and diseases to be treated according to the present invention can include acute pain, chronic pain, somatogenic pain, neuropathic pain, psycho genic pain, heat induced pain, physical pain and nociception in general, hyperalgesia, or any other forms of pain or pain asso ciated conditions which may not be listed in the aforementioned groups. In particular embodiments the pain is selected from neu ropathic pain, inflammatory pain, nociceptive pain, rheumatic pain, headache, low back pain, pelvic pain, myofascial pain, vascular pain, migraine, wound associated pain, inflammatory pain, arthritic pain, diabetic pain, post-herpetic pain, pain from cancer, mixed neuropathic and nociceptive pain, mixed pain or somatic visceral pain, all in both acute and chronic forms. The pain can also be related to phantom pain, pain from a part of the body that has been lost or from which the brain no longer receives physical signals. Pain can also be related to untoward events or injury in the central nervous system e.g. post-stroke WO 2013/167743 PCT/EP2013/059752 71 pain. Pain can be generally classified in two broad categories, acute and chronic. The treatment of any acute or chronic pain is subject matter of the present invention. Acute pain is usually associated with a specific cause such as a specific injury and is often sharp and severe. Acute pain begins suddenly and is not persistent. Chronic pain is long-term pain, with a typical dura tion of more than three months leading to significant psycholog ical and emotional problems. Chronic pain is generally associat ed with clinical conditions characterised by chronic and/or de generative lesions. Common examples of chronic pain are neuro pathic pain (e.g. painful diabetic neuropathy, post-herpetic neuralgia), rheumatoid arthritis, osteoarthritis, fibromyalgia, back pain, lower back pain with or without radiculopathy, head ache, carpal tunnel syndrome, cancer pain, and chronic post surgical pain. Pain can also be divided into a number of differ ent subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain. Also some types of pain can be classified in multiple categories, for example pain associated with cancer can have a nociceptive and neuro pathic component. Nociceptive pain consists of somatic pain (musculo-skeletal pain) and visceral pain (pain associated with the viscera, which encompass the organs of the abdominal cavi ty). Common causes of somatic pain include cancer metastasis such as to the bone and postsurgical pain from a surgical inci sion in addition to musculo-skeletal disorders such as dystro phinopathy, myalgia and polymyositis. Nociceptive pain also in cludes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Another type of inflammatory pain is visceral pain which includes pain associated with gas trointestinal disorders (GI) such as functional bowel disorder (FBD) and inflammatory bowel disease (IBD). Further examples of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatis and pelvic pain. Additional pain types include dysfunctional pain such as fibromyalgia, Temporomandibu lar Joint Disorder (TMJ), Irritable bowel syndrome (IBS) and musculo-skeletal pain. Neuropathic pain is caused by damage to the peripheral or central nervous system. Examples of central neuropathic pain include pain from spinal cord injury, multiple sclerosis, strokes and fibromyalgia. Diabetes and related meta- WO 2013/167743 PCT/EP2013/059752 72 bolic disorders are a common cause of peripheral neuropathic pain (diabetic neuropathy). Some of the human conditions and pa thologies characterised by the presence of neuropathic pain in clude, but are not limited to, cancer (cancer neuropathy), HIV neuropathy, Parkinson's disease, epilepsy, immunodeficiency, post-herpetic syndromes, trauma, ischaemia, sciatica, multiple sclerosis, peripheral neuropathy, trigeminal neuralgia, back pain, phantom limb pain, carpal tunnel syndrome, central post stroke pain and pain associated with chronic alcoholism, hypo thyroidism, uraemia, spinal cord injury, and vitamin deficiency. Preferably the pain is neuropathic pain, such as trigeminal neu ralgia, such as post-herpetic neuralgia, such as painful diabet ic neuropathy, such as painful diabetic peripheral neuropathy, such as diabetic polyneuropathy, such as sciatic pain, such as radiculopathy, such as radicular pain or such as non inflammatory neuropathic pain. In another preferred embodiment, the pain is lower back pain. In yet another preferred embodi ment, the pain is lower back pain with radiculopathy. In yet an other preferred embodiment, the pain is lower back pain without radiculopathy. In yet another preferred embodiment, the pain is associated with osteoarthritis. In yet another preferred embodi ment, the pain is associated with rheumatoid arthritis. Pain may be selected from fibromyalgia, postoperative pain, trigeminal neuralgia, post-herpetic neuralgia, painful diabetic neuropathy, painful diabetic peripheral neuropathy, diabetic polyneuropathy, sciatic pain, radiculopathy, radicular pain, lumbar pain. Pref erably the pain is caused by the conditions as mentioned above related to the given pain type. In particular the pain type can be the only pain type in a subject. E.g. preferably a neuro pathic pain is caused by affected nerves but not caused by in flammation, i.e. neuropathic pain is the only pain in the sub ject and is non-inflammatory. In another preferred embodiment, the neuropathic pain is associated with transitory or persistent inflammation, such as with transitory inflammation, such as with persistent inflammation. Chronic pain may in certain embodiments of the invention be nociceptive, such as inflammatory in nature. Furthermore, chronic pain may also be mixed nociceptive and neu ropathic. Finally, chronic pain may also be of a central origin, deriving from processes/conditions in the central or peripheral nervous system, such as e.g. post stroke pain or post-amputation WO 2013/167743 PCT/EP2013/059752 73 pain/phantom limb pain, which may, in certain circumstances, al so be considered neuropathic in nature. In certain embodiments pain may exclude excludes post herpetic neuralgia associated pain. Preferably this exclusion is for compounds Famciclovir, Cidofovir, Ribavirin, Aciclovir / acyclovir, Valaciclovir / valacyclovir, Ganciclovir,Penciclovir, Famciclovir, Vidarabine / adenine arabinoside, Idoxuridine, Tri fluridine / trifluorothymidine (TFT), Edoxudine / Edoxudin, Brivudine, Cytarabine / cytosine arabinoside (Ara - C), Foscar net, Docosanol, Tromantadine, Resiquimod. But of course it is also possible in further embodiments to treat post-herpetic neu ralgia associated pain with these compounds. "About" is used to refer to certain dosages that can vary from a given value, nevertheless with the same effects as the indicated dose. In some embodiments "about" may refer to +/- 20% or 10% of a given value. Preferably the compound is administered in a dosage suffi cient to treat or prevent pain or associated conditions and dis eases. Administration can e.g. be a single dose administration or a successive or repeated administration, e.g. three times a day, twice a day, daily or in an interval of at least 1 day, at least 2 days, at least 3 days, at least 1 week, preferably at least 2 weeks, at least 4 weeks, at least 8 weeks or even more preferred at least 12 weeks. In a preferred embodiment, admin istration is done once daily. Preventive administrations are usually a short time before expected pain, if controllable or foreseeable - such as in scheduled surgery - e.g. up to hour (h), 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h or up to 24h or even up to 48h beforehand, as well as any interval in between. According to a further preferred embodiment of the present invention, the compound is provided in a pharmaceutical composi tion or a medicament, in particular as an analgesic. The compo sition or medicament may comprise a pharmaceutical carrier. Pharmaceutical carrier substances serve for a better tolerance of the medicament and allow for a better solubility as well as a better bioavailability of the active substances contained in the medicament. Examples of this are emulsifiers, thickening agents, redox components, starch, alcohol solutions, polyethylene glycol or lipids. The choice of a suitable pharmaceutical carrier is highly dependent on the manner of administration. For oral ad- WO 2013/167743 PCT/EP2013/059752 74 ministrations, liquid or solid carriers may be used, for injec tions, liquid final compositions are required. For cellular tar geting, such as for inhibitory nucleic acids, suitable vehicles can be included such as liposomes or microsomes. Preferably, the medicament or the compound to be used ac cording to the invention comprises buffer substances or tonic substances. By means of a buffer, the pH of the medicament can be adjusted to physiological conditions, and moreover, pH fluc tuations can be attenuated, or buffered, respectively. An exam ple thereof is a phosphate buffer. Tonic substances serve for adjusting the osmolarity and may comprise ionic substances, such as, e.g., inorganic salts, such as NaCl, or also non-ionic sub stances, such as, e.g. glycerol or carbohydrates. The inventive compound or medicament can be administered topical, enteral or parenteral, in particular preferred oral or rectal, intravenous, intraarterial, intramuscular, subcutaneous, intradermal or intraperitoneal, transdermal, transmucosal or in halational. Preferred routes of administration of the inventive agent according to the present invention are parenteral routes, preferably intraperitoneal or intravenous administration, intra venous administration being specifically preferred. Intravenous administration can be performed e.g. via bolus injection or by continuous intravenous delivery over a longer time period (e.g. 30 min to 6 h, especially 1 to 3 h), in or not in combination with other agents which may be administered parenterally e.g. normal saline. Further routes include oral or transdermal or subcutaneous routes. Particularly preferred is oral administra tion. For digestible agents, such as active proteins, peptides or siRNA, parenteral routes are preferred. The medicament or the compound to be used according to the invention can be prepared to be suitable for oral or intranasal administration. These administration forms of the medicament of the present invention allow for a rapid and uncomplicated uptake of the active substances via the mucous membranes. For a nasal intake, nose drops or nose sprays are suitable. For an oral ad ministration, solid or liquid medicaments may, e.g., be taken directly or in a dissolved or diluted state, respectively. The medicament or compound to be used according to the in vention can be prepared for an intravenous, intra-arterial, in tramuscular, intravascular, systemic, intraperitoneal or subcu- WO 2013/167743 PCT/EP2013/059752 75 taneous administration. For this purpose, e.g., injections or transfusions are suitable. Administrations directly into the bloodstream have the advantage that the active substances of the medicament will be distributed in the entire body and will quickly reach the target tissue or cells, in particular the pe ripheral nerves, spinal cord cells or brain cells. The compound may be administered in an effective therapeutic dose. Effective doses are in the range of dosages known for the compounds for other, non-pain related administrations. In par ticular, for a specific use a dosage can be determined by a sim ple test using drosophila or rodent, such as preferably mouse, such as preferably rat test systems. Further possible therapeu tic doses of the compounds for the inventive treatment can be the same dosage disclosed or approved for other therapeutic uses for each of these compounds. Even further possible therapeutic doses can be a fraction or multiple of the dosage disclosed or approved for other therapeutic uses for each of the compounds according to the invention, such as at the most 0.1 times the dosage, such as at the most 0.2 times the dosage, such as at the most 0.3 times the dosage, such as at the most 0.4 times the dosage, such as at the most 0.5 times the dosage, such as at the most 0.6 times the dosage, such as at the most 0.7 times the dosage, such as at the most 0.8 times the dosage, such as at the most 0.9 times the dosage, such as at the most 1.1 times the dosage, such as at the most 1.2 times the dosage, such as at the most 1.3 times the dosage, such as at the most 1.4 times the dosage, such as at the most 1.5 times the dosage, such as at the most 1.6 times the dosage, such as at the most 1.7 times the dosage, such as at the most 1.8 times the dosage, such as at the most 1.9 times the dosage, such as at the most 2.0 times the dosage, such as at the most 2.2 times the dosage, such as at the most 2.4 times the dosage, such as at the most 2.6 times the dosage, such as at the most 2.8 times the dosage, such as at the most 3.0 times the dosage, such as at the most 3.5 times the dosage, such as at the most 4.0 times the dosage, such as at the most 5.0 times the dosage. Example dosages are at least 0.01 mg/kg, at least 0.1 mg/kg, at least 1 mg/kg, at least 10 mg/kg and/or up to 1 mg/kg, up to 10 mg/kg, up to 100 mg/kg, up to 1 g/kg, and any dosages in between. Preferred dosage ranges are between 0.01 mg/kg and 1 g/kg, preferably between 0.1 mg/kg and WO 2013/167743 PCT/EP2013/059752 76 100 mg/kg. The doses for tomeglovir are e.g. at least 0.01 mg/kg, pref erably at least 0.1 mg/kg, at least 1 mg/kg, and/or up to 100 mg/kg, up to 1 g/kg, and any dosages in between. Preferred dos age ranges are between 0.01 mg/kg and 1 g/kg, preferably between 0.1 mg/kg and 100 mg/kg, even more preferably between 1 and 10 mg/kg. The doses for emtricitabine e.g. at least 0.01 mg/kg, pref erably at least 0.1 mg/kg, at least 1 mg/kg, and/or up to 100 mg/kg, up to 1 g/kg, and any dosages in between. Preferred dos age ranges are between 0.01 mg/kg and 1 g/kg, preferably between 0.1 mg/kg and 100mg/kg, even more preferably between 1 and 10 mg/kg. The doses for entecavir are e.g. at least 0.01 pg/kg, pref erably at least 0.1 pg/kg, at least 1 pg/kg, and/or up to 100 pg/kg, up to 1 mg/kg, up to 10 mg/kg and any dosages in between. Preferred dosage ranges are between 0.01 pg/kg and 10 mg/kg, preferably 0.1 pg/kg and 1 mg/kg, even more preferably between 1 pg/kg and 0.1 mg/kg. The doses for famciclovir are e.g. at least 0.1 mg/kg, at least 1 mg/kg, and/or up to 100 mg/kg, up to 1 g/kg, and any dosages in between. Preferred dosage ranges are between 0.01 mg/kg and 1 g/kg, preferably between 0.1 mg/kg and 100mg/kg, even more preferably between 1 and 10 mg/kg. The doses for alamifovir are e.g. at least 1 pg/kg, at least 0.01 mg/kg, at least 0.1 mg/kg, and/or up to 10 mg/kg, up to 0.1 g/kg, up to 1 g/kg and any dosages in between. Preferred dosage ranges are between 1 pg/kg and 1 g/kg, preferably between 0.01 mg/kg and 0.1 g/kg, even more preferably between 0.1 and 1 mg/kg. The doses for racivir are at least 0.01 mg/kg, at least 0.1 mg/kg, and/or up to 10 mg/kg, up to 0.1 g/kg, and any dosages in between. Preferred dosage ranges are between 0.01 mg/kg and 1 g/kg, preferably between 0.1 mg/kg and 100mg/kg, even more pref erably between 1 and 10 mg/kg. The doses for opaviraline are at least 0.01 mg/kg, at least 0.1 mg/kg, and/or up to 10 mg/kg, up to 0.1 g/kg, and any dosag es in between. Preferred dosage ranges are between 0.01 mg/kg and 1 g/kg, preferably between 0.1 mg/kg and 100mg/kg, even more preferably between 1 and 10 mg/kg.
