WO2016207924A1 - Dexpramipexole for the treatment of pain - Google Patents
Dexpramipexole for the treatment of pain Download PDFInfo
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- WO2016207924A1 WO2016207924A1 PCT/IT2016/000163 IT2016000163W WO2016207924A1 WO 2016207924 A1 WO2016207924 A1 WO 2016207924A1 IT 2016000163 W IT2016000163 W IT 2016000163W WO 2016207924 A1 WO2016207924 A1 WO 2016207924A1
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- pain
- dexpramipexole
- diamine
- tetrahydrobenzo
- thiazole
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
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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]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
Definitions
- Pain is a frequent clinical status that needs rapid and efficient control in order to reduce patient distress. Unfortunately, pain control is often suboptimal and it is very important to identify new, potent and safe analgesics able to reduce or terminate pain that characterizes different human disorders. Pain can be of different types such as nociceptive, inflammatory, neuropathic, oncologic, post-surgery or related to headache.
- Prototypical analgesics are non-steroidal anti-inflammatory drugs, paracetamol, opioids including tramadol, as well as certain antidepressant and antiepileptic drugs.
- high doses of a single analgesic or association of analgesics are needed to fully activate anti-nociceptive mechanisms at the neuronal or brain level. Inevitably, this is frequently associated with side effects that reduce the efficacy of the analgesic therapy.
- the problem to be solved is therefore that of identifying innovative analgesics that on the one hand improve pain control, and on the other reduce the risk of untoward effects.
- the levo-isomer of pramipexole [A ⁇ -propyl ⁇ , 5,6,7- tetrahydrobenzo[c ]thiazole-2,6-diamine] S(-)-pramipexole is a drug able to potently activate dopamine receptors and therefore used for treatment of extrapyramidal disorders such as Parkinson disease and restless leg syndrome.
- the dextro-isomer R(+)-pramipexole also known as Dexpramipexole does not bind dopamine receptors.
- Mirapexin® i.e. the formulation of the levo-isomer (S)-pramipexole
- S levo-isomer
- Dexpramipexole reduces pain in different experimental models and can therefore be used as an analgesic to treat acute or chronic pain. It is known that intraperitoneal injection of low concentrations of acetic acid in the mouse triggers repetitive abdominal writhings which are the somatic manifestation of abdominal pain caused by chemical damage of peritoneal nociceptive terminals. Unexpectedly, we found that the number of abdominal writhing caused by acetic acid injection is reduced in a dose-dependent manner when mice are pretreated (1 h) with Dexpramipexole at 10 and 20 mg/kg intraperitoneally (Fig.1 ).
- a pretreatment with Dexpramipexole reduces in a dose-dependent manner the duration of painful somatic manifestation caused by formalin intraplantar injection in mice. This reduction occurs either if Dexpramipexole is injected intraperitoneally at 10 or 20 mg/kg 1 h before formalin (Fig. 2A), or if Dexpramipexole is injected locally by means of subcutaneous injections of 70 pg 10 min before formalin (Fig. 2B). It is known that neuropathic pain typically occurs during chemotherapy in neoplastic patients because of primary damage to nociceptive pathways by antineoplastic drugs.
- a classic model of neuropathic pain is development of allodynia (pain sensation triggered by tactile stimuli) in rodents after chronic treatment with the chemotherapeutic oxaliplatin.
- Development of allodynia can be determined by means of the Von Frey test that measures the animal pain threshold upon mechanical filament pressure on the hind paw.
- musculoskeletal, odontostomatologic and postsurgery pains have both visceral and inflammatory components.
- headache has typical neuropathic pain features, whereas glaucoma and oncologic pain add to the neuropathic pain a visceral pain component.
- animal pain models no adopted are known to be reliable and predictive of drug efficacy in different forms of pain (Le Bars et al. Animal models of nociception. Pharmacol Rev. 2001 ;53:597-652, and literature cited therein).
- Dexpramipexole can be formulated in ampoules, powders, tablets, capsules, extended release tablets and capsules, patches, syrups, suspensions, drops and lipid complexes, eye drops, pomades, ointments and creams.
- Dexpramipexole can be administered through the following routes: intravenous, intramuscular, oral,
- Dosage of Dexpramipexole can be from 10 to 2000 mg/day.
- Figure 1 shows the effect of Dexpramipexole in the Writhing test in mice.
- the 125 test consists in the intraperitoneal injection of acetic acid (200 ⁇ , 0.6% v/v) in mice as the painful stimulus that causes a number abdominal writhings proportional to the degree of pain.
- the Figure shows how the 1 h intraperitoneal pretreatment with dexpramipexole (DEX) at 10 and 20 mg/kg reduces the number of abdominal writhings caused by the intraperitoneal 130 injection of acetic acid. The intensity of pain has been determined as the number of abdominal writhings.
