WO2007141018A1 - Combinaison thérapeutique pour états médicaux douloureux - Google Patents

Combinaison thérapeutique pour états médicaux douloureux Download PDF

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Publication number
WO2007141018A1
WO2007141018A1 PCT/EP2007/005036 EP2007005036W WO2007141018A1 WO 2007141018 A1 WO2007141018 A1 WO 2007141018A1 EP 2007005036 W EP2007005036 W EP 2007005036W WO 2007141018 A1 WO2007141018 A1 WO 2007141018A1
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WIPO (PCT)
Prior art keywords
pain
combination
agent
lower alkyl
group
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PCT/EP2007/005036
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English (en)
Inventor
Bettina Beyreuther
Thomas STÖHR
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Schwarz Pharma Ag
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Priority claimed from US11/506,524 external-priority patent/US20070043120A1/en
Priority claimed from US11/506,578 external-priority patent/US20070048372A1/en
Priority claimed from PCT/EP2006/008171 external-priority patent/WO2007020103A2/fr
Priority claimed from US11/506,577 external-priority patent/US20070042969A1/en
Priority to BRPI0712494-5A priority Critical patent/BRPI0712494A2/pt
Priority to EP07725884A priority patent/EP2026788B1/fr
Application filed by Schwarz Pharma Ag filed Critical Schwarz Pharma Ag
Priority to AT07725884T priority patent/ATE530175T1/de
Priority to EA200802412A priority patent/EA200802412A1/ru
Priority to JP2009513597A priority patent/JP2009539792A/ja
Priority to MX2008015341A priority patent/MX2008015341A/es
Priority to AU2007256352A priority patent/AU2007256352A1/en
Priority to CA002652667A priority patent/CA2652667A1/fr
Publication of WO2007141018A1 publication Critical patent/WO2007141018A1/fr

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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
    • 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
    • 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
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to therapeutic combinations and methods of use of such combinations in treatment of medical conditions, more particularly such conditions, including arthritic conditions, where pain is present.
  • Rheumatoid arthritis is a chronic disease mainly characterized by inflammation of the lining, or synovium, of the joints. It can lead to long-term joint damage, resulting in chronic pain, loss of function and disability. Rheumatoid arthritis affects about 1% of the U.S. population or 2.1 million Americans.
  • Rheumatoid arthritis progresses in three stages.
  • the first stage includes swelling of the synovial lining, causing pain, warmth, stiffness, redness and swelling around the joint.
  • the second stage includes rapid division and growth of cells, or pannus, which causes the synovium to thicken.
  • the inflamed cells release enzymes that may digest bone and cartilage, often causing the involved joint to lose its shape and alignment, more pain, and loss of movement. Because rheumatoid arthritis is a systemic disease, it can also affect other organs in the body. Early diagnosis and treatment of rheumatoid arthritis is critical to continue living a productive lifestyle.
  • Osteoarthritis is an acquired musculoskeletal disorder that is believed to be noninflammatory in origin, occurring when the rate of cartilage degradation exceeds that of regeneration, resulting in cartilage erosion, subchondral bone thickening, and joint damage.
  • cartilage thins, its surface integrity can be lost, clefts can form, and the cartilage tends to be more easily eroded with joint motion.
  • new cartilage is formed, it tends to be more fibrous and less able to withstand mechanical stress.
  • underlying bone can be exposed that is less capable of withstanding mechanical stress, resulting in microfractures. Localized osteonecrosis can occur beneath the bone surface, leading to cysts that can further weaken the bone's support of the cartilage.
  • osteoarthritis As osteoarthritis progresses, it can eventually influence structures surrounding the joint. Local inflammation such as synovitis can occur, for example in response to inflammatory mediators released during the cartilage degradation process.
  • the joint capsule tends to thicken, and movement of nutrients into and metabolic waste products out of the joint can be restricted.
  • periarticular muscle wasting can become evident as osteoarthritis progresses, and the joint is used less often or improperly. Pain of osteoarthritis is thought to be due not to cartilage degradation per se but to effects on surrounding structures including bone, since cartilage is aneural.
  • osteoarthritis is the most common form of arthritic disease, affecting 21 million Americans. See http://www.cdc.gov/arthritis/data_statistics/arthritis_related_statistics.htm#2.
  • a typical patient with osteoarthritis is middle-aged or elderly and complains of pain in the knee, hip, hand or spine.