WO 2013/167743 PCT/EP2013/059752 77 The examples show that the inventive pain tests revealed pharmaceutical compounds that are well known to be therapeuti cally applicable for the treatment of human conditions and dis eases. The compounds may now also be used for the treatment of pain and pain associated secondary diseases. Of course the full list of compounds according to the invention provides new thera peutic concepts. The inventive compound can be used in combination with other active analgesic/anti-pain compounds, preferably only with those described herein or above or in the claims or in the tables 1 ,2 or 3 or the derivatives with the defined formulas herein, or used as single active analgesic/anti-pain compound. In further embodiments the inventive compounds may be combined with any one or more compound selected from Tenofovir (PMPA), dasatinib, AMG 706 (motesanib), BIRB 796 (Doramapimod), EKB-569 (Pelitinib), sorafenib , Vandetanib, CI-1033 (Canertinib), NSC161613, N6 Benzyladenosine-5'-phosphate, p-Aminobenzoly PAB-J acid, NSC47091, cilomilast , Nicotinamide (Nicotinamide), IBMX, Roflumilast, Filaminast, Piclamilast, V11294, CC-10004 (Apre milast), LAS31025 (Arofylline), CP80633 (Atizoram), Catrami last/Atopik (Catramilast), BRL-61063 (Cimpyfylline), Dax alipram/mesopram (Daxalipram), Doxofylline, Drotaverine, Eflox ate, Etamiphylline, Etazolate, Etofylline, Glaucine Hydrobromide (Broncholytine), GRC3886 (oglemilast), oxtriphyllin (Choline theophyllinate), Pumafentrine, Revamilast, Tofimilast, Tolafen trine, Seoanin (Trapidil), GW 842470 (AWD 12-281), CDP-840, YM 976, CI-1018, D-4418, Lirimilast, SCH-351591, RPL-554, IPL 455903 (HT-0712), GSK256066, Zardaverine, Vardenafil, OPC-6535 (Tetomilast), IC485, L-826,141, ONO-6126, CI-1044, MK-0873, T 2585, R1533 (MEM-1414), Ronomilast (ELB-353), UK-500,001, AN2728, DE-103, Tofisopam, (R)-Tofisopam (Dextofisopam), (S) Tofisopam (Levotofisopam (USAN)), EKB-568, SU-14813, LY-333531 (Ruboxistaurin), CGP-52421, SKI-606 (Bosutinib), Roscovitine, Tenofovir (PMPA), Methimazole, Adefovir dipivoxil (Bis-POM PMEA) (Adefovir), Acetazolamide, midostaurin (PKC-412), tozasertib (MK-0457, VX 680)or lestaurtinib (CEP-701). Further compounds that can be used in combination with the inventive compounds can be selected from one or more of the group of (1S,2S)-2-(2-(N ((3-benzimidazol-2-yl)propyl)-N-methylamino)ethyl)-6-fluoro 1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate WO 2013/167743 PCT/EP2013/059752 78 dihydrochloride, (5-(2-methoxy-5-chloro-5-phenyl)furan-2 ylcarbonyl)guanidine, (6S)-5,6,7,8-tetrahydrofolic acid, (T,G) A-L, 1 alpha-hydroxyergocalciferol, 1-(1-cyclohexylethylamino) 4-phenylphthalazine, 1-(2-methyl-4-methoxyphenyl)-4-((2 hydroxyethyl)amino)-6-trifluoromethoxy-2,3-dihydropyrrolo(3,2 c)quinoline, 1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-(2 (mopholin-4-yl)ethyl)-1H-indole, 1-(2,3-dihydro-1,4-benzodioxin 5-yl)-4-((5-(4-fluorophenyl)-3-pyridinyl)methyl)piperazine, 1 (6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H pyrrole-2,5-dione, 1-adamantyl propargyl ether, 1 aminobenzotriazole, 1-aminooxy-3-aminopropane, 1-hydrazino-4 (3,5-dimethyl)-1-pyrazolyl-5H-pyridazino(4,5-b)indole, 1 hydroxymethylmidazolam, 1-hydroxypyrene, 1-Methyl-4 phenylpyridinium, 1-Nitropyren-8-ol, 1-phosphatidyl-1D-myo inositol 3-phosphates, 1-stearoyl-2-oleoyl-sn-glycero-3 phosphocholine, 1,1-bis(3'-indolyl)-1-(4-t-butylphenyl)methane, 1,1-dimethylbutyl-1-deoxy-Delta(9)-THC, 1,1,1-trichloro-2-(4 hydroxyphenyl)-2-(4-methoxyphenyl)ethane, 1,2 bis(diphenylphosphino)ethane, 1,2-di-(4-sulfamidophenyl)-4 butylpyrazolidine-3,5-dione, 1,2-diacyl-sn-glycero-3 phosphocholines, 1,2-ethanedithiol, 1,2 oleoylphosphatidylcholine, 1,2,4-triazines, 1,25-dihydroxy-21 (3-hydroxy-3-methylbutyl)-23-yne-26,27 hexafluorocholecalciferol, 1,25-dihydroxyergocalciferol, 1,25D3, 1,3-Dcg, 1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4 carboxyphenyl)tetrahydroimidazole, 1,3-dipropyl-8-(3 noradamantyl)xanthine, 1,3,5-trimethylbenzene, 1,7-dioxa-2,6 diaza-4,4-dioxide-4,7a-dithia-3H,5H-benzo(cd)pentalene, 10 deoxymethynolide, 10-propargyl-10-deazaaminopterin, 10 undecynoic acid, 10,10-bis(4-pyridinylmethyl)-9(10H) anthracenone, 11-cis-retinal, 11-hydroxycannabinol, 12-Hht, 13 Lox, 13-oxo-9,11-octadecadienoic acid, 15 hete, 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, 17 (allylamino)-17-demethoxygeldanamycin, 17alpha-ethynylestradiol, 1843U89, 1D-myo-inositol 1,3,4,5-tetrakisphosphate, 1H-indole, 1H-pyrazole, 1H-pyrazolo(3,4-b)pyridine, 2 APB, 2-(1-(3 dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3 yl)maleimide, 2-(1-methyl-4-piperidinyl)-6-(2 phenylpyrazolo(1,5-a)pyridin-3-yl)-3(2H)-pyridazinone, 2-(2 hydroxyethylsulfanyl)-3-methyl-1,4-naphthoquinone, 2-(3,4- WO 2013/167743 PCT/EP2013/059752 79 dimethoxyphenyl)-5-amino-2-isopropylvaleronitrile, 2-(4-amino-3 methylphenyl)-5-fluorobenzothiazole, 2-(4-morpholinoanilino)-6 cyclohexylaminopurine, 2-(4-morpholinyl)-8-phenyl-4H-1 benzopyran-4-one, 2-(4-toluidino)-6-naphthalenesulfonic acid, 2 (cyclohexylmethylidenehydrazino)adenosine, 2-AAF, 2 acetylthiomethyl-3-(4-methylbenzoyl)propionic acid, 2-AG, 2 amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, 2-amino-3,4 dimethylimidazo(4,5-f)quinoline, 2-aminoethoxydiphenyl borate, 2-AP, 2-CADO, 2-chloro-5-nitrobenzanilide, 2-cyano-3-hydroxy-N (4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide, 2 cyanomethylthiopyridine-4-carbonitrile, 2-cyclopentyl-5-(5 isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole, 2-DG, 2 hydroxy-4-(2,2,3,3,3-pentafluoropropoxy)benzoic acid, 2 hydroxyamino-1-methyl-6-phenylimidazo(4,5-b)pyridine, 2 hydroxyamino-3-methylimidazolo(4,5-f)quinoline, 2-ME, 2 methoxyacetic acid [2-[2-[3-(1H-benzoimidazol-2-yl)propyl methyl-amino]ethyl]-6-fluoro-1-isopropyl-tetralin-2-yl] ester, 2-methyl-i-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine, 2-N-(4-(1-azitrifluoroethyl)benzoyl)-1,3-bis-(mannos-4-yloxy)-2 propylamine, 2-Naftol, 2-oxothiazolidine-4-carboxylic acid, 2 phenyl-4-oxohydroquinoline, 2,2,2-trichloroethane-1,1-diol, 2,2'-(hydroxynitrosohydrazono)bis-ethanamine, 2,2'-azobis(2,4 dimethylvaleronitrile), 2,2'-bipyridine, 2,2',4,4' tetrachlorobiphenyl, 2,3-bis(3'-hydroxybenzyl)butane-1,4-diol, 2,3-dihydroxyterephthalamide, 2,3,4-tri-O-acetylarabinopyranosyl isothiocyanate, 2,4-diaminoquinazoline, 2,4-thiazolidinedione, 21-hydroxy-9beta,10alpha-pregna-5,7-diene-3-ol-20-one, 25 desacetylrifabutin, 25-Hydroxycholesterol, 25(OH)D3, 3-((4-(4 chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine, 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3 hydroxypropyl)cyclohexanol, 3-(2h)-pyridazinone, 3 (cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide, 3-aminopyrazole, 3-beta-(2-(diethylamino)ethoxy)androst-5-en-17 one, 3-BHA, 3-hydroxybutanal, 3-hydroxyflunitrazepam, 3 Hydroxyquinine, 3-isobutyl-1-methyl-Xanthine, 3-keto desogestrel, 3-methoxy-4-aminoazobenzene, 3-Methoxymorphinan, 3 Methoxyoestradiol, 3-methylcholanthrene, 3-MI, 3,3',4,5' tetrahydroxystilbene, 3,4-DCI, 3,4,5-trihydroxybenzamidoxime, 4 (3-3,4-p-menthadien-(1,8)-yl)olivetol, 4-(3-Butoxy-4 methoxybenzyl)-2-imidazolidinone, 4-(4-(4-chlorophenyl)-4- WO 2013/167743 PCT/EP2013/059752 80 hydroxy-1-piperidinyl)-1-(4-fluorophenyl)-1-butanol, 4-(4-(N benzoylamino)anilino)-6-methoxy-7-(3-(1 morpholino)propoxy)quinazoline, 4-(4-fluorophenyl)-2-(4 hydroxyphenyl)-5-(4-pyridyl)imidazole, 4-(5-benzo(1,3)dioxol-5 yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide, 4-(benzodioxan-5 yl)-1-(indan-2-yl)piperazine, 4-(N-methyl-N-nitrosamino)-1-(3 pyridyl)-1-butanone, 4-AP, 4-azidosalicylic acid, 4 dimethylamino-3',4'-dimethoxychalcone, 4-hydroxy-N desmethyltamoxifen, 4-hydroxyacetophenone, 4-hydroxycoumarin, 4 hydroxyestradiol-17 beta, 4-hydroxynon-2-enal, 4 hydroxytriazolam, 4-methyl-N-(3-(4-methylimidazol-1-yl)-5 (trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2 yl)amino)benzamide, 4-phenylbutyric acid, 4-S-cysteaminylphenol, 4-sulfophenylmethallyl ether, 4,4'-DDE, 4,4'-dipyridyl disul fide, 4,8-dimethoxy-7-hydroxyfuro(2,3-b)quinoline, 4' epidoxorubicin, 4'-N-benzoylstaurosporine, 4(2' aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline, 4alpha phorbol 12,13-didecanone, 4alphaPDD, 5-((1,2-dihydro-2-oxo-3H indol-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-propanoic ac id, 5-(4'-(N-piperidinyl)phenylazo)indazole, 5-7-oxo-zeaenol, 5 AC, 5-acetylneuraminyl-(2-3)-galactosyl-(1-4)-(fucopyranosyl-(1 3))-N-acetylglucosamine, 5-azido-1H-indole-3-acetic acid, 5-HT, 5-methoxy-N,N-diisopropyltryptamine, 5-Mop, 5,10 methylenetetrahydrofolate, 5,6-dimethylxanthenoneacetic acid, 5'-0-(((2-decanoylamino-3 phenylpropyloxycarbonyl)amino)sulfonyl)uridine, 6 beta hydroxycortisol, 6-Aminochrysene-1,2-dihydrodiol, 6-chloro-2 pyridylmethyl nitrate, 6-deoxy-6-bromoascorbic acid, 6 hydroxydexamethasone, 6-Mercaptopurine, 6,6'-oxybis(2,2 dimethylhexanoic acid), 64Gd, 7-(1,1-dimethylethyl)-6-(2-ethyl 2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4 triazolo(4,3-b)pyridazine, 7-benzylamino-6-chloro-2-piperazino 4-pyrrolidinopteridine, 7-benzyloxyquinoline, 7-CDL, 7 hydroxystaurosporine, 7-ketocholesterol, 7,8-BF, 7,8 dihydroneopterin, 7'-Isothiocyanato-11-hydroxy-1',1' dimethylheptylhexahydrocannabinol, 7C3MT, 7H-Pyrrolo(2,3 d)pyrimidine, 8-((4-bromo-2,3-dioxobutyl)thio)-adenosine 3',5' cyclic monophosphate, 8-(2,6-dichlorophenyl)-10-methyl-3-((4 morpholin-4-ylphenyl)amino)-2,4,10-triazabicyclo(4.4.0)deca 1,3,5,7-tetraen-9-one, 8-(3-chlorostyryl)caffeine, 8- WO 2013/167743 PCT/EP2013/059752 81 anilinonaphthalene-1-sulfonic acid, 8-Hydroxy-2-(di-n propylamino)tetralin, 8-Isoprostane, 8,10-bis((2,2-dimethyl-1 oxopropyl)oxy)-11-methyl-1234-tetrahydro-6H benzo(beta)quinolizin-6-one, 9-(4'-aminophenyl)-9H-pyrido(3,4 b)indole, 9-anthroic acid, 9-CRA, 9-hydroxy-risperidone, 9,10 anthraquinone, 9H-xanthene, A 71915, A-300-I, a-ADP, A73025, Ab bott, abciximab, Absele, ABT-737, acetamide 45, Aceton, acetoni trile, acetyl-11-ketoboswellic acid, acetylcholine, acetyl valerenolic acid, Aclarubicin, Acolen, ACON, ACT D, actinium, Actosin, adalimumab, Adalin, Adanon, Adfeed, adinazolam, Adofeed, Adrenor, Adrin, AEBSF, Aeromax, afloqualone, AGMATINE, AIDSVAX, ajoene, ajulemic acid, alachlor, Aladerm, alaninate, Alat, Alcolo, Alcuronium, Aldara, ALDO, Aldrich, alemtuzumab, Alfarol, Alfentanil, ALIMTA, aliskiren, Alli, ALLN, alloxazine, allyl isothiocyanate, almokalant, aloesin, Alprenolol, Alvesco, AM 1387, AM 251, Am 80, AMD 070, Amiloride, Aminacrine, Amine BB, amino-polyethyleneoxide-sulfonate, aminoflavone, Amiodarone, Amlodipine, Amphotericin B, amprenavir, Amrinone, amsonic acid, Amygdalin, AN 207, Anaboleen, anacardic acid, Anandamide, Anco, Andrographis, Androtine, Aneol, Ang II, Anisomycin, Anon, Antho cyanins, anthra(1,9-cd)pyrazol-6(2H)-one, anthracene, anthralin, Anthricin, anthrone, antibiotic G 418, antibiotic H107, Antimy cin A, Anyvim, APAP, APDC, Aphidicolin, Aphloiol, apicidin, Apigenin, apocynin, Apotransferrin, aprepitant, APRL, AQ4N, arabinogalactan, Arac, Aralen, Arasine, Areca, Arecoline, Areether, argatroban, aripiprazole, Aron, Artein, Artra, arvan il, asiatic acid, asiaticoside, Asmax, Asmol, ASTA, astatine, Astemizole, Astragaloside A, atazanavir, ATL 146e, Atorel, atorvastatin, Atovaquone, ATRA, Atropine, Auranofin, AuTM, aux in, avasimibe, AVE 0118, avicularin, Avid, Axert, Axsain, Aza dC, Aza-deoxycytidine, azacyclonol, Azadc, azamulin, azaspirane, azelaic acid, azelastine, azelnidipine, azido ruthenium, Azine, Azithromycin, Azobisisobutyramidinium dichloride, Azole, Azoles, Azolidine, Azophen, Azor, BA (VAN), Ba 0108E, bacitracin, Baclo fen, bacterial lysate, bafilomycin Al, Bagren, baicalein, Barbi turate, Barnidipine, BAY 11-7085, BB-K8, BCNU, Beflavin, Belt, benazepril, bendamustine, Benidipine, benzamidine, benzimidaz olide, Benzodiazepines, Benzodioxoles, Benzphetamine, benzyda mine N-oxide, benzylamine, benzyloxycarbonylleucyl-leucyl leucine aldehyde, benzyloxycarbonylvalyl-alanyl-aspartyl fluoro- WO 2013/167743 PCT/EP2013/059752 82 methyl ketone, beractant, berberine, bergamottin, bergaptol, be ta-glycerophosphoric acid, beta-lapachone, beta-Naphthoflavone, beta-propiolactone, Bethanechol, betulinic acid, bexarotene, Bezafibrate, BG 9928, BGC945, biapigenin, BIBX 1382BS, biphenyl 4-ol, BIRB 796, bisindolylmaleimide I, bisindolylmaleimide III, Bisoprolol, bisperoxovanadium, Bisphenol A-Glycidyl Methacry late, bizelesin, BL1521, Bla-S, Blow, BM 41.440, BML 241, BMS 310705, BMS204352, BMS453, Bo-Xan, Boltin, Bonopen, boron, Bor relia-burgdorferi, bortezomib, bosentan, bosutinib, botrocetin, BPDE, BR-II, Brake, bredinin, Brefeldin A, Bromazepam, bromo cis-stilbene, brucine, bryostatin 1, Budesonide, bufalin, bufuralol, Bumetanide, BuOH, Bupivacaine, Buprenorphine, BU PROPION, Buspirone, Busulfan, Buthionine Sulfoximine, Butyrate, butyrolactone I, C 1027, C 76, CACP, Calcijex, Calcimycin, cal phostin C, Calyculin, Camptothecin, Canef, cangrelor, Canna binoids, Cannabis, Cantharidin, CAPE, Capsaicin, capsaicinoids, capsazepine, Carbachol, Carbamazepine, carbapenem, Carbapenems, carbobenzoxy-leucyl-leucyl-norvalinal, Carbolines, Carboxyethyl phenethylamino-ethylcarboxamidoadenosine, Cardiolipins, carebas tine, CARNOSOL, carrageenans, carvacrol, carvedilol, Casodex, caspofungin, casticin, catechins, CB 3717, Cbdca, CCPA, CD 437, CDP 840, Cefoxitin, celecoxib, cephalomannine, cephalosporins, cepharanthine, cerebrolysin, cerivastatin, Cetomacrogol, ce trorelix, cetuximab, CGP 12177, CGS 15943A, CGS 21680, CH-THF, CH2CHO, Chalcone, CHAPS, Chinine, Chitosan, Chloramphenicol, chlorophenyl-ethane, chlorophyllin, chlorophyllypt, chlorproma zine, Chlorpropham, Chlorzoxazone, Cholestanol, CHOLINE, Chon surid, chromophore, Chrysin, chymostatin, CI1033, cicaprost, cifostodine, ciglitazone, Cilazapril, Cilomilast, cilostazol, Cimetidine, cinacalcet, cinitapride, cinnamic aldehyde, cionin, Cipol N, Ciprofloxacin, Ciprol, cis-9, trans-11-conjugated lino leic acid, Cisapride, Citalopram, Citox, CITRULLINE, clebopride, clevidipine, clobazam, Clodronic Acid, clofarabine, Clofibric Acid, Clomipramine, Clonazepam, Clonidine, clopidogrel, clotiaz epam, Clozapine, clozapine N-oxide, CNI 1493, Co 2-1970, Coagu lin, Colchicine, compactin, CONT, Cotinine, Cotrim, coumarin, CRA 024781, CRA 026440, Crestor, Crodacid, Crypt-2,2,2, cryptdin 3, cryptotanshinone, cryptoxanthin, CUBE, CVT 3146, cyanidin 3 rutinoside, cyanidin-3-glucoside, cyanoginosin-LA, Cyclandelate, cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester, cyclo- WO 2013/167743 PCT/EP2013/059752 83 hexyl-methyl, cyclopamine, Cyclopentenone, cyclopiazonic acid, Cyproheptadine, Cyproterone Acetate, cystathionine, cysteamine, cysteinyl-leukotriene, Cytarabine, cytochalasin B, Cytochalasin D, cytochalasin E, D 22888, D 23129, DA 8159, Dacarbazine, DAD SO, daidzein, danaproid, Dapsone, Daral, Darifenacin, darunavir, dasatinib, Daunorubicin, Dayfen, DBPC, DDB, DDE, Debrisoquin, decursin, Deethylamiodarone, deferiprone, Deferoxamine, deguel