- DEX dexpramipexole
- Figure 2 shows the effect of Dexpramipexole in the formalin test in mice in case the drug has ben administered istically by intraperitoneal injection (A) or locally by locally by intraplantar injection (B).
- A intraperitoneal injection
- B intraplantar injection
- FIG. 135 formalin is injected in the mouse hind paw. This is a painful stimulus that causes flinches and licking of the injected paw. The intensity of pain is proportional to the cumulative time of flinches and lickings of the paw.
- Figure 2A shows how the 1 h pretreatment with Dexpramipexole (DEX) injected intraperitoneally at 10 or 20 mg/kg reduces the cumulative time of flinches
- Figure 2B shows how the time of flinches and lickings of the hind paw injected with formalin is reduced if the same paw is pretreated (10 min) with intraplantar dexpramipexole (DEX) at the dose of 70 pg.
- DEX intraplantar dexpramipexole
- Figure 3 shows the effect of Dexpramipexole in a neuropathic pain model of 145 allodynia in mice.
- Animals have been chronically treated with Oxaliplatin (2.4 mg/kg intraperitoneally) for 2 weeks. Later on, mice received in the hind paw subdermal injections of 70 pg of Dexpramipexole or corresponding volumes of 20 ⁇ of saline, 10 minutes before evaluating mechanical allodynia by means of Von Frey test.
- the best mode for carrying out the invention is to treat patients affected by different painful conditions or at risk of painful conditions with repeated daily doses of R(+)-pramipexole (Dexpramipexole) administered by different 155 routes such as, for example but not limited to, intramuscular (acute treatment) or oral (preventive treatment).
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Abstract
The use of R(+)-pramipexole (Dexpramipexole) [(R)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine] for the treatment of pain is described.
Description
DEXPRAMIPEXOLE FOR THE TREATMENT OF PAIN
Technical Field
The present invention refers to the field of drugs for the treatment of pain
Background Art
It is well known that there is a great interest for the identification of analgesic drugs able to counteract pain caused by different pathologies and nociceptive stimuli. The World Health Organization defines pain as "an unpleasant sensation and negative emotional experience related to actual or potential tissue damage or referred as such". Similarly, the International Association for the Study of Pain defines pain as an "unpleasant sensation or emotion due to real or potential tissue damage or referred as such".
Pain is a frequent clinical status that needs rapid and efficient control in order to reduce patient distress. Unfortunately, pain control is often suboptimal and it is very important to identify new, potent and safe analgesics able to reduce or terminate pain that characterizes different human disorders. Pain can be of different types such as nociceptive, inflammatory, neuropathic, oncologic, post-surgery or related to headache.
Prototypical analgesics are non-steroidal anti-inflammatory drugs, paracetamol, opioids including tramadol, as well as certain antidepressant and antiepileptic drugs. Usually, in order to efficiently control pain, high doses of a single analgesic or association of analgesics are needed to fully activate anti-nociceptive mechanisms at the neuronal or brain level. Inevitably, this is frequently associated with side effects that reduce the efficacy of the analgesic therapy.
The problem to be solved is therefore that of identifying innovative analgesics that on the one hand improve pain control, and on the other reduce the risk of untoward effects.
l
The levo-isomer of pramipexole [A^-propyl^, 5,6,7- tetrahydrobenzo[c ]thiazole-2,6-diamine] S(-)-pramipexole is a drug able to potently activate dopamine receptors and therefore used for treatment of extrapyramidal disorders such as Parkinson disease and restless leg syndrome. Conversely, the dextro-isomer R(+)-pramipexole (also known as Dexpramipexole) does not bind dopamine receptors. On this basis, formulations containing pramipexole available for clinical uses such as Mirapexin® or Mirapex® do not contain the racemate but only the levo- isomer (S)-pramipexole used as a dopamine receptor agonist. Conversely, Dexpramipexole has no current therapeutic uses. Recently, Dexpramipexole has been tested in patients with amyotrophic lateral sclerosis showing very good safety profile but no ability to delay disease development.
It is known that dopamine receptor activation within the mesolimbus affords analgesia (Altier & Stewart. The role of dopamine in the nucleus accumbens in analgesia. Life Sci 1999;65:2269-87). Accordingly, Mirapexin® (i.e. the formulation of the levo-isomer (S)-pramipexole) has been administered to fibromyalgic patients and, in keeping with its ability to potently activate dopamine receptors, reduced pain intensity (Holman & Myers. A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications. Arthritis Rheum. 2005;52:2495-505).