  • the distal and proximal interphalangeal joints of the hands are the most common sites of osteoarthritis but also the least likely to be exhibit symptoms.
  • the hip and knee are the second and third most common joints seen on X-ray to be affected, with knee pain being more likely to exhibit symptoms.
  • Osteoarthritic pain can have one or both of an inflammatory and a non-inflammatory component.
  • Anti-inflammatory agents such as NSAIDs (non-steroidal anti-inflammatory drugs) and cyclooxygenase-2 inhibitors can be useful in treating or managing the inflammatory component, while opioid and other analgesics can be useful in treating or managing the non-inflammatory component.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • opioid and other analgesics can be useful in treating or managing the non-inflammatory component.
  • drug therapies are not always effective and have side-effects that may not be well tolerated in all patients.
  • Non-inflammatory pain is often characterized by absence of swelling or warmth, absence of inflammatory or systemic features, and minimal or no morning stiffness.
  • Non-inflammatory osteoarthritic pain can contribute to a sedentary lifestyle, depression and sleep problems, particularly in the elderly.
  • the pain is often characterized as a deep, aching sensation that intensifies with motion. It is usually intermittent and often mild, but can become persistent and severe. Crepitus is usually noted in the affected joints.
  • Certain peptides are known to exhibit central nervous system (CNS) activity and are useful in the treatment of epilepsy and other CNS disorders. Such peptides are described, for example, in U.S. Patent No. 5,378,729.
  • Ar is a phenyl group that is unsubstituted or substituted with at least one halo substituent;
  • R 3 is Ci_ 3 alkoxy; and
  • Ri is methyl.
  • Lacosamide also called SPM 927 or harkoseride
  • SPM 927 is a compound of the above formula that has a mode of action which is not fully understood (Bialer et al. (2002) Epilepsy Res. 51 :31-71).
  • the mode of action of lacosamide and other peptide compounds disclosed in the above-referenced patents and publications differs from that of common antiepileptic drugs. Ion channels are not affected by these compounds in a manner comparable to other known antiepileptic drugs.
  • GABA gamma-aminobutyric acid
  • GABA gamma-aminobutyric acid
  • R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl or lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group, and/or at least one electron donating group;
  • Ri is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, lower alkyl heterocyclic, heterocyclic, lower cycloalkyl, or lower cycloalkyl lower alkyl, and may be unsubstituted or substituted with at least one electron-withdrawing group and/or at least one electron-donating group;
  • R 2 and R 3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Z-Y, wherein R 2 and R 3 are each independently unsubstituted or substituted with at least one electron-withdrawing group and/or at least one electron-donating group; Z is O 1 S, S(O) 3 , NR 4 , NR 6 , PR4 or a chemical bond;
  • Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, or lower alkyl heterocyclic, and may be unsubstituted or substituted with at least one electron-withdrawing group and/or at least one electron-donating group, provided that when Y is halo, Z is a chemical bond, or
  • Z-Y taken together is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , OPR 4 R 5 , PR 4 OR 5 , SNR 4 R 7 , NR 4 SR 7 , SPR 4 R 5 , PR 4 SR 7 , NR 4 PR 5 R 6 , PR4NR5R7, N + R 5 R 6 R 7 ,
  • R' 6 is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl, and may be unsubstituted or substituted with at least one electron-withdrawing group or/and at least one electron-donating group;
  • R 4 , R 5 and R 6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, and are each independently unsubstituted or substituted with at least one electron-withdrawing group or/and at least one electron-donating group;
  • R 7 is R 6 , COOR 8 , or COR 8 , and may be unsubstituted or substituted with at least one electron-withdrawing group or/and at least one electron-donating group;
  • R 8 is hydrogen, lower alkyl, or aryl lower alkyl, and may be unsubstituted or substituted with at least one electron-withdrawing group or/and at least one electron-donating group;
  • n 1-4;
  • a is 1-3; or a pharmaceutically acceptable salt thereof; and a second agent effective in combination therewith to (a) provide enhanced treatment of pain associated with or caused by a medical condition, by comparison with the first agent alone; and/or (b) treat another symptom or an underlying cause of the medical condition; the second agent comprising one or more drugs other than a compound of Formula (I)-
  • the medical condition in one embodiment is a condition wherein non-inflammatory pain is present.
  • the medical condition can be, for example, an arthritic condition.
  • the first agent and second agent can be provided separately or in a single dosage form. Accordingly, in one embodiment, a pharmaceutical dosage form is provided, comprising a first agent and a second agent as defined above.