in, dehydroaripiprazole, Dehydroepiandrosterone Sulfate, dehy droxymethylepoxyquinomicin, Delavirdine, delta8-THC, Denagard, denbinobin, denileukin diftitox, denopamine, Depas, de ramciclane, desethylchloroquine, desflurane, desisobutyrylci clesonide, desmethylazelastine, Desmethyldeprenyl, Devazepide, Dexfenfluramine, dexloxiglumide, Dextropropoxyphene, dFdC, DFMO, DHEA, DHLA, di-(1-isoquinolinyl)-di-(pyridyl-2')butane, Diaben, Diacomit, diadenosine tetraphosphate, Dial, Diamide, DIAN, di arsenic trioxide, Dibenzanthracene, Dicid, Diclofenac, Dicyclo hexylcarbodiimide, diethyl maleate, Diethyl-benzoquinone-imine, Digicor, Digitin, Digoxin, Dihydroqinghaosu, Dihydroxycholecal ciferols, diisopropyl fluorophosphate, dillapiol, Diltiazem, Di methadione, dimethyl fumarate, Dimethyl Sulfoxide, dimethyl hydrazide, dimethylamino-purine, dimuonium, dinitrophenol, Dino prostone, dioxirane, Dipalmitoyl, diphenylalanine, Diphenyla mine, diphenyleneiodonium, Dipyridamole, Dipyrone, discoder molide, Diterpenes, Dithionite, diuretic, Diuron, divinyl ben zene, dl-Ipr, DMGG, DMPX, DMSO, Dobutamine, Doca, Doconexent, dodecyl-phosphocholine, dodecyloctaethyleneglycol monoether, Domperidone, DOTA, Doxazosin, Doxorubicin, Doxycycline, DPC 681, DPCPX, Droxia, DTMC, dulcin, Durapatite, DX 9065a, Dxms, Dyna tra, E 10, E 3330, E-MIX 80, E.O., EACA, ebastine, ebrotidine, Echinomycin, Econ, econazole, ecteinascidin 743, Edetic Acid, Edex, efavirenz, EGCg, EGTA, eletriptan, Elicide, Empecid, Enal april, Endocannabinoids, endomorphin 1, Enediynes, enflurane, enone, Enoximone, entacapone, Entex, enzastaurin, EOS, EPC-K(1), EPEG, EPIB, epibatidine, Epicar, Epoprostenol, epoxybergamottin, epsilon-viniferin, erastin, ergosterol-5,8-peroxide, Eril, erlo tinib, erucin, Eryc, erythritol anhydride, esterbut-3, Estriol, ET18-Ome, Etfc cpd, Ethacrynic Acid, Ethan, Ethinyl-oestradiol, Ethylmorphine, Ethynodiol Diacetate, Eticol, Etidronic Acid, Etodolac, Etoposide, etoricoxib, etravirine, Eufor, Eugenol, eu patilin, everolimus, Evex, Evodin, exenatide, Exosurf, Expecto- WO 2013/167743 PCT/EP2013/059752 84 rants, Extina, Ezerin, ezetimib, Facet, Facid, facile, Factor IIa, FAMP, Fanchinine, Farnesyl-PP, farnesylthiosalicylic acid, febuxostat, felbamate, Felodipine, Fenfluramine, fenitrothion, fenofibric acid, Fenretinide, Fentanyl, ferulic acid, Filipin, fingolimod, fipronil, fisetin, Flanin F, Flavon, flavonols, fla vopiridol, Flavyl, FLCZ, Flecainide, Floxacillin, flufenamic ac id, Flunitrazepam, fluorexon, Fluorouracil, fluvoxamine, FOLATE ANALOG, fondaparinux, Fonofos, Format, Formyl-Tetrahydrofolate, Forskolin, fosamprenavir, Foscarnet, FR 120480, FR 235222, frax in, FTY 720P, fucoidan, fulvestrant, fumagillin, Fura-2, furafylline, Furamon, Furylfuramide, Gabexate, gadolinium, Gado linium DTPA, galactocerebroside, galactomannan, galangin, gala turonate, gallic acid, Gallogen, gambierol, Gambogic acid, gam ma-butyric-acid, Ganciclovir, gastrin 17, gatifloxacin, ge fitinib, Geldanamycin, Gemfibrozil, gemtuzumab, Gentamicins, gepirone, geraniol, geranylcoumarin, Gestodene, GF 120918, GGTI 298, GI 129471, gingerol, ginsenoside Rd, ginsenoside Rf, gin senoside Rgl, ginsenoside Rh2, Ginsenosides, GLCa, Gliclazide, Glumin, Glyoxal, Gnidimacrin, GnRH, Go 6976, gossypol, GR 79236X, gramicidin S, Granisetron, Gravistat, Grofo, Guggul sterone, GW 4064, GW 501516, H 89, Halan, halofuginone, harmine, Harzol, hassium, HDMTX, Hecogenin, Hectorol, Heet, helenalin, Hemicholinium 3, herbimycin, hesperadin, HESPERETIN, Hexadime thrine, hexarelin, Hgln, himbacine, Hk, Hocus, HOE 33342, honokiol, Horner, HS 1200, HU 211, HyateC, Hydoxin, hydride, Hy dromorphone, Hydroxychloroquine, hydroxycotinine, hydroxylamine, Hydroxytryptophol, Hyhorin, Hypaque, hyperforin, hypericin, Hy pericum-perforatum, hypochlorous acid, iberin, IBMX, ibopamine, ibudilast, IC 831423, icariin, icaritin, icilin, ICRF 193, IDS 23, Ifosfamide, Ikarugamycin, ilimaquinone, Iloprost, Imadyl, imatinib, imidafenacin, imidazo-pyridine, imidazolidin-2-one, imidazolidin-one, imidazolidine, Imidazoline, imidazolyl disulfide, Imipenem, Imizin, Immulina, Immunoferon, Impulsin, Imrecoxib, Imutex, Indinavir, indiplon, indirubin, indole-3 acetic acid, indole-3-methanol, indolin-2-one, indolin-one, in fliximab, inhibin B, INOmax, inositol-1,3,4,5-tetrakisphosphate, inulin, Iodoacetamide, iodomethane, iodoresiniferatoxin, Ionomy cin, ionophore, Iopanoic Acid, Iophendylate, IPADE, IPOMEANOL, Iressa, irinotecan, irisolidone, Isatin, isaxonine, isoamylol, isobutyl-methyl-Xanthine, Isodonol, isoflavone, isoflurane, WO 2013/167743 PCT/EP2013/059752 85 Isol, Isoliquiritigenin, isometronidazole, isoprenoids, Isopro pyl Thiogalactoside, Isoprostanes, Isorhamnetin, isosilybin A, Isosorbide Dinitrate, isothiocyanates, Isotretinoin, Isradipine, istradefylline, Itraconazole, ivabradine, Ivermectin, ixabepilo ne, jadomycin B, Jexin, JHW 015, JTE 013, K 252, K-PAM, K-SR, kaempferol, kaempferol-3-0-(2,3,4-tri-O-acetyl-alpha-l rhamnopyranoside), KAFA, Kaken, Kamalin, Kaolin, Kathon 886, KB 141, Kemi, kenpaullone, Ketamine, Keto-desogestrel, Keto pgflalpha, ketoglutarate, Kipca, KMD 3213, KMTB, Kojic acid, KR 31543, KRM 1648, L 365260, L 740,093, L-454,560, L-696,474, L T3, LAAM, lacidipine, lactacystin, lactisole, lamotrigine, Lanol, lansoprazole, lapatinib, laquinimod, latrunculin A, latrunculin B, lavendustin A, LBH589, leflunomide, lenalidomide, Lendorm, Lentinan, leptomycin B, Leucovorin, Leukotriene C4, Leukotriene D4, leukotrienes, Leupeptin, Levamisole, Levitra, levobupivacaine, Levonorgestrel, levugen, liarozole, Lidocaine, lilopristone, Lipoate, Lipofectamine, lipoteichoic acid, Lipox ins, lissamine rhodamine B, lithocholic acid, LMWH, LNAC, lo nafarnib, Loperamide, lopinavir, Loratadine, Lorazepam, Lorex, lorglumide, Losartan, Lovan, loxiglumide, LUF 5831, lupeol, lu teolin, LY 117018, LY 293111, LY231514, LYCOPENE, lysophospha tidic acid, Lysophosphatidylcholines, Lysophosphatidylglycerol, lysyl-arginyl-alanyl-lysyl-alanyl-lysyl-threonyl-threonyl-lysyl lysyl-arginine, M&B22948, Malix, manidipine, manumycin, mara viroc, Matrine, MCYST-LR, Me-nle-asp-phe-NH2, mead ethanolamide, MeAsO(OH)2, Mebumal, Mechlorethamine, Medroxyprogesterone 17 Acetate, Mefenamic Acid, Megalomicin, Melarsoprol, Melatol, me letin, melitten, meloxicam, Melphalan, Memantine, menadiol, Men haden oil, menthofuran, Meperidine, Mephenytoin, mesalamine, Me saton, Meth, methanandamide, methanethiosulfonate ethylammonium, Methimazole, methionyl-leucyl-phenylalanine, Methorphan, Methox salen, Methoxy-psoralen, methoxyamine, methoxychlor, methoxy morphinan, methyl chloroformate, Methyl glycine, Methyl paraben, methyl salicylate, methyl tryptophan, methyl-dopa, methyl phosphorothioate, methyl-Pyridinium, methylamine, Methyla mylnitrosamine, Methylene-tetrahydrofolate, methylenetetrahydro folates, methylglyoxal, methylnaltrexone, methyloxidanyl, methylparaben, methylphosphate, Methylprednisolone, methylxan thines, Metoclopramide, Metopiron, Metribolone, mevalonic acid, micafungin, miconazole, Mictonorm, Midazolam, Mifepristone, WO 2013/167743 PCT/EP2013/059752 86 MIII, Milrinone, Mimosine, mirtazapine, Mit-C, mithramycin, Mi toTracker-Red, Mitoxantrone, mizolastine, MLN8054, mofarotene, Monensin, mono-N-demethyladinazolam, mono(2-ethylhexyl) phthalate, monoethylglycinexylidide, monomethylarsonic acid, monoterpenes, monuron, MORIN, morpholine, morusin, motexafin gadolinium, Motuporin, moxifloxacin, MPEG, Muraglitazar, mutali pocin II, mycophenolic acid, Mycose, Myocol, myricetin, myxothi azol, N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide, N-(2 hydroxypropyl)methacrylamide, N-(3-(4-chlorophenyl)-2-(3 cyanophenyl)-1-methylpropyl)-2-methyl-2-((5 (trifluoromethyl)pyridin-2-yl)oxy)propanamide, N-(3 methoxyphenyl)-4-chlorocinnamanilide, N-(3 oxododecanoyl)homoserine lactone, N-(4-(6-(4-(1-(4 fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4 yloxy)benzo(d)thiazol-2-yl)acetamide, N-(4-(6-(4 trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2 yl)acetamide, N-(4-cyano-benzo(b)thiophene-2-carbonyl)guanidine, N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2 thiazolyl)-4-piperidinecarboxamide, N-acetylcysteine lysinate, n-acetylmuramyl-l-alanyl-d-isoglutamine, N-acetylneuraminic ac id, N-desmethylclobazam, N-ethylmaleimide, N-methyl-N (trimethylsilyl)trifluoroacetamide, N-methylsulfonyl-6-(2 propargyloxyphenyl)hexanamide, N-oleoyldopamine, N-phenyl-1 naphthylamine, N,N,N',N'-tetramethylethylenediamine, N(6) cyclohexyl-2-0-methyladenosine, N(6)-cyclopentyladenosine, N3 IQ, Nadroparin, naftifine, nal-NH2, NALS, nanchangmycin, Naprox en, naratriptan, narbonolide, NARIGENIN, Narkotil, Nasol, na talizumab, nateglinide, Naxy, nebivolol, Nefazodone, nefirace tam, Nelfinavir, Neomycin, Neopterin, Neostigmine, Neut, Nevi rapine, NFBA, Nialk, Nicardipine, Niflumic Acid, nimesulide, ni obium, nitecapone, nitroanilide, nitroaspirin, Nitrofurans, NI TROPYRENE, nitrosamines, Nitrosoanabasine, Nitrosocysteine, ni trosulindac, Nizatidine, NK 104, NK314, NMDA, NN 703, Noan, No biletin, NOC 18, Nocodazole, nodularin, Nodularin v, nolatrexed, Nonoxynol, noralfentanil, norbuprenorphine, Norclozapine, Nordi hydroguaiaretic Acid, Norethindrone, noreximide, norfluoxetine, Norgestrel, norharman, norketobemidone, norlaudanosoline, normeperidine, Nortilidine, norverapamil, novobiocin, NS-187, NSC 23766, NSC 366140, NSC 663284, NSC-134754, NU2058, number one, nutlin 3, NVP-AEW541, Nylon, 0- WO 2013/167743 PCT/EP2013/059752 87 (chloroacetylcarbamoyl)fumagillol, 0-desethylreboxetine, 0-Due, o-quinone, obovatol, OCDD, octanediol, Octoxynol, Octreotide, Okadaic Acid, olanzapine, olefins, oleoylethanolamide, olmelin, olmesartan, olomoucine, olomoucine II, Oltipraz, omalizumab, omega-agatoxin, omega-Conotoxin GVIA, omega-N-Methylarginine, Omeprazole, omeprazole sulfone, onapristone, ONCB, Ondansetron, ONO4819, Optef, OR 1246, oroxylin A, Orphenadrine, Osten, oste um, OSU 03012, Ouabain, OVEX, Ovex, oxaliplatin, Oxarol, oxaspi rodion, oxatomide, Oxazepam, oxcarbazepine, Oxotremorine, oxo tremorine M, Oxymorphone, Oxyntomodulin, Oxytrol, p-ABA, p-XSC, p-Xylol, Paclitaxel, paeonol, palladium, palmitoleate, PALMITO YL, Palmitoylcarnitine, pamidronate, panaxadiol, panepoxydone, pantoprazole, Papaverine, Papite, PAPP, parecoxib, Paroxetine, Parsal, Parthenolide, PC 314, PCA 4230, PCSO, PD 134308, PD 144795, PD 180988, PD 98059, pectin, Pemetrexed, Penicillins, Penite, Pentagastrin, Pentoxifylline, Peplomycin, peppermint oil, Pepstatin A, Perazine, Pergolide, Perillol, Perilymph, pe riodate, perospirone, perovskite, PFPA, Phebestin, phen, pheno late, Phenols, phenoxodiol, Phenprocoumon, Phentermine, phenyl propionamide, phenyl-Pyridinium, Phenytoin, pheophorbide a, phloretin, PHOB, phorate, phorbol, phorbol 12-phenylacetate 13 acetate 20-homovanillate, phosphatidylethanolamines, Phosphati dylinositol 4,5-Diphosphate, phosphatidylinositol phosphate, PtdIns(4,5)P2, phytanic acid, Picibanil, picric acid, pifithrin, Pilot, pimecrolimus, pioglitazone, pipecoloxylidide, piperidine, piperine, Pira, pirinixic acid, Piroxicam, PKC412, plumbagin, Pluronic p 85, PMDT, PMPA, PMSF, PNPP, Podophyllotoxin, polido canol, poly-gamma-glutamate, ponicidin, poractant alfa, posacon azole, potassium tellurate (IV), PQQ Cofactor, pranlukast, Pravastatin, Prazosin, PRDL, Precursor mrna, Prednisone, preg nane, Pregnanes, Pregnanolone, pregnenolone 16alpha carbonitrile, Pregnyl, preussin, Primidone, Proadifen, Proantho cyanidins, Probenecid, Probucol, Procasil, Procetofen, procya nidin B2, Prodix, prolactin, polymeric, Propafenone, Propanesul fonate, Propofol, propyl pyrazole triol, propyne, prostratin, protopanaxadiol, protopanaxatriol, PS 15, Pseudohypericin, Pseu domonas-exotoxin, Psoralens, psychosine-3'-sulfate ester, PTBP, pteridine, Pterostilbene, PURAC, Puromycin, putrescine, Pyocya nine, Pyra, pyranones, pyrazole, Pyrethrins, pyridazine, Py rimethamine, pyrimidin-2-one beta-ribofuranoside, Pyro, pyrogal- WO 2013/167743 PCT/EP2013/059752 88 lol sulfonphthalein, pyrrole-2-carboxylic acid, pyrrolidine di thiocarbamic acid, pyrroloazepinone, Qingkailing, quercitrin, quetiapine, Quicifal, quinazoline, Quinolinium, Quinpirole, qui nuclidin-3'-yl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2 carboxylate monosuccinate, quinupristin-dalfopristin, R-138727, R-99224, Raloxifene, raltitrexed, Ramipril, ramiprilat, RAMP, Ranitidine, RAPA, rasagiline, rebamipide, reboxetine, remifen tanil, renzapride, repaglinide, Resiniferotoxin, resiquimod, Re tardex, Riacon, Ribavirin, Riboflavin, Rifabutin, rifamycins, Rifocin, rimonabant, risedronic acid, risperidone, Ristocetin, Ritonavir, rituximab, Ro 13-8996, Ro 23-7553, Ro 23-7637, Ro 24 7429, Ro 31-6233, Ro 31-7549, Ro 31-8220, R04383596, Robitet, rofecoxib, roflumilast, rokitamycin, Rolipram, romidepsin, roop erol, ropivacaine, roscovitine, rosiglitazone, rosmarinic acid, rosuvastatin, Roxithromycin, Rozevin, RPR 121056, RU 58668, rub oxistaurin, rugosin E, rutecarpine, Rutin, S-(beta-p methoxypropiophenone)thiamine, S-Nitroso-N-Acetylpenicillamine, S-Nitrosothiols, S-phenyl-N-acetylcysteine, sabarubicin, sab comeline, Safingol, Safrole, SAGA, SAHA, saikosaponin, Salicin, salvin, samarium, SAMe, sanguinarine, sapogenins, Saquinavir, Sarasar, Sarna, sauchinone, saxatilin, SB 218078, SB 225002, SB 415286, SB-705498, scandium, SCH 66712, schizandrer A, scopa rone, Scopoletin, Score, SDX 308, Selegiline, seocalcitol, Sep Pak, Serad, sertindole, sevoflurane, SEW2871, shikonin, sidero phore, Sildenafil, silvestrol, silybin, Sincalide, Sizofiran, SK-7041, SK&F 106528, SM 7368, Sodium pentosan poly sulfate, So dium Salicylate, sorafenib, sorbinil, Sorbo, Sorbose, spiroglu mide, Spironolactone, squamocin, SR 144528, SR 27897, SR 48692, SR 80327A, SR 90107A-ORG 31540, ST 638, stallimycin, Stanozolol, staurosporine, Stearin, Stereoisomerism, Steviol, Stevioside, STIL, stilbene-disulphonate, Stilbenes, Stim, Streptomycin, Sty rene, styrene-methylmethacrylate copolymer, SU 5416, SU 6668, SU 9516, suberate, suberosin, succinic semialdehyde, Sufentanil, Suldox, sulfadoxine-pyrimethamine, Sulfamethazine, sulfamethoxa zole hydroxylamine, Sulfaphenazole, Sulfasalazine, sulfate cel lufine, sulfate-sulfate, sulfidonitrogen(.), Sulfinpyrazone, sulfo-N-succinimidyl oleate, sulfo-succinimidyl-oleate, sulfoga lactosylglycerolipid, sulfones, sulfonic acid, sulfonyl-phenyl ethyl, Sulforafan, Sulindac, sulindac sulfone, sultopride, sunitinib, Synthos, T 0070907, T 0901317, Tacrine, Tacrolimus, WO 2013/167743 PCT/EP2013/059752 89 tadalafil, Tamogel, Tamoxifen, tandospirone, Tangeretin, tanshinone, taurocholic acid, Taurodeoxycholic Acid, taurour sodeoxycholic acid, tautomycetin, TAXOTERE, TBDZ, TBHQ, TCAT, technetium, Tegafur, Teleocidin, telithromycin, Temazepam, te mozolomide, temsirolimus, terbinafine, terephthalic acid, Ter fenadine, teriflunomide, terrein, territrem A, territrem B, ter ritrem