The state of the art therefore teaches that the levo-isomer of pramipexole (specifically Mirapexin®) affords analgesia in patients with fibromyalgia thanks to its central action on mesolimbic dopamine receptors. The expert of the field, however, does not find any teaching in the state of the art that the dopamine receptor-inactive dextro-isomer of pramipexole, Dexpramipexole, reduces nociception and behaves as a central and/or topical analgesic. Disclosure of the invention
Unexpectedly we found, and is the subject of the present invention, that Dexpramipexole reduces pain in different experimental models and can therefore be used as an analgesic to treat acute or chronic pain.
It is known that intraperitoneal injection of low concentrations of acetic acid in the mouse triggers repetitive abdominal writhings which are the somatic manifestation of abdominal pain caused by chemical damage of peritoneal nociceptive terminals. Unexpectedly, we found that the number of abdominal writhing caused by acetic acid injection is reduced in a dose-dependent manner when mice are pretreated (1 h) with Dexpramipexole at 10 and 20 mg/kg intraperitoneally (Fig.1 ).
It is known that subcutaneous intraplantar formalin injection rapidly triggers local pain of about 10 min duration (First Phase), followed after further 10 min by a delayed local painful sensation of about 40 min (Second Phase).
It is known that during these two phases pain caused by this intraplantar injection in the mouse appears with somatic manifestations such as flinching and liking of the paw, and that durations of such actions are directly proportional to intensity of pain.
We have now unexpectedly found that a pretreatment with Dexpramipexole reduces in a dose-dependent manner the duration of painful somatic manifestation caused by formalin intraplantar injection in mice. This reduction occurs either if Dexpramipexole is injected intraperitoneally at 10 or 20 mg/kg 1 h before formalin (Fig. 2A), or if Dexpramipexole is injected locally by means of subcutaneous injections of 70 pg 10 min before formalin (Fig. 2B). It is known that neuropathic pain typically occurs during chemotherapy in neoplastic patients because of primary damage to nociceptive pathways by antineoplastic drugs. A classic model of neuropathic pain is development of allodynia (pain sensation triggered by tactile stimuli) in rodents after chronic treatment with the chemotherapeutic oxaliplatin. Development of allodynia can be determined by means of the Von Frey test that measures the animal pain threshold upon mechanical filament pressure on the hind paw. We have now unexpectedly found that administration of Dexpramipexole (70 pg, subdermal in the hind paw) but not an equal volume of saline (20 μΙ) by the same route, reduces allodynic pain evaluated with the Von Frey test 10 min after injections in mice rendered allodynic by means of chronic treatment (2 weeks) with oxaliplatin (Fig. 3).
Given that both the number of writhings that follows intraperitoneal injection of acetic acid, the duration of flinching and liking of the paw injected with formalin, as well as the mechanical force necessary to reach the pain threshold are directly proportional to the pain intensity experienced by the loo mice, our data for the first time demonstrate that Dexpramipexole reduces pain intensity when administered systemically or topically and is therefore endowed with unexpected analgesic properties.
Of note, it is well known that the visceral, inflammatory and neuropathic pain models adopted reproduce the principal components of pain characterizing
105 different clinical conditions. For instance musculoskeletal, odontostomatologic and postsurgery pains have both visceral and inflammatory components. Similarly, headache has typical neuropathic pain features, whereas glaucoma and oncologic pain add to the neuropathic pain a visceral pain component. It is known, indeed, that the animal pain models no adopted are known to be reliable and predictive of drug efficacy in different forms of pain (Le Bars et al. Animal models of nociception. Pharmacol Rev. 2001 ;53:597-652, and literature cited therein). Hence, the analgesic effects of Dexpramipexole we have found in the different pain models adopted is predictive of efficacy in the above-mentioned different clinical pain conditions. lis According to the invention, Dexpramipexole can be formulated in ampoules, powders, tablets, capsules, extended release tablets and capsules, patches, syrups, suspensions, drops and lipid complexes, eye drops, pomades, ointments and creams. According to the invention Dexpramipexole can be administered through the following routes: intravenous, intramuscular, oral,
120 rectal, sublingual, topical, subcutaneous and transdermal. Dosage of Dexpramipexole can be from 10 to 2000 mg/day.
Brief description of drawings
Figure 1 shows the effect of Dexpramipexole in the Writhing test in mice. The 125 test consists in the intraperitoneal injection of acetic acid (200 μΙ, 0.6% v/v) in mice as the painful stimulus that causes a number abdominal writhings proportional to the degree of pain. The Figure shows how the 1 h
intraperitoneal pretreatment with dexpramipexole (DEX) at 10 and 20 mg/kg reduces the number of abdominal writhings caused by the intraperitoneal 130 injection of acetic acid. The intensity of pain has been determined as the number of abdominal writhings.