  • a method for treating a painful medical condition and/or pain related thereto in a subject comprising administering to the subject a therapeutic combination as described above.
  • a method for treating an arthritic condition and/or pain related thereto in a subject comprising administering to the subject a therapeutic combination as described above, wherein the second agent comprises one or more anti-arthritis drugs.
  • an illustrative compound of Formula (I) is lacosamide, (R)-2-acetamido-N-benzyl-3-methoxypropionamide.
  • SPM 927 refers to lacosamide.
  • Fig. 1 is a graphical representation of results of the study of Example 1, showing effect of lacosamide at 3, 10 and 30 mg/kg on muscle pressure hyperalgesia induced by TNF.
  • Fig. 2 is a graphical representation of results of the study of Example 1 , showing maximal possible effect (MPE) of lacosamide at 3, 10 and 30 mg/kg, in comparison to pregabalin, gabapentin and metamizol (dipyrone), on muscle pressure hyperalgesia induced by TNF.
  • MPE maximal possible effect
  • Fig. 3 is a graphical representation of results of the study of Example 1 , effect of lacosamide at 3, 10 and 30 mg/kg on biceps muscle grip strength after TNF- induced muscle pain.
  • Fig. 4 is a graphical representation of results of the study of Example 1 , showing maximal possible effect (MPE) of lacosamide at 3, 10 and 30 mg/kg, in comparison to pregabalin, gabapentin and metamizol (dipyrone), on biceps muscle grip strength after TNF-induced muscle pain.
  • MPE maximal possible effect
  • Figs. 5A-C are graphical representations of results of the study of Example 2, showing effects of lacosamide and morphine on monosodium iodoacetate-induced tactile allodynia at days 3, 7 and 14 of the study respectively.
  • Figs. 6A-C are graphical representations of results of the study of Example 2, showing effect of diclofenac on monosodium iodoacetate-induced tactile allodynia at days 3, 7 and 14 of the study respectively.
  • Figs. 7A-C are graphical representations of results of the study of Example 2, showing effects of lacosamide and morphine on monosodium iodoacetate-induced mechanical hyperalgesia at days 3, 7 and 14 of the study respectively.
  • Figs. 8A-C are graphical representations of results of the study of Example 2, showing effect of diclofenac on monosodium iodoacetate-induced mechanical hyperalgesia at days 3, 7 and 14 of the study respectively.
  • Therapeutic combinations, pharmaceutical dosage forms and methods of use of such combinations and dosage forms for treating arthritic conditions and/or pain related thereto are provided.
  • therapeutic combination refers to a plurality of agents that, when administered to a subject together or separately, are co-active in bringing therapeutic benefit to the subject. Such administration is referred to as “combination therapy,” “co-therapy,” “adjunctive therapy” or “add-on therapy.”
  • one agent can potentiate or enhance the therapeutic effect of another, or reduce an adverse side effect of another, or one or more agents can be effectively administered at a lower dose than when used alone, or can provide greater therapeutic benefit than when used alone, or can complementarily address different aspects, symptoms or etiological factors of a disease or condition.
  • a “medical condition” herein can be a disease, disorder or syndrome, typically one that has been clinically diagnosed.
  • Medical conditions addressed by the present invention are accompanied by pain, or have pain as a symptom thereof, and are referred to herein as "painful medical conditions".
  • the pain may be inflammatory or non-inflammatory in nature, or can have both inflammatory and noninflammatory components.
  • Many arthritic conditions, for example, have both noninflammatory and inflammatory pain components.
  • Non-limiting examples of medical conditions and/or types of pain for which the present therapeutic combinations and methods can be useful include those listed immediately below, recognizing that many of the conditions and types of pain listed are overlapping:
  • cancer-related neuropathic pain e.g., painful compression by tumor growth of adjacent nerves, the brain or the spinal cord;
  • hyperalgesia (occurring independently or as a symptom of another condition);
  • migraine including classical migraine and common migraine
  • an “arthritic condition” herein is a musculoskeletal disorder, usually accompanied by pain, of one or more joints of a subject, and includes arthritis associated with or secondary to conditions that are not necessarily primarily arthritic.
  • arthritis associated with or secondary to conditions that are not necessarily primarily arthritic.
  • osteoarthritis which can be idiopathic or primary in origin, or secondary to other conditions; and rheumatoid arthritis, including juvenile rheumatoid arthritis.