C, tertiapin, tetra-mu3-sulfido-tetrairon, tetrachloroe thene, tetradecanoyl-phorbol-acetate, Tetrahydrocannabinol, tet ramethyirhodamine, tetramethylsilane, tetraphene, Tetraprenol, tetrasulfanide, Thalidomide, Thapsigargin, thiamine disulfide, thiazole, Thiazolidinediones, thioacetamide, Thioacetazone, thi obenzamide, thiocoraline, Thiole, Thiopental, thioredoxin dithi ol, thioridazine, Thiostrepton, thrombin receptor peptide SFLLRNP, thrombin Tokushima, Thromboxane A2, thromboxane B2, Thyminose, thymol, thymoquinone, Thyrotropin, Ticlopidine, Ti lidine, tipranavir, tirilazad, titanium alloy (TiAl6V4), TMC 95A, Tmndga, TMSI, Tobrex, tocotrienols, tofisopam, tolrestat, Tolterodine, toluene, TOLUENE-DITHIOL, topiramate, Topotecan, Toremifene, Tosylarginine Methyl Ester, Tosyllysine Chloromethyl Ketone, Tosylphenylalanyl Chloromethyl Ketone, TPN+, Tracer, Tramadol, trans-resveratrol, trastuzumab, Trazodone, Tremode, Tremorine, Tretinoin, Triad, Triamcinolone, triazolam, tria zoles, tributylstannane, trichostatins, Triclosan, triethyla mine, Trifluoperazine, trimethylaminocarboxyldihydroboran, trioctyl phosphine oxide, Triolein, tripterine, triptolide, triterpenoids, troglitazone, Troleandomycin, TTNPB, tubocap sanolide A, Tunicamycin, tyrphostin AG 1478, tyrphostin AG-490, tyrphostin AG17, U 0126, Ubizol, Ufur, UK 157147, Uprima, uranyl acetate, urethane, Urex, urinastatin, Urso, USAN, valerenic ac id, valspodar, venlafaxine, Verapamil, verlukast, vesnarinone, Viagra, Vigil, vincristine, vinflunine, vinorelbine, vinpoce tine, violacein, Vira-A, voriconazole, vorozole, VX680, Warfa rin, WAY-169916, Win 55212-2, withaferin A, WLN: QR BG, WLN: RVR, WLN: ZSWR, xanthohumol, Xaxa, Xylit, Y 27632, yristate, Z 338, zafirlukast, Zalcitabine, zardaverine, ZD 9331, Zeara lenone, Zeldox, zerumbone, Zidovudine, zileuton, Zocor, zopi clone, Zymosan, Trospium chloride, Valproic Acid. These com pounds are described in patent application no. PCT/EP2011/069986 (incorporated herein by reference). The invention also relates to the administration of one or WO 2013/167743 PCT/EP2013/059752 90 more of the inventive compounds to a cell, especially in order to reduce pain signalling e.g. by modulation of biochemical sig nalling pathways involved in pain sensation or transmission. The cell can be a nerve cell, including pain or thermosensitive nerve cells, and/or preferably selected from spinal cord cells, brain cells or peripheral nerve cells. The cell can be of the "pain matrix" such as the thalamus, the Si and S2 somatosensory cortex, the cingulum, amygdala, hypothalamus, or the motor cor tex. The inventive administration may be for treatment, allevia tion or prevention of pain or hyperalgesia, or any other forms of pain or pain associated states or conditions in a subject. In a further aspect the present invention relates to a meth od of screening active compounds suitable for the treatment of pain comprising testing for modulation, including suppression or activation, preferably suppression, of pain. The test may com prise administration of a compound according to the invention to a cell or model animal of pain as described in the examples and detecting a deviation in pain sensation or responses e.g. by as sessment of behavioural read-outs when compared to normal levels observed when no compound or only vehicle or a compound known to have effect against pain has been administered. Especially pre ferred tests include the use of animal models models such as drospohila, or preferably rodents, such as preferably mice, such as preferably rats and testing the compounds for behavioural changes when exposed to pain, such rodent tests are disclosed in the examples. Additional information on optimal dosages can be obtained with these tests. In an aspect of the invention, the following is claimed: a therapeutic compound selected from the compounds of any one of tables 1 to 3 for use in treating or preventing pain in a sub ject. In yet another aspect, the following is claimed: any salt of a therapeutic compound selected from the compounds of any one of tables 1 to 3 or derivatives thereof for use in treating or pre venting pain in a subject. In yet another aspect, the following is claimed: any ester of a therapeutic compound selected from the compounds of any one of tables 1 to 3 or derivatives thereof for use in treating or preventing pain in a subject. In yet another aspect, the following is claimed: any salt of WO 2013/167743 PCT/EP2013/059752 91 any ester of a therapeutic compound selected from the compounds of any one of tables 1 to 3 or derivatives thereof for use in treating or preventing pain in a subject. The present invention is further illustrated by the follow ing figures and examples. Figures: Figure 1. Efficacy testing of anti-pain compounds in the chronic constriction injury model of neuropathic pain A: Von Frey's assay for pregabalin (positive control) and adefo vir in the CCI model as described in Example 1.3. Data are pre sented as mean values + SEM, n=8-10. Significantly different by Mann-Whitney U test compared to post surgery withdrawal thresh olds * p<0.05, ** p<0.01, *** p<0.001. B: Von Frey's assay for pregabalin and tenofovir in the CCI mod el as described in Example 1.3. Data are presented as mean val ues + SEM, n=8-10. Significantly different by Mann-Whitney U test compared to post surgery withdrawal thresholds * p<0.05, ** p<0.01, *** p<0.
0 01 . Figure 2: Efficacy testing of anti-pain compounds in the com plete freund's adjuvant model of inflammatory pain A: Von Frey's assay for Indomethacin (positive control) and Tenofovir in the CFA model as described in Example 3.3. Data are presented as mean values + SEM, n=6-10. Significantly different by Mann-Whitney U test compared to T=0 paw withdrawal thresholds (* p<0.05, ** p<0.01, *** p<0.001). B: Von Frey's assay for Indomethacin and Adefovir in the CFA model as described in Example 3.3. Data are presented as mean values + SEM, n=8-10. Significantly different by Mann-Whitney U test compared to T=0 paw withdrawal thresholds (* p<0.05, ** p<0.01, *** p<0.001). Figure 3: Testing of anti-pain compounds, acute inflammatory pain model. Weight bearing difference (%) between the ipsilat eral and contralateral limb for vehicle control and tomeglovir as described in Example 3.3.1. Data are presented as mean val ues, n=7-8 animals per test group.
WO 2013/167743 PCT/EP2013/059752 92 Figure 4: Testing of anti-pain compounds, acute inflammatory pain model. Weight bearing difference (%) between the ipsilat eral and contralateral limb for vehicle control and emtricita bine as described in Example 3.3.2. Data are presented as mean values, n=7-8 animals per test group. Figure 5: Testing of anti-pain compounds, acute inflammatory pain model. Weight bearing difference (%) between the ipsilat eral and contralateral limb for vehicle control and entecavir as described in Example 3.3.3. Data are presented as mean values, n=7-8 animals per test group. Figure 6: Testing of anti-pain compounds, acute inflammatory pain model. Weight bearing difference (%) between the ipsilat eral and contralateral limb for vehicle control and famciclovir as described in Example 3.3.4. Data are presented as mean val ues, n=7-8 animals per test group. Examples: The basic principle of animal models of human pain involve the induction of a pain-like state in the organism resulting in characteristic behavioral and physical responses, such as hyper sensitivity to touch (mechanical allodynia) and temperature (cold allodynia). The assessment of the efficacy of potential analgesics is determined based on said compound's ability to at tenuate/ameliorate these symptoms. Example 1: Assessing chronic pain in animal models - Chronic Constriction Injury The Bennett and Xie chronic constriction injury (CCI) model is a model of mononeuropathic pain (Bennett and Xie, 1988). Rodents are subjected to a surgical procedure where gut ligatures are tied loosely around the sciatic nerve at the mid-thigh level. Symptoms of neuropathy develop in the operated paw over the fol lowing days including tactile allodynia and cold allodynia, which are measured using Von Frey's hairs and paw withdrawal from a cold plate, respectively. Operated animals also exhibit other symptoms of spontaneous pain including thermal hyperalge sia, ectopic and spontaneous firing of sensory afferents, autot- WO 2013/167743 PCT/EP2013/059752 93 omy, licking and guarding of paw and sleep architecture abnor malities (Blackburn-Munro and Erichsen, 2005). Furthermore, electrophysiological studies have demonstrated the presence of both sensory nerve hyperexcitability and central sensitisation (wind up) in the dorsal horn and elsewhere (Blackburn-Munro and Erichsen, 2005). The Bennett and Xie model is thought to have predictive validity as an 88% concordance has been observed be tween activity in the model (any endpoint) and clinical efficacy in neuropathic pain (Kontinen and Meert 2003). Multiple drug classes including NSAIDs are ineffective in the clinical treat ment of neuropathic pain and fail to ameliorate symptoms in the Bennett model despite the presence of an inflammation in the in itial phase after surgery (eg Schafers et al., 2004; Takahashi et al., 2004, LaBuda and Little, 2005). Pregabalin, a drug ap proved for the treatment of various types of (chronic) pain, in cluding neuropathic pain associated with diabetic peripheral neuropathy in humans, is effective at ameliorating symptoms of pain in the CCI model. Example 1.1 Test System The CCI surgical procedure is performed as follows: Male Spra gue-Dawley rats are habituated to the mechanical test apparatus during 5-10 min periods spread over two days and once to the cold plate set at 100C for 3 minutes, both according to Example 1.2. Following habituation animals undergo the CCI surgical pro cedure requiring anaesthetization under isoflurane, shaving of the left (ipsilateral) hind limb and swabbing with antiseptic followed by administration of sodium pentobarbitone. An incision is made to reveal the left sciatic nerve which is tied off with four loose ligatures of chromic cat gut. The exposed muscle is sutured with non-absorbable silk and the wound closed with sur gical clips. The animals are monitored in the hours post surgery and on a daily basis thereafter. Animals showing signs of ill health or autotomy are removed from the study. Approximately 12 and 18 days after surgery the animals are reassessed for sensitivity to Von Frey's hairs and to the cold plate. Animal subjects meeting pre-defined criteria for hypersensitivity to mechanical (ipsi lateral hind-paw moved at a pressure of 4 g) and thermal stimu- WO 2013/167743 PCT/EP2013/059752 94 li ( 78s withdrawal latency) in the operated (ipsilateral) hind paw are allocated according to baseline mechanical and cold sen sitivity scores to produce balanced treatment groups of 8 to 12 animals in each group. Example 1.2: Test apparatus Mechanical allodynia is assessed by Von Frey's hairs. These con sist of a series of wires of progressive thickness each of which bend when a critical pressure (1.4, 2, 4, 6, 8, 10, 15 g) is ap plied. Animals are placed in floorless Perspex testing boxes resting on a wire mesh tray. Von Frey's hairs are then applied through the mesh floor to the sole of the left and right hind paws until either the animal senses discomfort and moves the paw or the pressure applied to the Von Frey's hair exceeds the crit ical level and it is observed to bend. Von Frey's hairs are ap plied in ascending order until either a pain response (the paw is moved) is registered or the cut-off of 15 g is reached, using the Von Frey hair with the highest rating. Hairs are applied to each heel 8-10 times at a frequency of approximately 1 Hz. If a limb is moved in response to a probe, further testing is halted and the sensitivity to a mechanical stimulus is deemed to have been reached. Sensitivity to cold (cold allodynia) is assessed by placing ani mal subjects on a cold plate held at 100C. The latency (time) to lift the respective hind paw clear off the cold plate is meas ured. A cut-off of 180 s is applied. Weight bearing is an objective measure of pain. Rats are placed in a plexiglass chamber so that each hind paw rests on a sepa rate force plate (pressure sensor). The rats are allowed to ac climate to the chamber for at least 5 minutes. A total of three one second readings are taken to reflect the amount of pressure exerted on both the left and right hind paw while the rat is po sitioned in the chamber. The force exerted by each hind paw is measured in grams and calculated as the left hind paw weight distribution-right hind paw weight distribution. Thus, the final paw weight distribution for each animal is an average of the three one second readings.
WO 2013/167743 PCT/EP2013/059752 95 Example 1.3: Single dose/acute dosing This example demonstrates the effectiveness of acute/single dos ing of compound(s) according to the invention in ameliorating mechanical and cold allodynia and weight bearing sensitivities, as described in Example 1.2, in rats with peripheral mononeurop athy induced by loose ligation of the sciatic nerve as described in Bennett and Xie, 1988 and in Example 1.1. Each group of animals according to Example 1.1 is administered a single dose of either a positive control drug (pregabalin formu lated in a vehicle of 0.5% methyl cellulose to a con- centration of 12 mg/mL and administered per oral in a 5 mL/kg dosing volume to give a dose of 60 mg/kg) or a compound according to the in vention. Animal subjects are reassessed for mechanical, cold al lodynia and weight bearing 30 min, 90 min, 180 min, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after administration of the respective compound, using Von Frey's hairs and a cold plate set at 100C as described in Example 1.2. Example 1.4: Chronic studies This example demonstrates the effectiveness of sub-chronic dos ing of compound(s) according to the invention in ameliorating mechanical and cold allodynia and weight bearing sensitivities, as described in Example 1.2, in rats with peripheral mononeurop athy induced by loose ligation of the sciatic nerve as described in Bennett and Xie, 1988 and in Example 1.1. Each group of animals according to Example 1.1 is administered either a positive control drug (pregabalin formulated in a vehi cle of 0.5% methyl cellulose to a concentration of 12 mg/mL and administered per oral in a 5 mL/kg dosing volume to give an ef fective dose (e.g. 60 mg/kg)) or a compound according to the in vention. Dosing is carried out one or several times daily for two days to eight weeks. Animal subjects are reassessed for me chanical and cold allodynia either daily, weekly, biweekly, monthly or at the end of the study at one or several time points: 30 min, 90 min, 180 min, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours and 1 week after administra tion of the respective compound, using Von Frey's hairs and a cold plate set at 100C as described in Example 1.2.