Figure 2 shows the effect of Dexpramipexole in the formalin test in mice in case the drug has ben administered sistemically by intraperitoneal injection (A) or locally by locally by intraplantar injection (B). In this pain model
135 formalin is injected in the mouse hind paw. This is a painful stimulus that causes flinches and licking of the injected paw. The intensity of pain is proportional to the cumulative time of flinches and lickings of the paw. Figure 2A shows how the 1 h pretreatment with Dexpramipexole (DEX) injected intraperitoneally at 10 or 20 mg/kg reduces the cumulative time of flinches
140 and lickings of the paw injected with formalin. Figure 2B shows how the time of flinches and lickings of the hind paw injected with formalin is reduced if the same paw is pretreated (10 min) with intraplantar dexpramipexole (DEX) at the dose of 70 pg.
Figure 3 shows the effect of Dexpramipexole in a neuropathic pain model of 145 allodynia in mice. Animals have been chronically treated with Oxaliplatin (2.4 mg/kg intraperitoneally) for 2 weeks. Later on, mice received in the hind paw subdermal injections of 70 pg of Dexpramipexole or corresponding volumes of 20 μΙ of saline, 10 minutes before evaluating mechanical allodynia by means of Von Frey test.
150
Best mode for carrying out the invention
The best mode for carrying out the invention is to treat patients affected by different painful conditions or at risk of painful conditions with repeated daily doses of R(+)-pramipexole (Dexpramipexole) administered by different 155 routes such as, for example but not limited to, intramuscular (acute treatment) or oral (preventive treatment).
Claims
160 1. (R)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (Dexpramipexole) for use for the treatment of pain.
2. (R)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (Dexpramipexole) for use for the prevention of pain.
3. (R)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine 165 (Dexpramipexole) for use according to claims 1 and 2 in case of musculoskeletal pain
4. (R)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (Dexpramipexole) for use according to claims 1 and 2 in case of visceral pain
5. (R)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine 170 (Dexpramipexole) for use according to claims 1 and 2 in case of inflammatory pain
6. (R)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (Dexpramipexole) for use according to claims 1 and 2 in case of neuropathic pain
175 7. (R^Ne-propyM.S.ej-tetrahydrobenzoldJthiazole^.e-diamine (Dexpramipexole) for use according to claims 1 and 2 in case of oncologic pain
8. (R)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (Dexpramipexole) for use according to claims 1 and 2 in case of
180 odontostomatologic pain
9. (R)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (Dexpramipexole) for use according to claims 1 and 2 in case of post- surgery pain
10. (R)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine 185 (Dexpramipexole) for use according to claims 1 and 2 in case of headache pain
11. (R)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (Dexpramipexole) for use according to claims 1 and 2 in case of pain due to glaucoma
190 12. (R)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (Dexpramipexole) for use in formulations for the treatment of pain in which said formulations can be formulated as ampoules, powders, tablets, capsules, extended release tablets and capsules, patches, syrups, suspensions, drops and lipid complexes, eye drops, pomades, ointments and
195 creams.
13. Formulations according to claim 12 in which said formulations can be administered through the following routes: intravenous, intramuscular, oral, rectal, sublingual, topical, subcutaneous and transdermal.
14. Formulations according to claims 12-13 in which said formulations 200 contain the compound according to claims 1-11 in amounts ranging from 10 to 2000 mg.
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| IT1020150000027486 | 2015-06-25 | ||
| ITUB20152000 | 2015-06-25 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010148409A1 (en) * | 2009-06-19 | 2010-12-23 | Knopp Neurosciences, Inc. | Compositions and methods for treating amyotrophic lateral sclerosis |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010148409A1 (en) * | 2009-06-19 | 2010-12-23 | Knopp Neurosciences, Inc. | Compositions and methods for treating amyotrophic lateral sclerosis |
Non-Patent Citations (4)
| Title |
|---|
| ALTIER; STEWART: "The role of dopamine in the nucleus accumbens in analgesia.", LIFE SCI, vol. 65, 1999, pages 2269 - 87, XP002481751, DOI: doi:10.1016/S0024-3205(99)00298-2 |
| HOLMAN A J ET AL: "A Randomized Double Blind Placebo Controlled Trial of Pramipexole, a Dopamine Agonist, in Patinets with Fibromyalgia Receiving Concimitant Medication", ARTHRITIS & RHEUMATISM, WILEY, US, vol. 52, no. 8, 1 January 2005 (2005-01-01), pages 2495 - 2506, XP002454911, ISSN: 0004-3591, DOI: 10.1002/ART.21191 * |
| HOLMAN; MYERS: "A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications", ARTHRITIS RHEUM, vol. 52, 2005, pages 2495 - 505 |
| LE BARS ET AL.: "Animal models of nociception", PHARMACOL REV., vol. 53, 2001, pages 597 - 652, XP002338281 |
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