  • Other disorders embraced herein as “arthritic conditions” include without limitation psoriatic arthritis, infectious arthritis, ankylosing spondylitis, neurogenic arthropathy and polyarthralgia.
  • Conditions to which arthritis can be secondary include without limitation Sjogren's syndrome, Behget's syndrome, Reiter's syndrome, systemic lupus erythematosus, rheumatic fever, gout, pseudogout, Lyme disease, sarcoidosis and ulcerative colitis.
  • Non-inflammatory osteoarthritic pain is a specific type of non-inflammatory musculoskeletal pain which typically arises from effects of osteoarthritis-related morphological alterations, such as cartilage degradation, bone changes on sensory neurons, and vascularization of bone remodeling. It is distinguished herein from inflammatory osteoarthritic pain, which typically occurs from synovial inflammation following pathological processes in cartilage and bone involving tissue damage and macrophage infiltration (resulting in edema) associated with a classical immune system response.
  • the term "treat,” “treating” or “treatment” herein includes preventive or prophylactic use of a combination, for example a combination of a first agent and second agent as defined herein, in a subject at risk of, or having a prognosis including, a medical condition having noninflammatory pain as a symptom thereof, e.g., an arthritic condition such as osteoarthritis, as well as use of such a combination in a subject already experiencing such a condition, as a therapy to alleviate, relieve, reduce intensity of or eliminate the condition or pain associated therewith or an underlying cause thereof.
  • a medical condition having noninflammatory pain as a symptom thereof e.g., an arthritic condition such as osteoarthritis, as well as use of such a combination in a subject already experiencing such a condition, as a therapy to alleviate, relieve, reduce intensity of or eliminate the condition or pain associated therewith or an underlying cause thereof.
  • subject refers to a warm-blooded animal, generally a mammal such as, for example, a cat, dog, horse, cow, pig, mouse, rat or primate, including a human.
  • subject is a human, for example a patient having a clinically diagnosed arthritic condition.
  • synergism refers to a stronger therapeutic effect of a combination of two or more compounds in comparison with the additive effects of the compounds alone.
  • a therapeutic combination as described herein may have a synergistic effect in the prevention, alleviation or/and treatment of pain associated with or caused by a medical condition as described herein.
  • a therapeutic combination as described herein may also have a synergistic effect in reduction of side effects or/and toxicity if administered in the prevention, alleviation or/and treatment of a medical condition as described herein or pain associated with or caused by a medical condition as described herein.
  • the therapeutic combination of the present invention comprises a first agent comprising a compound of Formula (I) as set forth above, or a pharmaceutically acceptable salt thereof. More than one such compound or salt thereof can optionally be present in the first agent.
  • Terms used in the description of Formula (I) and elsewhere in the present specification unless otherwise indicated, are defined as follows.
  • the term "alkyl,” alone or in combination with another term(s), means a straight- or branched-chain saturated hydrocarbyl substituent typically containing from 1 to about 20 carbon atoms, more typically from 1 to about 8 carbon atoms, and even more typically from 1 to about 6 carbon atoms.
  • lower alkyl refers to an alkyl substituent containing from 1 to 6 carbon atoms, especially 1 to 3 carbon atoms, that may be straight-chain or branched. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like, and isomers thereof.
  • alkenyl alone or in combination with another term(s), means a straight- or branched-chain hydrocarbyl substituent containing one or more double bonds and typically from 2 to about 20 carbon atoms, more typically from 2 to about 8 carbon atoms, and even more typically from 2 to about 6 carbon atoms. Alkenyl groups, where asymmetric, can have cis or trans configuration.
  • lower alkenyl refers to an alkenyl substituent containing from 2 to 6 carbon atoms that may be straight-chained or branched and in the Z or E form. Examples include vinyl, propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z)- 2-pentenyl, (E)-2-pentenyl, (Z)-4-methyl-2-pentenyl, (E)-4-methyl-2-pentenyl, pentadienyl, e.g., 1 , 3 or 2,4-pentadienyl, and the like.
  • alkynyl alone or in combination with another term(s), means a straight- or branched-chain hydrocarbyl substituent containing one or more triple bonds and typically from 2 to about 20 carbon atoms, more typically from 2 to about 8 carbon atoms, and even more typically from 2 to about 6 carbon atoms.
  • lower alkynyl refers to an alkynyl substituent containing 2 to 6 carbon atoms that may be straight-chained or branched. It includes such groups as ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1- pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl and the like.