WO 2013/167743 PCT/EP2013/059752 96 Example 2: Assessing chronic pain in animal models - Spinal nerve ligation Spinal nerve ligation (SNL) model is model of peripheral mo noneuropathy. The spinal nerves L5 and L6, together with L4 form the sciatic nerve. In the previously described CCI model only the L4 spinal nerve is ligated. In the SNL model rodents are subjected to a surgical procedure where the spinal nerves L5 and L6, or L5 alone, are tightly ligated distal to the dorsal root ganglion (Kim and Chung, 1992) and proximal to the lumbar plex us. This model has the benefit of allowing a more standardized procedure for partial nerve lesion. Induction of nerve injury is associated with the development of spontaneous pain-like behav iour as well as long lasting allodynia and hyperalgaesia (Bridg es et al., 2001). Following induction of nerve injury, there is an initial inflammatory component albeit lower than that ob served in the CCI model. A similar onset of sensory threshold changes in mechanical and cold allodynia can be observed in both models but with a greater magnitude of change in sensory thresh olds can be observed in the SNL model (Kim et al., 1997). Me chanical allodynia is greatest in the SNL model with an ~80% re sponse frequency. There is also a more significant involvement of the sympathetic nervous system component in the sensory re sponse to SNL (Kim et al., 1997). Treatment with NSAIDs is not effective in the initial inflammatory phase of the SNL model. Current approved treatments for neuropathic pain such as pregab alin and gabapentin are efficacious in this model at doses equivalent to the efficacious human dose. Example 2.1 Test system Rats undergo a surgical procedure to induce peripheral mononeu ropathy induced by ligation of the spinal nerves L5 and L6, or L5 alone, as described in Bennett et al., 2003 as follows: While under anesthesia using pentobarbital sodium and after the area of surgery is shaved, the rat is placed in a prone position and the left paraspinal muscles are separated from the spinous pro cess at the L4-S2 levels. The L6 vertebral transverse process is carefully removed with a small rongeur to visually identify the L4-L6 spinal nerves. The left L5 and spinal nerves are isolated and tightly ligated with 6-0 silk thread. The muscle is then WO 2013/167743 PCT/EP2013/059752 97 closed with 4-0 silk sutures and the skin is closed by a clamp. Following surgery, the rats are returned to the cage and will remain under a heating lamp until they awake. The animals are monitored in the hours post surgery and on a daily basis thereafter. Animals showing signs of ill health or autotomy are removed from the study. Approximately 12 and 18 days after surgery the animals are assessed for sensitivity to Von Frey's hairs and to the cold plate. Only animals expressing mechanical allodynia and cold allodynia, as described in Example 2.2, are included in the study. Example 2.2: Test apparatus Mechanical allodynia is assessed by the Von Frey test. Graded Von Frey filaments are applied to the hind paw to assess the 50% withdrawal threshold using the Dixon Up-Down Method (Chaplan et al., 1994) in L5 spinal nerve ligated animals. Behavioral test ing is performed during the day portion of the circadian cycle only. Animals are placed in a plastic cage (W 200xL 200xH 145 mm) with a wire mesh bottom, which allows full access to the paws. The area tested is the mid-plantar left hind paw, in the sciatic nerve distribution, avoiding the less sensitive tori (footpads). The paw is touched with 1 of a series of 8 Von Frey filaments - 0.4, 0.6, 1, 2, 4, 6, 8 and 15 g (Stoelting). The Von Frey filaments are presented perpendicularly to the plantar surface with sufficient force to cause slight buckling against the paw and are held for approximately 6-8 seconds. Stimuli are presented at intervals of several seconds, allowing for apparent resolution of any behavioral responses to previous stimuli. A positive response is noted if the paw is sharply withdrawn. Cold allodynia is assessed by the acetone test. Rats are placed in a transparent plastic cage and habituated to the test chamber for 5 minutes before measurement. Acetone is gently applied on the plantar surface of the hind paw using an Eppendorf (New York, NY) multistepper pipette. The brisk foot withdrawal re sponse after the acetone application is considered as a positive response this response is monitored for 30 seconds. The response is graded according to a four-point scale: 0 - no response; 1 brisk withdrawal or flick of the paw; 2 - repeated flicking of WO 2013/167743 PCT/EP2013/059752 98 the paw; 3 - repeated flicking of the hind paw and licking of the paws. Example 2.3: Single dose/acute dosing This example demonstrates the effectiveness of acute/single dos ing of compound(s) according to the invention in ameliorating mechanical and cold allodynia, as described in Example 2.2, in rats with peripheral mononeuropathy induced by ligation of the spinal nerves L5 and L6, or L5 alone, as described in Bennett et al., 2003 and in Example 2.1. Each group of animals according to Example 2.1 is administered a single dose of either a positive control drug (pregabalin formu lated in a vehicle of 0.5% methyl cellulose to a concentration of 12 mg/mL and administered per oral in a 5 mL/kg dosing volume to give a dose of 60 mg/kg) or a compound according to the in vention. Animal subjects are reassessed for mechanical and cold allodynia 30 min, 90 min, 180 min, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after administration of the respective com pound, using Von Frey's hairs and the acetone test according to Example 2.2. Example 2.4: Chronic studies This example demonstrates the effectiveness of chronic dosing of compound(s) according to the invention in ameliorating mechani cal and cold allodynia in rats, as described in Example 2.2, with peripheral mononeuropathy induced by ligation of the spinal nerves L5 and L6, or L5 alone, as described in Bennett et al., 2003 and in Example 2.1. Each group of animals according to Example 2.1 is administered either a positive control drug (pregabalin formulated in a vehi cle of 0.5% methyl cellulose to a concentration of 12 mg/mL and administered per oral in a 5 mL/kg dosing volume to give an ef fective dose (e.g. 60 mg/kg)) or a compound according to the in vention. Dosing is carried out one or several times daily for two days up to eight weeks. Animal subjects are reassessed for mechanical and cold allodynia either daily, weekly, biweekly, monthly or at the end of the study at one or several time points: 30 min, 90 min, 180 min, 4 hours, 6 hours, 8 hours, 12 WO 2013/167743 PCT/EP2013/059752 99 hours, 24 hours, 48 hours, 72 hours and 1 week after administra tion of the respective compound, using Von Frey's hairs and the acetone test according to Example 2.2. Example 3: Assessing inflammatory pain in animal models - Com plete Freunds Adjuvant (CFA) Complete Freunds Adjuvant (CFA) consists of heat-killed mycobac terium suspended in mineral oil. When injected systemically into rodents, an immune response is triggered resulting in chronic inflammation of many organs such as skin, liver, spleen, eyes, bone marrow and particularly peripheral joints. The inflammatory response results in bone resorption and periosteal bone prolif eration. Importantly, this inflammatory state results in sponta neous pain and ectopic nerve cell firing. Thus, the resultant adjuvant disease exhibits polyarthritic symptoms. When CFA is injected unilaterally into the limbs it elicits a monoarthritic-like condition and is thus used to model chronic inflammatory conditions. Unilateral injection allows the analy sis of ipsilateral and contralateral effects of localised joint pain (Millan et al., 1988). Injection of CFA results in oedema of the affected joint, mechanical allodynia and mechanical and thermal hyperalgesia (Butler et al., 1992; Hsieh et al., 2010; Meotti et al., 2006; Staton et al., 2007). As these features re semble the clinical pathology of rheumatoid arthritis, CFA- in duced chronic inflammation has been widely used as a model of this condition. A wide variety of treatments acting via different mechanisms that have generated positive data in rat adjuvant-induced ar thritic models have proven effective in subsequent clinical tri als for rheumatoid arthritis (Hegen et al., 2008). Indeed, an analysis by Whiteside (Whiteside et al., 2008), concluded that activity in the rat CFA test could be used to predict the expo sure needed for clinical efficacy. Both morphine-like opioids, steroids and NSAID analgesics can attenuate inflammation associated allodynia/hyperalgesia and normalise nociceptive sen sitivity (Jett et al., 1999, da Silva Filho et al., 2004). Example 3.1: Test system This example demonstrates the effectiveness of a compound ac cording to the invention in ameliorating weight bearing distri- WO 2013/167743 PCT/EP2013/059752 100 bution between injured (ipsilateral)and healthy (contralateral) limb, mechanical and thermal hypersensitivity in rats with in flammatory pain induced by injection of an adjuvant (CFA) into the limbs. The test apparatus according to Example 2 is used for assessing mechanical and thermal sensitivities. Male Sprague-Dawley rats are habituated to the test apparatus and tested for weight bearing and basal sensitivity to mechani cal and thermal stimuli in both the right (ipsilateral) and left (contralateral) paws using incapacitance tester, Von Freys hairs and a radiant heat source, respectively, on the day prior to Complete Freunds Adjuvant (CFA) administration (Day 0). The fol lowing morning (Day 1), animals are subjected to intraarticular injection into the ipsilateral ankle or a subplantar injection of 50% complete CFA in a 100 pL injection volume into the ipsi lateral hind-paw. Two days later (Day 3), baseline weight bear ing, mechanical and thermal sensitivities are reassessed in the CFA-injected (ipsilateral) and non-injected (contralateral) hind-paws. 42 rats meeting pre-defined criteria for hypersensi tivity to mechanical (ipsilateral hind-paw moves at a pressure of <4g) and thermal stimuli (>30% difference in latency time be tween ipsi- and contra-lateral hind- paws) are assigned to treatment groups of at least 7 animals in each group. One hour later, at T=0, drug administration commences. Example 3.2: Test apparatus Mechanical allodynia is assessed by the Von Frey test. Graded Von Frey filaments are applied to the hind paw to assess the 50% withdrawal threshold using the Dixon Up-Down Method (Chaplan et al., 1994) in L5 spinal nerve ligated animals. Behavioral test ing is performed during the day portion of the circadian cycle only. Animals are placed in a plastic cage (W 200xL 200xH 145 mm) with a wire mesh bottom, which allows full access to the paws. The area tested is the mid-plantar left hind paw, in the sciatic nerve distribution, avoiding the less sensitive tori (footpads). The paw is touched with 1 of a series of 8 Von Frey filaments - 0.4, 0.6, 1, 2, 4, 6, 8 and 15 g (Stoelting). The Von Frey filaments are presented perpendicularly to the plantar surface with sufficient force to cause slight buckling against the paw and are held for approximately 6-8 seconds. Stimuli are WO 2013/167743 PCT/EP2013/059752 101 presented at intervals of several seconds, allowing for apparent resolution of any behavioral responses to previous stimuli. A positive response is noted if the paw is sharply withdrawn. Thermal hypersensitivity is a measure of the pain threshold that accompanies pain associated with arthritis and inflammation. It is evoked by the radiant heat source and is assessed by the Har greave's plantar test. Animals are placed in floorless perspex Hargreaves plantar boxes (18cm (length) x 11cm (width) x 8.5cm (height) on a glass Hargreaves tray (Ugo Basile model 7373/7375). A mobile radiant (infra-red) heat source (Ugo Basile emitter-detector vessel model 7372) and controller (Ugo Basile model 7371) are utilized to assess thermal sensitivity. This is placed under the glass tray and moved to a position where the heat beam is incident on the relevant rat paw. The latency to move the paw from the heat source is recorded. A 30 s cut off time is applied throughout the study. The intensity of the heat source is preset to give a baseline withdrawal latency of ap prox. 12-15 seconds in untreated rats. Weight bearing is an objective measure of pain which addresses persistent pain by measuring weight distribution between the in jured and non-injured hind limbs, reflecting pain sensation in any of the limb joints. It is often used in the clinical setting to assess pain in patients with arthritis. Thus weight bearing serves as a preferred endpoint in the inflammatory pain models according to Example 3. Rats are placed in a plexiglass chamber of the incapacitance meter (IITC Life Science, Series 8) so that each hind paw rests on a separate force plate (pressure sensor). The rats are allowed to acclimate to the chamber for several minutes. A total of three one second readings are taken in a 5 sec period to reflect the amount of pressure exerted on both the left and right hind paw while the rat is positioned in the cham ber. The force exerted by each hind paw is measured in grams and calculated as the (left hind paw weight distribution)-(right hind paw weight distribution). Thus, the final paw weight dis tribution for each animal is an average of the three one second readings. Paw swelling is a measurement of the level of inflammation of WO 2013/167743 PCT/EP2013/059752 102 the affected limb. Digital calipers are placed aligned along the centre of the affected paw pad and the dorso-ventral thickness is measured and recorded. Example 3.3: Acute/single dosing This example demonstrates the effectiveness of acute/single dos ing of compound(s) according to the invention in ameliorating mechanical, thermal sensitivities and hypersensitivity, weight bearing incapacitance and paw swelling in rats with acute in flammation and arthritic-like symptoms induced according to Ex ample 3.1. One group of animals according to Example 3.1 is administered a single dose of the drug indomethacin (positive control), an NSAID with demonstrated efficacy in the CFA model and in human inflammatory/arthritic diseases. Indomethacin is formulated in 50% 0.1 M Na 2
CO
3 ; 47.5% phosphate buffered saline (PBS) : taken to pH 7 with 2.5% 1M HCl at a concentration of 2 mg/mL to give a dose of 10 mg/kg when administered intraperitoneally in a 5 mL/kg injection volume. The remaining groups of animals are ad ministered a single dose of compound(s) according to the inven tion. 30, 90, 180 min 4 hours, 6 hours, 8 hours, 12 hours and 24h post-dose, all groups of rats are re-assessed for mechanical allodynia, thermal hyperalgesia in both the treated and untreat ed hind-paws, using Von Frey's hairs and a Hargreave's plantar test in accordance with Example 3.2. All readings are compared to the basal sensitivity reading (T=0) of the (ipsilateral) paw in each animal. The described procedure is performed with the compounds according to the invention being adefovir (adminis tered as adefovir dipivoxil) (Fig 1A and Fig 2B) and tenofovir (administered as tenofovir disoproxil fumarate) (Fig 1B and Fig 2A). Alternatively, compounds are tested as follows: one group of 8 animals according to Example 3.1 is administered a single dose of morphine hydrochloride as a positive control of model devel opment. Morphine hydrochloride is formulated at a concentration of 1.2 mg/ml in phosphate buffered saline (PBS) to give a dose of 3 mg/kg when administered subcutaneously in a 2.5 mL/kg in jection volume. The remaining groups of 7-8 animals are adminis- WO 2013/167743 PCT/EP2013/059752 103 tered a single dose of compound(s) or a vehicle only (0.5% methylcellulose) according to the invention. 30, 90, 180 min and 4, 6, 8, 12 and 24 h post-dose, all groups of rats are reas sessed for weight bearing and thermal hypersensitivity in both the treated and untreated hind-paws, using incapacitance meter and Hargreaves plantar test apparatus according to the example 3.2. All readings are compared to the readings of the vehicle control group of animals. Example 3.3.1 Test with tomeglovir The procedure as described in Example 3.3 was performed with the compound according to the invention being tomeglovir. In total, three groups of animals were included: one group of 8 animals received the positive control drug, morphine, subcutaneously at a dose of 3 mg/kg. Three groups of 7-8 animals each received ei ther 100 mg/kg tomeglovir, 30 mg/kg tomeglovir, or vehicle only, respectively (Fig. 3). Tomeglovir was formulated in a vehicle (0.5% methylcellulose) to concentrations of 20 and 6 mg/mL and was administered orally in a 5 mL/kg dosing volume to give doses of 100 and 30 mg/kg. Example 3.3.2 Test with emtricitabine The procedure as described in Example 3.3 was performed with the compound according to the invention being emtricitabine. In to tal, three groups of animals were included: one group of 8 ani mals received the positive control drug, morphine, subcutaneous ly at a dose of 3 mg/kg. Three groups of 7-8 animals each re ceived either 100 mg/kg emtricitabine, 20 mg/kg emtricitabine, or vehicle only, respectively (Fig. 4). Emtricitabine was formu lated in a vehicle (0.5% methylcellulose) to concentrations of 20 and 4 mg/mL and is administered orally in a 5 mL/kg dosing volume to give doses of 100 and 20 mg/kg. Example 3.3.3 Test with entecavir The procedure as described in Example 3.3 was performed with the compound according to the invention being entecavir. In total, three groups of animals were included: one group of 8 animals received the positive control drug, morphine, subcutaneously at a dose of 3 mg/kg. Three groups of 7-8 animals each received ei ther 0.2 mg/kg entecavir, 0.02 mg/kg entecavir, or vehicle only, WO 2013/167743 PCT/EP2013/059752 104 respectively (Fig. 5). Entecavir was formulated in a vehicle (0.5% methylcellulose) to concentrations of 0.04 and 0.004 mg/mL and is administered orally in a 5 mL/kg dosing volume to give doses of 0.2 and 0.02 mg/kg. Example 3.3.4 Test with famciclovir The procedure as described in Example 3.3 was performed with the compound according to the invention being famciclovir. In total, three groups of animals were included: one group of 8 animals received the positive control drug, morphine, subcutaneously at a dose of 3 mg/kg. Three groups of 7-8 animals each received ei ther 1000 mg/kg famciclovir, 250 mg/kg famciclovir, or vehicle only, respectively (Fig. 6). Famciclovir was formulated in a ve hicle (0.5% methylcellulose) to concentrations of 200 and 50 mg/mL and was administered orally in a 5 mL/kg dosing volume to give doses of 0.2 and 0.02 mg/kg. Example 3.3.5 Test with alamifovir The procedure as described in Example 3.3 is performed with the compound according to the invention being alamifovir (adminis tered as alamifovir disoproxil fumarate). In total, three groups of animals are included: one group of at least 4 animals re ceives the positive control drug, morphine, subcutaneously at a dose of 3 mg/kg. Three groups of at least 7 animals each receive either 20 mg/kg alamifovir, 2 mg/kg alamifovir, or vehicle only, respectively. Alamifovir disoproxil fumarate is formulated in a vehicle (0.5% methylcellulose) to concentrations of 4 and 0.4 mg/mL and is administered orally in a 5 mL/kg dosing volume to give doses of 20 and 2 mg/kg. Example 3.3.6 Test with racivir The procedure as described in Example 3.3 is performed with the compound according to the invention being racivir. In total, three groups of animals are included: one group of at least 4 animals receives the positive control drug, morphine, subcutane ously at a dose of 3 mg/kg. Three groups of at least 7 animals each receive either 100 mg/kg racivir, 20 mg/kg racivir, or ve hicle only, respectively. Racivir is formulated in a vehicle (0.5% methylcellulose) to concentrations of 20 and 4 mg/mL and is administered orally in a 5 mL/kg dosing volume to give doses WO 2013/167743 PCT/EP2013/059752 105 of 20 and 2 mg/kg. Example 3.3.7 Test with opaviraline The procedure as described in Example 3.3 is performed with the compound according to the invention being opaviraline. In total, three groups of animals are included: one group of at least 4 animals receives the positive control drug, morphine, subcutane ously at a dose of 3 mg/kg. Three groups of at least 7 animals each receive either 30 mg/kg opaviraline, 1 mg/kg opaviraline, or vehicle only, respectively. Opaviraline is formulated in a vehicle (0.5% methylcellulose) to concentrations of 6 and 0.2 mg/mL and is administered orally in a 5 mL/kg dosing volume to give doses of 30 and 1 mg/kg. Example 3.4: Chronic studies This example demonstrates the effectiveness of chronic dosing of compound(s) according to the invention in ameliorating mechani cal and thermal hypersensitivity, weight bearing incapcaitance and paw swelling, according to Example 3.2, in rats with ar thritic-like symptoms induced according to Example 3.1. Each group of animals according to Example 3.1 is administered either a positive control drug, such as diclofenac or morphine, or a compound according to the invention. Dosing is carried out one or several times daily for two days to eight weeks. Animal subjects are reassessed for weight bearing incapacitance, paw swelling, mechanical and thermal hypersensitivity, either daily, weekly, biweekly, monthly or at the end of the study at one or several time points: 30 min, 90 min, 180 min, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours and 1 week after administration of the respective compound, using Von Frey's hairs and the Hargreave's plantar test according to Example 3.2. Weight bearing and paw swelling is also measured according to Example 3.2. Example 4: Clinical study Patients with a long term or chronic pain condition are eligible for the study. After initial screening, a total of 20 to 200 pa tients are randomized to one of two treatment groups. Patients in one treatment group receive a compound according to the in- WO 2013/167743 PCT/EP2013/059752 106 vention at a pharmaceutically active dose and patients in the other (control) treatment group receive either placebo or an ac tive control drug at a pharmaceutically active dose. A preferred active control drug is pregabalin or an NSAID such as Celecoxib. Preferably, the study is carried out in a double-blinded fash ion. Treatment duration is between 1 and 15 weeks, and efficacy evaluation is carried out as the average of the pain scores rec orded for the past 1 to 7 days (preferably 7 days) relative to the day chosen for efficacy evaluation, comparing the group re ceiving the compound according to the invention with the control group. The pain scores are preferably assessed based on patients' daily pain diaries, in which they record their daily pain score on an 11-point (0 = "no pain" to 10 = "worst possible pain") numeric rating scale (NRS) [Arezzo et al., 2008]. The primary endpoint of the study is preferably a comparison of the average pain score for the last 7 available pain diary en tries at the end of the treatment phase. Example 5: Painful diabetic peripheral neuropathy (PDPN) A clinical study according to Example 4 is carried out with the following key inclusion criteria: patients are men or women 18 years of age with type 1 or type 2 diabetes with HbA1C 11% and painful diabetic peripheral neuropathy of at least 3 months' du ration. Patients score at least 40 mm on the Short-Form McGill Pain Questionnaire (SF-MPQ) Visual Analog Scale (VAS) [Arezzo et al., 2008], or any other standard VAS. At randomization, pa tients have completed at least four daily pain diary entries (using an 11-point NRS) and should have an average daily pain score 4 over the past 7 days. Example 6: Post-herpetic neuralgia A clinical study according to Example 4 is carried out with the following key inclusion criteria: patients are men or women 18 years of age with persistent pain for at least 6 months after the onset of herpes zoster rash. Patients score at least 40 mm on the Short-Form McGill Pain Questionnaire (SF-MPQ) Visual Ana log Scale (VAS) [Arezzo et al., 2008], or any other VAS. Example 7: Mixed neuropathy WO 2013/167743 PCT/EP2013/059752 107 A clinical study according to Example 4 is carried out with pa tients selected according to inclusion criteria in Example 5 as well as Example 6. Example 8: Painful osteoarthritis A clinical study according to Example 4 is carried out with the following key inclusion criteria: patients are men or women 18 years of age with recurring or persistent or recurring persis tent pain for at least 1 month, such as at least 3 months, such as at least 6 months, such as at least 12 months related to di agnosed osteoarthritis. References: Arezzo, J.C., Rosenstock, J., LaMoreaux, L., Pauer, L., (2008), Efficacy and safetyof pregabalin 600 mg/d for treating painful diabetic peripheral neuropathy: a double-blind placebo controlled trial. BMC Neurology, 16;8:33. Bennett GJ, Chung JM, Honore M, Seltzer Z. (2003) Curr Protoc Pharmacol. Jul;Chapter 5:Unit5.32. Bennett G.J., Xie Y.K., (1988). Pain, 33, 87-107. Blackburn-Munro G, Erichsen H.K., (2005). Current Pharm Des, 11, 2961-2975. Bridges, D., Thompson, S.W., Rice, A.S., (2001). Mechanisms of neuropathic pain. Br J Anaesth, 87(1):12-26. Butler, S.H., Godefroy, F., Besson, J.-M., Weil-Fugazza, J., (1992). Pain, 48; 73-81. Chaplan, S.R., Bach, F.W., Pogrel, J.W., Chung, J.M., Yaksh, T.L., (1994). Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods, 53(1):55-63. da Silva Filho A.A., Andrade e Silva M.L., Carvalho J.C., Bastos J.K., (2004). Evaluation of analgesic and anti-inflammatory ac tivities of Nectandra megapotamica (Lauraceae) in mice and rats. J Pharm Pharmacol., 56(9):1179-84. Hegen, M., Keith, J.C., Collins, M., Nickerson-Nutter, C.L., (2008). Ann Rheum Dis, 67: 1505-1515. Hsieh, G.C., Chandran, P., Salyers, A.K., Pai, M., Zhu, C.Z., Wensink, E.J., Witte, D.G., Miller, T.R., Mikusa, J.P., Baker, S.J., Wetter, J.M., Marsh, K.C., Hancock, A.A., Cowart, M.D., Esbenshade, T.A., Brioni, J.D., Honore, P., (2010). Pharmacol WO 2013/167743 PCT/EP2013/059752 108 Biochem Behav, 95; 41-50. Jett, M.F., Ramesha, C.S., Brown, C.D., Chiu, S., Emmett, C., Voronin, T., Sun, T., O'Yang, C., Hunter, J.C., Eglen, R.M., Johnson, R.M., (1999). Characterization of the analgesic and an ti-inflammatory activities of ketorolac and its enantiomers in the rat. J Pharmacol Exp Ther, 288(3):1288-97. Kim KJ, Yoon YW, Chung JM., (1997) Exp Brain Res. Feb;113(2):200-6. Kim SH, Chung JM., (1992) Pain. Sep;50(3):355-63. Kontinen V.K., and Meert T.F., (2003). In: eds Dostrovsky J.O., Carr D.B., and Koltzenburg, M., Prog in Pain Res Management 24, pp489-498, IASP press, Seattle. LaBuda, C.J., and Little, P., (2005) J Neurosci Meths, 144, 175 181. Meotti, F.C., Missau, F.C., Ferreira, J., Pizzolatti, M.G., Mi zuzaki, C., Nogueira, C.W., Santos, A.R.S., (2006). Biochem Pharmacol, 72; 1707-17134. Millan, M.J., Czlonkowski, A., Morris, B., Stein, C., Arendt, R., Huber, A., et al., (1988). Pain, 35, 299-312. Schafers, M., Marziniak, M., Sorkin, L.S., Yaksh, T.L., Sommer C., (2004) Exp Neurol ., 185, 160-168. Staton, P.C., Wilson, A.W., Bountra, C., Chessell, I.P., Day, N.C., (2007). Eur J Pain' 11; 283-289. Takahashi M., Kawaguchi, M., Shimada, K.,, Konishi, N., Furuya H., Nakashima, T., (2004). Neurosci Letts, 356, 37-40. Whiteside, G.T., Adedoyin, A., Leventhal, L., (2008). Neuro pharmacology, 54, 767-775.
Claims (90)
1. A therapeutic compound of the group of aromatic sulphonic ac ids and sulphonamides with molecular weight less than 1200 Da, a) wherein the compound is an aromatic sulfonic acid, the com pound being selected from Tomeglovir, Evans Blue, Tipranavir, Resobene, 5-[(2,3-dichlorobenzoyl)amino]-3-[2-[4-[2-[8-[(2,4 dichlorobenzoyl)amino]-1-hydroxy-3,6-disulfo-2 naphthalenyl]diazenyl]-2,5-dimethoxyphenyl]diazenyl]-4-hydroxy 2,7-Naphthalenedisulfonicacid, 4,4-(carbonylbis(imino(1-methyl 1H-pyrrole-4,2-diyl)carbonylimino(1-methyl-1H-pyrrole-4,2 diyl)carbonylimino))bis-1,7-Naphthalenedisulfonic acid; b) with the nitrogen adjacent to the aromatic sulfonamide group being substituted, the compound being selected from Tomeglovir, Fosamprenavir, Darunavir, Amprenavir, Brecanavir, A-837093, L 870810, N-[(3-fluorophenyl)methyl]glycyl-N-[(1S,2R)-3-[[(3 aminophenyl)sulfonyl] ( 2-methylpropyl)amino]-2-hydroxy-1 (phenylmethyl)propyl]-3-methyl-L-Valinamide (DPC-681),, 4H Thieno(3,4-e)-1,2,4-thiadiazine-4-acetonitrile, 2-((3 fluorophenyl)methyl)-2,3-dihydro-3-oxo-, 1,1-dioxide, Fasudil; c) with the nitrogen adjacent to the sulfonic acid group being bound to a hydrogen, the compound being selected from Tomeglovir, Flamazine, Silvadene, Silver sulphadiazine, Sulfadi azine silver salt, Thermazene, Dermazin, silver sulfadiazinate, Zafirlukast, Ramatroban, 4-cyano-N-[3-[cyclopropyl(5,6,7,8,9,10 hexahydro-4-hydroxy-2-oxo-2H-cycloocta[bipyran-3 yl)methyl]phenyl]-Benzenesulfonamide; d) wherein the compound is a non-aromatic sulphonic compound se lected from Danoprevir, 5-cyclopropyl-2-(4-fluorophenyl)-6-[(2 hydroxyethyl) (methylsulfonyl)amino]-N-methyl-3 Benzofurancarboxamide, 2-amino-6-[(3,5-dimethylphenyl)sulfonyl] Benzonitrile, N-[(1S,2R)-3-[(2S)-4-[(2-chloro-6-methyl-4 pyridinyl)methyl]-2-[[(1,1-dimethylethyl)amino]carbonyl]-1 piperazinyl]-2-hydroxy-1-(phenylmethyl)propyl]-(2R,3R) tetrahydro-2-(1-methylethyl)-1,1-dioxido-3-thienyl carbamic acid ester (L 738872), 2-(3,4-dichlorophenyl)-6-methylsulfonyl-3,4 dihydro-2H-pyrano[2,3-b]pyridine (MDL 20610); e) wherein the compound binds the ATP binding site of an ATP re ceptor or is a ATP mimick, being selected from Bay 11-7821, Leflunomide, Incadronic, ,N-(2',3'-didehydro-3'-deoxy-P-phenyl- WO 2013/167743 PCT/EP2013/059752 110 5'-thymidylyl)-L-Alanine methyl ester, [[(S)-2-(4-amino-2-oxo 1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]-phosphonic acid, mono[3-(hexadecyloxy)propyl] ester, Fosalvudine, f) or a pharmaceutically acceptable salt, analogue or derivative of any compound of a) to e), for use in treating or preventing pain in a subject.
2. A therapeutic compound of the group of pyrimidine containing nucleotide or nucleoside analogs selected from Tezacitabine, 1 (2-Cyano-2-deoxy-beta-D-arabinofuranosyl)cytosine, Sapacitabine, Alkasar-18, Ethynylcytidine, Troxacitabine, Torcitabine, Hexa decyloxypropyl-cidofovir, 4'-C-Azidocytidine, Balapiravir hydro chloride, 1-(2'-Deoxy-2'-fluoro-2'-C-methyl-beta-D ribofuranosyl)cytosine, Mericitabine, cis-4'-Azido-5'-O-[4(S) (3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-2',3'-0 bis(propionyl)uridine, Sofosbuvir, Dioxolane T; Dioxolane thy mine nucleoside, 3'-Azido-3'-deoxythymidylyl-(5',5')-2',3' dideoxy-5'-inosinic acid, Apricitabine; (±)-cis-1-[2 (Hydroxymethyl)-1,3-oxathiolan-4-yl]cytosine; (±)-2'-Deoxy-3' oxa-4'-thiocytidine (dOTC), (-)-(S)-6-Chloro-2-[1-(furo[2,3 c]pyridin-5-yl)ethylsulfanyl]pyrimidine-4-amine (PNU-142721), Phosphonovir, Festinavir, Emtricitabine, Lamivudine, Clevudine, Edoxudine, Zidovudine, Apricitabine, AVX754, Stampidine, Elvu citabine, Dexelvucitabine, Racivir, Festinavir, Emivirine, Floxuridine, Fluorouracil, Idoxuridine, Trifluridine, Cytara bine, 2'-O-Methylcytidine, Stavudine, 2',3'-Dideoxythymidine, Telbivudine, Zalcitabine, Fiacitabine, Fialuridine, Brivudine, Sorivudine, 2'-Fluoro-5-ethylarabinosyluracil, Raltegravir, Mericitabine, PSI-6130, Valopicitabine, Valtorcitabine, 6 Fluoro-3-hydroxypyrazine-2-carboxamide, 5-Iodo-2-pyrimidinone 2'-deoxyribose, Cidofovir, Alovudine, Navuridine, PS17977, 3 Deazauridine, 3'-azido-2',3'-dideoxy-5-methylcytidine, Cyclocyt idine for use in treating or preventing pain in a subject.