  • cycloalkyl alone or in combination with another term(s), means a completely or partially saturated alicyclic hydrocarbyl group containing from 3 to about 18 ring carbon atoms. Cycloalkyl groups may be monocyclic or polycyclic.
  • Cycloalkyl includes the cis or trans forms. Cycloalkyl groups may be unsubstituted or mono- or polysubstituted with electron withdrawing or/and electron donating groups as described below. Furthermore, the substituents may either be in endo- or exo-positions in bridged bicyclic systems. "Lower cycloalkyl" groups have 3 to 6 carbon atoms.
  • alkoxy alone or in combination with another term(s), means an alkylether, i.e., -O-alkyl, substituent.
  • lower alkoxy refers to an alkoxy substituent containing from 1 to 6 carbon atoms, especially 1 to 3 carbon atoms, that may be straight-chain or branched. Examples include methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert- butoxy, pentoxy, hexoxy and the like.
  • aryl alone or in combination with another term(s), means an aromatic group which contains from about 6 to about 18 ring carbon atoms, and includes polynuclear aromatics.
  • Aryl groups may be monocyclic or polycyclic, and optionally fused.
  • a polynuclear aromatic group as used herein encompasses bicyclic and tricyclic fused aromatic ring systems containing from about 10 to about 18 ring carbon atoms.
  • Aryl groups include phenyl, polynuclear aromatic groups (e.g., naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like), and groups such as ferrocenyl.
  • Aryl groups may be unsubstituted or mono- or polysubstituted with electron-withdrawing and/or electron-donating groups as described below.
  • Aryl lower alkyl groups include, for example, benzyl, phenylethyl, phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl, 1 ,1-diphenylethyl, 1 ,2-diphenylethyl, and the like.
  • disubstituted amino alone or in combination with another term(s) means an amino substituent wherein one of the hydrogen radicals is replaced by a non-hydrogen substituent.
  • disubstituted amino alone or in combination with another term(s), means an amino substituent wherein both of the hydrogen atoms are replaced by non-hydrogen substituents, which may be identical or different.
  • halo or halogen includes fluoro, chloro, bromo, and iodo.
  • carboxy refers to -CO-O-alkyl, wherein alkyl may be lower alkyl as defined above.
  • haloalkyl means an alkyl substituent wherein at least one hydrogen radical is replaced with a halogen radical.
  • haloalkyl substituents include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 ,1 ,1-trifluoroethyl, and the like.
  • haloalkoxy means an alkoxy substituent wherein at least one hydrogen radical is replaced by a halogen radical.
  • haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), 1 ,1 ,1 ,-trifluoroethoxy, and the like. It should be recognized that if a substituent is substituted with more than one halogen radical, those halogen radicals may be identical or different, unless otherwise stated.
  • acyl includes alkanoyl containing from 1 to about 20 carbon atoms, preferably 1 to 6 carbon atoms, and may be straight-chain or branched.
  • Acyl groups include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, tertiary butyryl, pentanoyl and isomers thereof, and hexanoyl and isomers thereof.
  • electrostatically-withdrawing and “electron-donating” refer to the ability of a substituent to withdraw or donate electrons, respectively, relative to that of hydrogen if a hydrogen atom occupied the same position in the molecule. These terms are well understood by one skilled in the art and are discussed, for example, in March (1985), Advanced Organic Chemistry. New York: John Wiley & Sons, at pp. 16-18, the disclosure of which is incorporated herein by reference.
  • Electron-withdrawing groups include halo (including fluoro, chloro, bromo, and iodo), nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamido, aryl, quaternary ammonium, haloalkyl (such as trifluoromethyl), aryl lower alkanoyl, carbalkoxy, and the like.
  • Electron-donating groups include hydroxy, lower alkoxy (including methoxy, ethoxy, and the like), lower alkyl (including methyl, ethyl, and the like), amino, lower alkylamino, di(lower alkyl)amino, aryloxy (such as phenoxy), mercapto, lower alkylthio, lower alkylmercapto, disulfide (lower alkyldithio), and the like.
  • substituents may be considered to be electron-donating or electron-withdrawing under different chemical conditions.
  • the present invention contemplates any combination of substituents selected from the above- identified groups.
  • heterocyclic means a ring substituent that contains one or more sulfur, nitrogen and/or oxygen ring atoms.
  • Heterocyclic groups include heteroaromatic groups and saturated and partially saturated heterocyclic groups.