3. A therapeutic compound of the group of purine containing nu cleotide or nucleoside analogs selected from Clofarabine, 7 Deaza-2'-C-methyladenosine, Bis(2,2-dimethylpropionic acid) 1 (2-amino-9H-purin-9 ylmethyl)cyclopropoxymethylphosphorylbis(oxymethylene) diester, 2'-C-Methylguanosine, Filibuvir, 5'-O-[(Benzylamino) [2-(3- WO 2013/167743 PCT/EP2013/059752 111 hydroxy-2,2-dimethylpropionylsulfanyl)ethoxylphosphoryl]-2'-C methylguanosine, 6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6 cyclopentyl-3-(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2 ylsulfanyl)-4-hydroxy-5,6-dihydropyran-2-one, 1-(2-Amino-6 ethoxy-9H-purin-9-yl)-2-fluoro-2-C-methyl-1,2-dideoxy-beta-D ribofuranose 3,5-cyclic [P(R)I-isopropylphosphate, 6-0-Methyl 2'-C-methyl-5'-O-[0-(2,2-dimethylpropyl)-L-alanino] (naphthalen 1-yloxy)phosphoryl]guanosine, 3'-Azido-3'-deoxythymidylyl (5',5')-2',3'-dideoxy-5'-inosinic acid, Lagociclovir valactate, Tenofovir alafenamide fumarate, [S(P)]-[5(R)-(9H-Adenin-9-yl)-4 fluoro-2,5-dihydrofuran-2(R)-yloxymethyl]-N-[l(S) (ethoxycarbonyl)ethyl]phosphonamidic acid phenyl ester, Entecavir, organic salt of bis-glycine-L-cysteinyl-bis-(g -L glutamate)-9-b -D-ribofuranozilhypoxanthine, CMX 157, HDP tenofovir, hexadecyloxypropyl tenofovir, Acyclovir, valacyclovir hydrochloride, Vidarabine, Alamifovir, GS 7340, Penciclovir, Ganciclovir, Phosphonic acid,P-[2-[2-[(2-amino-1,6-dihydro-6 oxo-9H-purin-9-yl)methyl]phenyl]ethenyl]-, Tiviciclovir, Famciclovir, Carbovir, Molixan; NOV-205, Lobucavir, Abacavir, Amdoxovir, Valganciclovir, INX189, Dideoxyadenosine, Cladribine, Fludarabine, Pentoxifylline, Didanosine, 2'-Deoxy-2' fluoroguanosine, Dideoxyguanosine, 2',3'-DIDEOXY-3'-FLUORO GUANOSINE, 3-Deazaneplanocin, Maribavir, Valomaciclovir, Omaciclovir, Seliciclib; roscovitine, Lodenosine for use in treating or preventing pain in a subject.
4. A therapeutic compound of the group of pentose ring containing nucleotide/nucleoside analogs selected from Clofar abine, Tezacitabine, 1-(2-Cyano-2-deoxy-beta-D arabinofuranosyl)cytosine, Sapacitabine, Alkasar-18, Ethynylcyt idine, Troxacitabine, Torcitabine, 7-Deaza-2'-C-methyladenosine, 4'-C-Azidocytidine, 2'-C-Methylguanosine, Balapiravir hydrochlo ride, 1-(2'-Deoxy-2'-fluoro-2'-C-methyl-beta-D ribofuranosyl)cytosine, Mericitabine, 5'-O-[(Benzylamino) [2-(3 hydroxy-2,2-dimethylpropionylsulfanyl)ethoxyiphosphoryl]-2'-C methylguanosine, cis-4'-Azido-5'-O-[4(S)-(3-chlorophenyl)-2-oxo 1,3,2-dioxaphosphorinan-2-yl]-2',3'-0-bis(propionyl)uridine, 1 (2-Amino-6-ethoxy-9H-purin-9-yl)-2-fluoro-2-C-methyl-1,2 dideoxy-beta-D-ribofuranose 3,5-cyclic [P(R)] isopropylphosphate, 6-0-Methyl-2'-C-methyl-5'-0-[0-(2,2- WO 2013/167743 PCT/EP2013/059752 112 dimethylpropyl)-L-alanino] (naphthalen-1 yloxy)phosphoryl]guanosine, Sofosbuvir, Dioxolane T; Dioxolane thymine nucleoside, 3'-Azido-3'-deoxythymidylyl-(5',5')-2',3' dideoxy-5'-inosinic acid, Apricitabine; (±)-cis-1-[2 (Hydroxymethyl)-1,3-oxathiolan-4-yl]cytosine; (±)-2'-Deoxy-3' oxa-4'-thiocytidine (dOTC), Phosphonovir, Lagociclovir valac tate, Festinavir, [S(P)]-[5(R)-(9H-Adenin-9-yl)-4-fluoro-2,5 dihydrofuran-2(R)-yloxymethyl]-N-[l(S) (ethoxycarbonyl)ethyl]phosphonamidic acid phenyl ester, Clevudine, Edoxudine, Zidovudine, Stampidine, Elvucitabine, Dex elvucitabine, Festinavir, Floxuridine, Idoxuridine, Tri fluridine, Cytarabine, 2'-O-Methylcytidine, Stavudine, 2',3' Dideoxythymidine, Telbivudine, Zalcitabine, Fiacitabine, Fi aluridine, Brivudine, Sorivudine, 2'-Fluoro-5 ethylarabinosyluracil, Mericitabine, PSI-6130, Valopicitabine, Valtorcitabine, 5-Iodo-2-pyrimidinone-2'-deoxyribose, Alovudine, Navuridine, PS17977, 3-Deazauridine, 3'-azido-2',3'-dideoxy-5 methylcytidine, Cyclocytidine, Entecavir, Vidarabine, Carbovir, Molixan; NOV-205, Abacavir, Amdoxovir, Valganciclovir, INX189, Dideoxyadenosine, Cladribine, Fludarabine, Didanosine, 2'-Deoxy 2'-fluoroguanosine, Dideoxyguanosine, 2',3'-DIDEOXY-3'-FLUORO GUANOSINE, 3-Deazaneplanocin, Maribavir, Lodenosine, Ribavirin for use in treating or preventing pain in a subject.
5. A therapeutic compound of the group of nucleotide analogs se lected from 2'-C-Methylguanosine, 5'-0-[(Benzylamino) [2-(3 hydroxy-2,2-dimethylpropionylsulfanyl)ethoxyiphosphoryl]-2'-C methylguanosine, cis-4'-Azido-5'-O-[4(S)-(3-chlorophenyl)-2-oxo 1,3,2-dioxaphosphorinan-2-yl]-2',3'-O-bis(propionyl)uridine, 1 (2-Amino-6-ethoxy-9H-purin-9-yl)-2-fluoro-2-C-methyl-1,2 dideoxy-beta-D-ribofuranose 3,5-cyclic [P(R)] isopropylphosphate, 6-0-Methyl-2'-C-methyl-5'-O-[0-(2,2 dimethylpropyl)-L-alanino] (naphthalen-1 yloxy)phosphoryl]guanosine, Sofosbuvir, 3'-Azido-3' deoxythymidylyl-(5',5')-2',3'-dideoxy-5'-inosinic acid, Phos phonovir, [S(P)]-[5(R)-(9H-Adenin-9-yl)-4-fluoro-2,5 dihydrofuran-2(R)-yloxymethyl]-N-[l(S) (ethoxycarbonyl)ethyl]phosphonamidic acid phenyl ester, CMX 157, HDP-tenofovir, hexadecyloxypropyl tenofovir, Alamifovir, P-[2 [2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9- WO 2013/167743 PCT/EP2013/059752 113 yl)methyl]phenyl]ethenyl]-Phosphonic acid, INX189, Alamifovir disoproxil fumarate, Alamifovir disoproxil hemifumarate for use in treating or preventing pain in a subject.
6. A therapeutic compound of the group of nucleoside analogs se lected from Clofarabine, Tezacitabine, 1-(2-Cyano-2-deoxy-beta D-arabinofuranosyl)cytosine, Sapacitabine, Alkasar-18, Ethynyl cytidine, Troxacitabine, Torcitabine, 7-Deaza-2'-C methyladenosine, 4'-C-Azidocytidine, Balapiravir hydrochloride, 1-(2'-Deoxy-2'-fluoro-2'-C-methyl-beta-D-ribofuranosyl)cytosine, Mericitabine, Dioxolane T; Dioxolane thymine nucleoside , Apri citabine; (±)-cis-1-[2-(Hydroxymethyl)-1,3-oxathiolan-4 yl]cytosine; (±)-2'-Deoxy-3'-oxa-4'-thiocytidine (dOTC), Festi navir, Emtricitabine, Lamivudine, Clevudine, Edoxudine, Zidovu dine, Apricitabine, AVX754, Stampidine, Elvucitabine, Dexelvu citabine, Racivir, Festinavir, Floxuridine, Idoxuridine, Tri fluridine, Cytarabine, 2'-O-Methylcytidine, Stavudine, 2',3' Dideoxythymidine, Telbivudine, Zalcitabine, Fiacitabine, Fi aluridine, Brivudine, Sorivudine, 2'-Fluoro-5 ethylarabinosyluracil, Mericitabine, PSI-6130, Valopicitabine, Valtorcitabine, 5-Iodo-2-pyrimidinone-2'-deoxyribose, Alovudine, Navuridine, PS17977, 3-Deazauridine, 3'-azido-2',3'-dideoxy-5 methylcytidine, Cyclocytidine, Entecavir, organic salt of bis glycine-L-cysteinyl-bis-(g -L-glutamate)*9-b -D ribofuranozilhypoxanthine, Vidarabine, Carbovir, Molixan; NOV 205, Lobucavir, Abacavir, Amdoxovir, Valganciclovir, Dideoxy adenosine, Cladribine, Fludarabine, Didanosine, 2'-Deoxy-2' fluoroguanosine, Dideoxyguanosine, 2',3'-DIDEOXY-3'-FLUORO GUANOSINE, 3-Deazaneplanocin, Maribavir, Lodenosine for use in treating or preventing pain in a subject.
7. A therapeutic compound selected from the group of acyclic nu cleoside analog selected from Filibuvir, 6-[2-(5-Chloro-2,4 dimethoxyphenyl)ethyl]-6-cyclopentyl-3-(5,7 dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-ylsulfanyl)-4-hydroxy 5,6-dihydropyran-2-one, (-)-(S)-6-Chloro-2-[1-(furo[2,3 c]pyridin-5-yl)ethylsulfanyl]pyrimidine-4-amine (PNU-142721), Lagociclovir valactate, Emivirine, Raltegravir, 6-Fluoro-3 hydroxypyrazine-2-carboxamide, Acyclovir, valacyclovir hydro chloride, GS 7340, Penciclovir, Ganciclovir, Tiviciclovir, WO 2013/167743 PCT/EP2013/059752 114 Famciclovir, Pentoxifylline, Valomaciclovir, Omaciclovir, Seliciclib; roscovitine for use in treating or preventing pain in a subject.
8. A therapeutic compound selected from the group of acyclic nu cleotide analogs selected from Hexadecyloxypropyl-cidofovir, Bis(2,2-dimethylpropionic acid) 1-(2-amino-9H-purin-9 ylmethyl)cyclopropoxymethylphosphorylbis(oxymethylene) diester, Tenofovir alafenamide fumarate, Cidofovir, CMX 157, HDP tenofovir, hexadecyloxypropyl tenofovir, Alamifovir, P-[2-[2 [(2-amino-1,6-dihydro-6-oxo-9H-purin-9 yl)methyl]phenyl]ethenyl]-phosphonic acid, Alamifovir disoproxil fumarate, Alamifovir disoproxil hemifumarate for use in treating or preventing pain in a subject.
9. A therapeutic compound selected from the group of 5-ring het erocycles compounds selected from Amitivir, 2-Oxothiazolidine-4 carboxylic acid, Levcycloserine for use in treating or prevent ing pain in a subject.
10. A therapeutic compound selected from the group of nucleotide analogues being phosphonic acid derivatives selected from ala mifovir, besifovir, cidofovir, Alamifovir disoproxil fumarate, alamifovir disoproxil hemifumarate for use in treating or pre venting pain in a subject.
11. A therapeutic compound selected from the group of bicyclic heterocyclic compounds selected from aciclovir, buciclovir, desciclovir, detiviciclovir, famciclovir, ganciclovir, lago ciclovir, lagociclovir valactate, omaciclovir, penciclovir, ro ciclovir, tiviciclovir, valaciclovir, valganciclovir, valomaciclovir for use in treating or preventing pain in a sub ject.
12. A therapeutic compound selected from the group of carbocy clic nucleosides selected from abacavir, entecavir, lobucavir, Carbovir, 3-Deazaneplanocin for use in treating or preventing pain in a subject.
13. A therapeutic compound selected from the group of phosphate WO 2013/167743 PCT/EP2013/059752 115 containing nucleotide analogues, further being defined as a. purino(a)cyclophosphate selected from Alamifovir, Alamifovir disoproxil fumarate, alamifovir disoproxil hemifumarate, Stam pidine, Fozivudine, Fosalvudine, Fosalvudine tidoxil, b. purinophosphonic acids selected from P-[2-[2-[(2-amino-1,6 dihydro-6-oxo-9H-purin-9-yl)methyl]phenyl]ethenyl]-Phosphonic acid, P-[(3R)-3-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9 yl)methoxy]-4-hydroxybutyl]-Phosphonic acid, MDL, c. Oligonucleotides selected from Fomivirsen, fomivirsen sodium, DNA,d(dmt-T-G-G-G-A-G-G-T-G-G-G-T-C-T-G) (9CI), Trecovirsen, Afovirsen, for use in treating or preventing pain in a subject.
14. A therapeutic compound selected from the group of phosphate free purino-nucleosides, being further defined as a. a purino pseudonucleoside, being Amdoxovir, b. purino Seconucleosides of the Cl-Type selected from Acyclo vir, Valaciclovir, Ganciclovir, Valganciclovir, Valomaciclovir, c. Purinoalkanols selected from Penciclovir, Tiviciclovir, Famciclovir, Pentoxifylline, 9-(3-fluoro-2 phosphonylmethoxypropyl)adenine, d. Purine Nucleosides selected from bis-glycine-L-cysteinyl bis-(g -L-glutamate)*9-b -D-ribofuranozilhypoxanthine, Vidara bine, Dideoxyadenosine, Cladribine, Fludarabine, Didanosine, Ma ribavir, 2'-Deoxy-2'-fluoroguanosine, 2',3'-DIDEOXY-3'-FLUORO GUANOSINE, Lodenosine, Dideoxyguanosine, e. Purine Carbonucleosides selected from Entecavir, Carbovir, Abacavir, Lobucavir, Oxetanocin, 3-Deazaneplanocin, f. a purine base selected from Adenosine, Guanosine, for use in treating or preventing pain in a subject.
15. A therapeutic compound selected from the group of phosphate free pyrimidino-nucleoside compounds further defined as a. pyrimidino pseudonucleosides selected from Emtricitabine, Apricitabine, AVX754, Racivir, Lamivudine, 2(1H)-Pyrimidinone,4 amino-1-[(2R,4R)-2-(hydroxymethyl)-1,3-oxathiolan-4-yl]-, rel-, 4-amino-5-fluoro-1-[(2R,4R)-2-(hydroxymethyl)-1,3-dioxolan-4 yl]pyrimidin-2(1H)-one, b. pyrimidino Nucleosides selected from Cytarabine, Tri fluridine, Floxuridine, Idoxuridine, Telbivudine, Clevudine, WO 2013/167743 PCT/EP2013/059752 116 Edoxudine, Brivudine, Zidovudine, Elvucitabine, Stavudine, Cy clocytidine, Edoxudine, Zalcitabine, Alovudine, Fiacitabine, Fi aluridine, Brivudine, Navuridine, FEAU, Sorivudine, IPdR, Raluridine, Dexelvucitabine, Gemcitabine, Valtorcitabine, Valopicitabine, PSI-6130, Tunicamycin, c. Pyrimidines selected from Fluorouracil, Etravirine, Rilpi virine, 2,4(1H,3H)-Pyrimidinedione, 6-[(3,5 dimethylphenyl)methyl]-1-(ethoxymethyl)-5-(1-methylethyl), for use in treating or preventing pain in a subject.
16. A therapeutic compound selected from the group of nucleobase mimics further defined as a. Artificial Base Nucleosides selected from Ribavirin, Tari bavirin hydrochloride, Taribavirin, Triciribine, Isatoribine, ICN, b. Purine mimics selected from Peldesine, Imiquimod, Resiquimod, Bay 11-7821, c. Purine mimics selected from Carbendazim, Oxibendazole, Flubendazole, Carbendazim, Fenbendazole, Albendazole, BMS, N (1H-benzimidazol-2-ylmethyl)-2,4,5-trideoxy-4-[[[(2R,4S)-5,5 dimethyl-2-[(1R)-2-oxo-1-[(2-phenylacetyl)amino]-2 [(phenylmethyl)amino]ethyl]-4-thiazolidinyl]carbonyl]amino]-5 phenyl-D-threo-Pentonamide, Oxfendazole, d. Indol type purine mimics selected from Methisazone, Arbidol, 5-Chloro-3-phenylthioindole-2-carboxamide, Mopyridone, e. Pyrimidine mimics selected from Oltipraz, Flutimide, Carbam ic acid,N,N-diethyl-, [1,4-bis(3,4,5-trimethoxybenzoyl)-2 piperazinylimethyl ester, f. Sulphonamide or sulphonic acid type ATP mimics selected from Tomeglovir, Evans Blue, Quinobene, Resobene, A-837093, g. Phosphate mimics selected from Foscarnet Sodium, 1 ribofuranosylpyrazole-3,4-dicarboxamide, Fenbendazole, for use in treating or preventing pain in a subject.
17. A therapeutic compound selected from the group of nucleotide and nucleoside reverse transcriptase inhibitors, selected from Emtricitabine, Lamivudine, Clevudine, Zidovudine, Apricitabine, AVX754, Stampidine, Elvucitabine, Dexelvucitabine, Racivir, Fes tinavir, Emivirine, Stavudine, Telbivudine, Zalcitabine, Entecavir, CMX 157, HDP-tenofovir, hexadecyloxypropyl tenofovir, WO 2013/167743 PCT/EP2013/059752 117 GS 7340, Carbovir, Lobucavir, Abacavir, Amdoxovir, Didanosine, Lodenosine, Capravirine, Clevudine for use in treating or pre venting pain in a subject.