  • Heterocyclic groups may be monocyclic, bicyclic, tricyclic or polycyclic and can be fused rings. They typically contain up to 18 ring atoms, including up to 17 ring carbon atoms, and can contain in total up to about 25 carbon atoms, but preferably are 5- to 6- membered rings.
  • Heterocyclic groups also include the so-called benzoheterocyclics.
  • heterocyclic groups include furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl, imadazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl
  • Heterocyclic groups may be unsubstituted or mono- or polysubstituted with electron-withdrawing and/or electron-donating groups.
  • a heterocyclic group is selected from thienyl, furyl, pyrrolyl, benzofuryl, benzothienyl, indolyl, methylpyrrolyl, morpholinyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, and pyridazinyl, especially furyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, and pyridazinyl, more especially furyl and pyridyl.
  • a heterocyclic group is selected from furyl, optionally substituted with at least one lower alkyl group (preferably one having 1-3 carbon atoms, for example methyl), pyrrolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl and thiazolyl, especially furyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl and thiazolyl, more especially furyl, pyridyl, pyrimidinyl and oxazolyl.
  • at least one lower alkyl group preferably one having 1-3 carbon atoms, for example methyl
  • pyrrolyl imidazolyl
  • pyridyl pyrazinyl
  • pyrimidinyl oxazolyl
  • thiazolyl especially furyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl
  • R in the compound of Formula (I) is illustratively aryl lower alkyl, especially benzyl where the phenyl ring thereof is unsubstituted or substituted with one or more electron-donating groups and/or electron-withdrawing groups, such as halo (e.g., fluoro).
  • halo e.g., fluoro
  • R 1 in the compound of Formula (I) is preferably hydrogen or lower alkyl, especially methyl.
  • Particularly suitable electron-withdrawing and/or electron-donating substituents are halo, nitro, alkanoyl, formyl, arylalkanoyl, aryloyl, carboxyl, carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, amino lower alkyl, mercapto, mercaptoalkyl, alkylthio, and alkyldithio.
  • sulfide encompasses mercapto, mercapto alkyl and alkylthio, while the term disulfide encompasses alkylthio.
  • Preferred electron-withdrawing and/or electron-donating groups are halo and lower alkoxy, especially fluoro and methoxy. These preferred substituents may be present in any one or more of the groups R, R 1 , R 2 , R 3 , R4, Rs, RQ, R'e, R 7 or Re as defined herein.
  • Z-Y groups representative of R 2 and/or R 3 include hydroxy, alkoxy (such as methoxy and ethoxy), aryloxy (such as phenoxy), thioalkoxy (such as thiomethoxy and thioethoxy), thioaryloxy (such as thiophenoxy), amino, alkylamino (such as methylamino and ethylamino), arylamino (such as anilino), lower dialkylamino (such as dimethylamino), trialkylammonium salt, hydrazino, alkylhydrazino and arylhydrazino (such as N-methylhydrazino and N-phenylhydrazino), carbalkoxy hydrazino, aralkoxycarbonyl hydrazino, aryloxycarbonyl hydrazino, hydroxylamino (such as N-hydroxylamino (-NHOH)), lower alkoxyamino (NHOR 18 wherein Ri 8
  • Preferred heterocyclic groups representative of R 2 and/or R 3 are monocyclic 5- or 6-membered heterocyclic moieties of the formula
  • n is O or 1 ;
  • R 50 is hydrogen or an electron-withdrawing or electron-donating group;
  • A, E, L, J and G are independently CH, or a heteroatom selected from the group consisting of N, O and S; but when n is O, G is CH, or a heteroatom selected from the group consisting of N, O and S; with the proviso that at most two of A, E, L, J and G are heteroatoms.
  • n O
  • the above monocyclic heterocyclic ring is 5-membered, while if n is 1 , the ring is 6-membered.
  • R 2 or R 3 comprises a heterocyclic group of the above formula, it may be bonded to the main chain by a ring carbon atom.
  • R 2 or R 3 may additionally be bonded to the main chain by a nitrogen ring atom.
  • R 2 and R 3 are hydrogen, aryl (e.g., phenyl), arylalkyl (e.g., benzyl), and alkyl. Such moieties can be unsubstituted or mono- or polysubstituted with electron-withdrawing and/or electron-donating groups.
  • R 2 and R 3 are independently hydrogen; lower alkyl, either unsubstituted or substituted with one or more electron-withdrawing and/or electron-donating groups such as lower alkoxy (e.g., methoxy, ethoxy, and the like); N-hydroxylamino; N-lower alkylhydroxyamino; N-lower alkyl-O-lower alkyl; or alkylhydroxylamino.
  • lower alkoxy e.g., methoxy, ethoxy, and the like
  • N-hydroxylamino N-lower alkylhydroxyamino
  • N-lower alkyl-O-lower alkyl or alkylhydroxylamino.
  • one of R 2 and R 3 is hydrogen.
  • n in Formula (I) is 1 and one of R 2 and R 3 is hydrogen.
  • R 2 is hydrogen and R 3 is lower alkyl or Z-Y where Z is O, NR 4 or PR 4 , and Y is hydrogen or lower alkyl; or Z-Y is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , NR 4 C-R 5 or NR 4 C-OR 5 .
  • n is 1
  • R 2 is hydrogen
  • R 3 is lower alkyl which is unsubstituted or substituted with an electron-withdrawing or electron-donating group, NR 4 OR 5 , or ONR 4 R 7 .
  • n 1 ;
  • R is aryl lower alkyl, which aryl group is unsubstituted or substituted with an electron-withdrawing group, for example aryl can be phenyl, which is unsubstituted or substituted with halo;
  • Ri is lower alkyl;
  • R 2 is hydrogen;
  • R 3 is lower alkyl which is unsubstituted or substituted with hydroxy, lower alkoxy, NR 4 OR 5 or ONR 4 R 7 , wherein R 4 , R 5 and R 7 are independently hydrogen or lower alkyl.
  • R 2 is hydrogen and R 3 is hydrogen, an alkyl group which is unsubstituted or substituted with at least one electron-withdrawing or electron-donating group or Z-Y.
  • R 3 is illustratively hydrogen, an alkyl group such as methyl, which is unsubstituted or substituted with an electron-donating group such as lower alkoxy, more especially methoxy or ethoxy, or with NR 4 OR 5 or ONR 4 R 7 , wherein R 4 , R 5 and R 7 are independently hydrogen or lower alkyl.
  • R 2 and R 3 are independently hydrogen, lower alkyl, or Z-Y; Z is O, NR 4 or PR 4 ; Y is hydrogen or lower alkyl; or Z-Y is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 , NR 4 C-R 5 or NR 4 C-OR 5 .
  • R is aryl lower alkyl.
  • the most preferred aryl for R is phenyl.
  • the most preferred R group is benzyl.
  • the aryl group is unsubstituted or substituted with an electron-withdrawing or electron-donating group. If the aryl ring in R is substituted, it is most preferred that it is substituted with an electron- withdrawing group,
  • the most preferred electron-withdrawing group for R is halo, especially fluoro.
  • the preferred Ri is lower alkyl, especially methyl.
  • R is aryl lower alkyl, e.g., benzyl
  • Ri is lower alkyl, e.g., methyl.
  • R is aryl or aryl lower alkyl, such as benzyl, wherein the aryl group is unsubstituted or substituted with an electron-withdrawing or electron- donating group;
  • Ri is lower alkyl;
  • R 2 is hydrogen; and
  • R 3 is hydrogen, a lower alkyl group, especially methyl which is substituted with an electron-withdrawing or electron-donating group, or Z-Y.
  • R 3 is hydrogen, a lower alkyl group, especially methyl, which may be substituted with an electron-donating group such as lower alkoxy (e.g., methoxy, ethoxy or the like), NR 4 OR 5 or ONR 4 R 7 wherein these groups are as defined hereinabove.
  • an electron-donating group such as lower alkoxy (e.g., methoxy, ethoxy or the like), NR 4 OR 5 or ONR 4 R 7 wherein these groups are as defined hereinabove.
  • the compound is represented by Formula (II)
  • Ar is aryl, especially phenyl, which is unsubstituted or substituted with at least one halo;
  • Ri is lower alkyl, especially C 1--3 alkyl, for example methyl
  • R 3 is hydrogen or lower alkyl, which is unsubstituted or substituted with at least one electron-withdrawing or electron-donating group or Z-Y; for example R 3 is -CH 2 -Q, wherein Q is lower alkoxy, especially Ci_ 3 alkoxy, for example methoxy.
  • the compound has formula (I) wherein n is 1 ;
  • R is unsubstituted or substituted benzyl, in particular halo-substituted benzyl; Ri is lower alkyl, especially Ci_ 3 alkyl, for example methyl; R 2 is hydrogen; and R 3 is as broadly defined herein.