18. A therapeutic compound selected from the group of nucleoside and nucleotide DNA or RNA polymerase inhibitors selected from Emtricitabine, Lamivudine, Clevudine, Edoxudine, Zidovudine, Apricitabine, AVX754, Stampidine, Elvucitabine, Dexelvucitabine, Racivir, Festinavir, Emivirine, Idoxuridine, Trifluridine, Cy tarabine, 2'-O-Methylcytidine, Stavudine, 2',3' Dideoxythymidine, Telbivudine, Zalcitabine, Fiacitabine, Fi aluridine, Brivudine, Sorivudine, 2'-Fluoro-5 ethylarabinosyluracil, Cidofovir, PS17977, Entecavir, CMX 157, HDP-tenofovir, hexadecyloxypropyl tenofovir, Acyclovir, valacy clovir hydrochloride, Vidarabine, Alamifovir, GS 7340 , Penciclovir, Ganciclovir, Tiviciclovir, Famciclovir, Carbovir, Lobucavir, Abacavir, Amdoxovir, Valganciclovir, INX189, Didano sine, Valomaciclovir, Omaciclovir, Lodenosine, Capravirine, Clevudine for use in treating or preventing pain in a subject.
19. A therapeutic compound selected from the group of non nucleotide and nucleoside reverse transcriptase inhibitors se lected from Opaviraline, Atevirdine, Nevirapine, Tivirapine, Efavirenz (EFV), Loviride, Trovirdine, Fosamprenavir, Dapi virine, Etravirine, Rilpivirine, Talviraline, Lersivirine; UK 453061, Calanolide A, Oltipraz, Delavirdine, Capravirine, Tro virdine for use in treating or preventing pain in a subject.
20. A therapeutic compound selected from the group of non nucleoside and nucleotide DNA or RNA polymerase inhibitors se lected from Opaviraline, Methisazone, Atevirdine, Nevirapine, Tivirapine, rifampicin sodium, Efavirenz (EFV), Loviride, Tro virdine, Fosamprenavir, Dapivirine, Etravirine, Rilpivirine, Talviraline, Foscarnet, Lersivirine; UK-453061, Calanolide A, Oltipraz, Delavirdine, Capravirine, Trovirdine for use in treat ing or preventing pain in a subject.
21. A therapeutic compound selected from the group of viral in tegrase inhibitors selected from Raltegravir, Elvitegravir, Do lutegravir, Globoidnan A, MK-2048, BI 224436, or from the group WO 2013/167743 PCT/EP2013/059752 118 of viral terminase inhibitors selected from Tomeglovir, 2-bromo 5,6-dichloro-1-D-ribofuranosyl benzimidazole (BDCRB), GW-275175X for use in treating or preventing pain in a subject.
22. A therapeutic compound selected from the group of Inosine Monophosphate Dehydrogenase (IMPDH) Inhibitors selected from Ribavirin, Taribavirin, Mycophenolate, Amitivir for use in treating or preventing pain in a subject.
23. A therapeutic compound selected from the group of Viral Fu sion inhibitors selected from Docosanol, Enfuvirtide, Tifuvir tide, Sifuvirtide for use in treating or preventing pain in a subject.
24. A therapeutic compound selected from the group of CMV Imme diate-Early Protein 2 (IE2) mRNA Inhibitors selected from Fom ivirsen, Afovirsen for use in treating or preventing pain in a subject.
25. A therapeutic compound selected from the group of Virus rep lication inhibitors selected from Floxuridine, Fluorouracil, Ac etylcysteine, tromantadine hydrochloride, Podophyllotoxin, Tro mantadine for use in treating or preventing pain in a subject.
26. A therapeutic compound selected from the group of TLR-7 ac tivators selected from Imiquimod, Resiquimod for use in treating or preventing pain in a subject.
27. A therapeutic compound selected from the group of Virus pro tein synthesis inhibitors selected from Methisazone, rifampicin sodium for use in treating or preventing pain in a subject.
28. A therapeutic compound selected from the group of CCR5 an tagonists selected from Maraviroc, cenicriviroc mesylate, Mara viroc, Vicriviroc, Ancriviroc, Aplaviroc for use in treating or preventing pain in a subject.
29. A therapeutic compound selected from the group of Viral pro tease inhibitors selected from Saquinavir, Telinavir, Palinavir, Ciluprevir, Indinavir, Ritonavir, Droxinavir, Nelfinavir, Ampre- WO 2013/167743 PCT/EP2013/059752 119 navir, Tipranavir, Lopinavir, Atazanavir, Darunavir, Rupin trivir, Fosamprenavir, Boceprevir, Telaprevir, Mozenavir, Lasinavir, Brecanavir for use in treating or preventing pain in a subject.
30. A therapeutic compound selected from the group of Protein Ion Channel Blockers selected from Amantadine, Rimantadine f or use in treating or preventing pain in a subject.
31. A therapeutic compound selected from the group of Neuramini dase inhibitors selected from Zanamivir, Peramivir, Oseltamivir, Laninamivir; Inavir for use in treating or preventing pain in a subject.
32. A therapeutic compound selected from the group of Kinase in hibitors selected from Gefitinib, Tyrphostin, Erbstatin, Fasudil, Tyrphostin, Fascaplysin, Alvocidib for use in treating or preventing pain in a subject.
33. A therapeutic compound selected from the group of NMDA Channel blockers selected from tromantadine hydrochloride, Ada mantylamide, Tromantadine, Rimantadine, Amantadine for use in treating or preventing pain in a subject.
34. A therapeutic compound selected from the group of Topoiso merase inhibitors selected from Topotecan, Irinotecan, Rubi tecan, Camptothecin, Rescinnamine for use in treating or pre venting pain in a subject.
35. A therapeutic compound selected from the group of Antibacte rial antibiotics selected from rifampicin sodium, Rifabutin, Lexithromycin, Griseofulvin, Gramicidin, Neomycin, Cyclo heximide, Thiostrepton, Narasin for use in treating or prevent ing pain in a subject.
36. A therapeutic compound selected from the group of HIV-entry inhibitors selected from Enfuvirtide, Sifuvirtide, Tifuvirtide, cenicriviroc mesylate, Maraviroc, Vicriviroc, Ancriviroc, Aplaviroc for use in treating or preventing pain in a subject. WO 2013/167743 PCT/EP2013/059752 120
37. A therapeutic compound selected from the group of Viral si alidase blockers selected from Zanamivir, Oseltamivir, 4 hydroxy-6-[1-(phenylmethyl)propyl]-3-(1-phenylpropyl)-2H-Pyran 2-one for use in treating or preventing pain in a subject.
38. A therapeutic compound selected from the group of Steroid hormones selected from Dehydroepiandrosterone, Clomiphene, Des oxycorticosterone, Diethylstilbestrol, Cosalane, Fulvestrant, Exemestane, Methyltestosterone, Testosterone, Dienestrol, Torem ifene, VGX, Raloxifene, Mometasone, ADS, Tamoxifen, Budesonide, Masoprocol, Pinosylvin, Stanozolol, Piceatannol, U18666A, Hal cinonide, Quinestrol, Dydrogesterone, 2-Methoxyestradiol, Mes terolone for use in treating or preventing pain in a subject.
39. A therapeutic compound selected from the group of Antihista minic drugs selected from Cyproheptadine, Doxepin, Chlorphenox amine, Meclizine, Oxeladin, Desloratadine, Maprotiline, Lorata dine, Azelastine for use in treating or preventing pain in a subject.
40. An adefovir derivative, excluding adefovir, selected from the compounds of table 1 for use in treating or preventing pain in a subject.
41. A therapeutic compound selected from the group of the com pounds of any one of tables 1 to 3 or derivatives thereof for use in treating or preventing pain in a subject.
42. Method of treating or reducing pain in a subject comprising administering a compound of any one of claims 1 to 41 or any pharmaceutically acceptable salt, prodrug, derivative, ester or analogue thereof to a subject suffering from pain.
43. Method of preventing pain in a subject comprising adminis tering a compound of any one of claims 1 to 41 or any pharmaceu tically acceptable salt, prodrug, derivative, ester or analogue thereof to a subject as prophylaxis from pain.
44. Use of a compound of claims 1 to 41 or any pharmaceutically acceptable salt, prodrug, derivative, ester or analogue thereof WO 2013/167743 PCT/EP2013/059752 121 for the manufacture of an analgesic or a medicament for the treatment of pain.
45. The method or use of a compound of any one of claim 1 to 44, characterized in that the compound is administered topically, enterally or parenterally, in particular preferred orally or rectally, intravenously, intraarterially, intramuscularly, sub cutaneously, intradermally, intraperitoneally, transdermally, transmucosally or by inhalation.
46. The method or use of a compound of any one of claims 1 to 45, characterized in that the subject to be treated is a mammal, preferably a human, or a non human-animal, preferably a non human mammal or bird.
47. The method or use of a compound according to claim 46 where in the animal is a dog, cat, horse, cow, pig.
48. The method or use of a compound of any one of claims 1 to 47, characterized in that the compound is provided in a medica ment.
49. The method or use of a compound of any one of claims 1 to 48, characterized in that the compound is provided together with a pharmaceutically acceptable carrier or buffer.
50. The method or use of a compound of any one of claims 1 to 49, characterized in that the compound is administered in a therapeutically effective dosage, preferably a dosage of between 0.01 mg/kg and 1 g/kg.
51. The method or use of a compound of any one of claims 1 to 50, wherein pain is selected from or associated with a chronic pain.
52. The method or use of a compound of any one of claims 1 to 51, wherein pain is selected from or associated with an acute pain.
53. The method or use of a compound of any one of claims 1 to 52, wherein pain is selected from or associated with a hyperal gesia pain. WO 2013/167743 PCT/EP2013/059752 122
54. The method or use of a compound of any one of claims 1 to 53, wherein pain is selected from or associated with a somato genic pain.
55. The method or use of a compound of any one of claims 1 to 54, wherein pain is selected from or associated with a neuro pathic pain.
56. The method or use of a compound of any one of claims 1 to 55, wherein pain is selected from or associated with a psycho genic pain.
57. The method or use of a compound of any one of claims 1 to 56, wherein pain is selected from or associated with a heat in duced pain.
58. The method or use of a compound of any one of claims 1 to 57, wherein pain is selected from or associated with a physical pain.
59. The method or use of a compound of any one of claims 1 to 57, wherein pain is selected from or associated with nociceptive pain.
60. The method or use of a compound of any one of claims 1 to 59, wherein pain is selected from or associated with a hyperal gesia.
61. The method or use of a compound of any one of claims 1 to 60, wherein pain is selected from or associated with a rheumatic pain.
62. The method or use of a compound of any one of claims 1 to 61, wherein pain is selected from or associated with a headache low back pain.
63. The method or use of a compound of any one of claims 1 to 62, wherein pain is selected from or associated with low back pain.
64. The method or use of a compound of any one of claims 1 to 63, wherein pain is selected from or associated with a pelvic pain.
65. The method or use of a compound of any one of claims 1 to 64, wherein pain is selected from or associated with a myofas cial pain.
66. The method or use of a compound of any one of claims 1 to 65, wherein pain is selected from or associated with a vascular pain.
67. The method or use of a compound of any one of claims 1 to WO 2013/167743 PCT/EP2013/059752 123 66, wherein pain is selected from or associated with a migraine wound associated pain.
68. The method or use of a compound of any one of claims 1 to 67, wherein pain is selected from or associated with wound asso ciated pain.
69. The method or use of a compound of any one of claims 1 to 68, wherein pain is selected from or associated with inflammato ry pain.
70. The method or use of a compound of any one of claims 1 to 69, wherein pain is selected from or associated with an arthrit ic pain.
71. The method or use of a compound of any one of claims 1 to 70, wherein pain is selected from or associated with a diabetic pain.
72. The method or use of a compound of any one of claims 1 to 71, wherein pain is selected from or associated with a pain from or associated with cancer.
73. The method or use of a compound of any one of claims 1 to 72, wherein pain is selected from or associated with a somatic visceral pain.
74. The method or use of a compound of any one of claims 1 to 73, wherein pain is selected from or associated with a fibrom yalgia.
75. The method or use of a compound of any one of claims 1 to 74, wherein pain is selected from or associated with a postoper ative pain.
76. The method or use of a compound of any one of claims 1 to 75, wherein pain is selected from or associated with a phantom pain.
77. The method or use of a compound of any one of claims 1 to 76, wherein pain is selected from or associated with a trigemi nal neuralgia.
78. The method or use of a compound of any one of claims 1 to 77, wherein pain is selected from or associated with a post herpetic neuralgia.
79. The method or use of a compound of any one of claims 1 to 78, wherein pain is selected from or associated with a painful diabetic neuropathy.
80. The method or use of a compound of any one of claims 1 to 79, wherein pain is selected from or associated with a painful WO 2013/167743 PCT/EP2013/059752 124 diabetic peripheral neuropathy.
81. The method or use of a compound of any one of claims 1 to 80, wherein pain is selected from or associated with a diabetic polyneuropathy.
82. The method or use of a compound of any one of claims 1 to 81, wherein pain is selected from or associated with a sciatic pain.
83. The method or use of a compound of any one of claims 1 to 82, wherein pain is selected from or associated with a radicu lopathy.
84. The method or use of a compound of any one of claims 1 to 83, wherein pain is selected from or associated with a radicular pain.
85. The method or use of a compound of any one of claims 1 to 84, wherein pain is selected from or associated with a lumbar pain.
86. The method or use of a compound of any one of claims 1 to 85, wherein pain is selected from or associated with a pain as sociated with osteoarthritis.
87. The method or use of a compound of any one of claims 1 to 86, wherein pain is selected from or associated with a pain as sociated with rheumatoid arthritis.
88. The method or use of a compound of any one of claims 1 to 68 and 70 to 87, wherein pain is selected from or associated with non-inflammatory pain.
89. The method or use of a compound of any one of claims 1 to 77 and 79 to 88, wherein pain excludes post-herpetic neuralgia as sociated pain.
90. Compound, use or method according to any one of claims 1 to 89 wherein said compound is used in combination with one or more further analgesic or anti-pain compounds, preferably a further compound according to any one of claims 42 or of tables 1 to 3 or a derivative thereof or a compound selected from the group of Tenofovir (PMPA), dasatinib, AMG-706 (motesanib), BIRB 796 (Doramapimod), EKB-569 (Pelitinib), sorafenib , Vandetanib, CI 1033 (Canertinib), NSC161613, N6-Benzyladenosine-5'-phosphate, p-Aminobenzoly PAB-J acid, NSC47091, cilomilast , Nicotinamide (Nicotinamide), IBMX, Roflumilast, Filaminast, Piclamilast, V11294, CC-10004 (Apremilast), LAS31025 (Arofylline), CP80633 (Atizoram), Catramilast/Atopik (Catramilast), BRL-61063 WO 2013/167743 PCT/EP2013/059752 125 (Cimpyfylline), Daxalipram/mesopram (Daxalipram), Doxofylline, Drotaverine, Efloxate, Etamiphylline, Etazolate, Etofylline, Glaucine Hydrobromide (Broncholytine), GRC3886 (oglemilast), ox triphyllin (Choline theophyllinate), Pumafentrine, Revamilast, Tofimilast, Tolafentrine, Seoanin (Trapidil), GW 842470 (AWD 12 281), CDP-840, YM-976, CI-1018, D-4418, Lirimilast, SCH-351591, RPL-554, IPL-455903 (HT-0712), GSK256066, Zardaverine, Varden afil, OPC-6535 (Tetomilast), IC485, L-826,141, ONO-6126, CI 1044, MK-0873, T-2585, R1533 (MEM-1414), Ronomilast (ELB-353), UK-500,001, AN2728 , DE-103, Tofisopam, (R)-Tofisopam (Dex tofisopam), (S)-Tofisopam (Levotofisopam (USAN)), EKB-568, SU 14813, LY-333531 (Ruboxistaurin), CGP-52421, SKI-606 (Bosu tinib), Roscovitine, Tenofovir (PMPA), Methimazole, Adefovir dipivoxil (Bis-POM PMEA) (Adefovir), Acetazolamide, midostaurin (PKC-412), tozasertib (MK-0457, VX 680) or lestaurtinib (CEP 701).
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-
2013
- 2013-05-10 EP EP13721770.9A patent/EP2846788A1/en not_active Withdrawn
- 2013-05-10 JP JP2015510836A patent/JP2015520144A/en active Pending
- 2013-05-10 AU AU2013257951A patent/AU2013257951A1/en not_active Abandoned
- 2013-05-10 WO PCT/EP2013/059752 patent/WO2013167743A1/en active Application Filing
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11103465B2 (en) | 2017-11-22 | 2021-08-31 | Ted's Brain Science, Inc. | Trans-resveratrol topical medication for the treatment of pain and method of manufacture thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2013167743A1 (en) | 2013-11-14 |
| JP2015520144A (en) | 2015-07-16 |
| EP2846788A1 (en) | 2015-03-18 |
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