  • the compound is represented by Formula (III)
  • R 4 is one or more substituents independently selected from the group consisting of hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, carboxy, formyl, carboxyamido, aryl, quaternary ammonium, haloalkyl, aryl alkanoyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryloxy, mercapto, alkylthio, alkylmercapto, and disulfide;
  • R 3 is selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, N-alkoxy-N-alkylamino, and N-alkoxyamino; and Ri is alkyl.
  • Alkyl, alkoxy, alkenyl and alkynyl groups in a compound of Formula (III) are lower alkyl, alkoxy, alkenyl and alkynyl groups having no more than 6, more typically no more than 3, carbon atoms.
  • R 4 substituents in a compound of Formula (III) are independently selected from hydrogen and halo, more particularly fluoro, substituents.
  • R 3 in a compound of Formula (III) is alkoxyalkyl, phenyl, N- alkoxy-N-alkylamino or N-alkoxyamino.
  • Ri in a compound of Formula (III) is Ci_ 3 alkyl.
  • R 4 is fluoro and all others are hydrogen
  • R 3 is selected from the group consisting of methoxymethyl, phenyl, N-methoxy-N-methylamino and N-methoxyamino
  • R 1 is methyl.
  • R-i, R 2 , R 3 and R groups and values of n are contemplated to be within the scope of the present invention.
  • the present invention also encompasses therapeutic combinations that comprise a compound having one or more elements of each of the Markush groupings described for R 1 , R 2 , R 3 and R and the various combinations thereof.
  • Ri and R may independently be one or more of the substituents listed hereinabove in combination with any of the R 2 and R 3 substituents, independently with respect to each of the n
  • Compounds useful herein may contain one or more asymmetric carbons and may exist in optically active forms.
  • the configuration around each asymmetric carbon can be either the D or L configuration. Configuration around a chiral carbon atom can also be described as R or S in the Cahn-Prelog-lngold system. All of the various configurations around each asymmetric carbon, including the various enantiomers and diastereomers as well as mixtures of enantiomers, diastereomers or both, including but not limited to racemic mixtures, are contemplated by the present invention.
  • the compounds useful herein can comprise the L- or D-stereoisomer as defined above, or any mixture thereof, including without limitation a racemic mixture.
  • the D-stereoisomer is generally preferred.
  • the D-stereoisomer corresponds to the R-enantiomer according to R 1 S terminology.
  • the compound for example lacosamide, is substantially enantiopure.
  • substantially enantiopure means having at least 88%, preferably at least 90%, more preferably at least 95%, 96%, 97%, 98% or 99% enantiomeric purity.
  • Illustrative compounds that can be used in the present combination include: (R)-2-acetamido-N-benzyl-3-methoxypropionamide (lacosamide); (R)-2-acetamido-N-benzyl-3-ethoxypropionamide; O-methyl-N-acetyl-D-serine-m-fluorobenzylamide; O-methyl-N-acetyl-D-serine-p-fluorobenzylamide; N-acetyl-D-phenylglycinebenzylamide;
  • certain of the present compounds may form salts.
  • compounds of Formulas (I), (II) and (III) can form salts with a wide variety of acids, inorganic and organic, including pharmaceutically acceptable acids.
  • Such salts can have enhanced water solubility and may be particularly useful in preparing pharmaceutical compositions for use in situations where enhanced water solubility is advantageous.
  • salts are those having therapeutic efficacy without unacceptable toxicity.
  • Salts of inorganic acids such as hydrochloric, hydroiodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids as well as salts of organic acids such as tartaric, acetic, citric, malic, benzoic, perchloric, glycolic, gluconic, succinic, arylsulfonic (e.g., p-toluene sulfonic, benzenesulfonic), phosphoric and malonic acids and the like, can be used.
  • inorganic acids such as hydrochloric, hydroiodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids
  • organic acids such as tartaric, acetic, citric, malic, benzoic, perchloric, glycolic, gluconic, succinic, arylsulfonic (e.g., p-toluene sul
  • a compound as described herein is used in a therapeutically effective amount.
  • a physician can determine a suitable dosage of a compound, which can vary with the particular compound chosen, the route and method of administration, and the age and other characteristics of the individual patient.
  • the physician can initiate treatment with small doses, for example substantially less than an optimum dose of the compound, and increase the dose by small increments until an optimum effect under the circumstances is achieved.
  • larger quantities of the compound may be required to produce the same therapeutic benefit as a smaller quantity given parenterally.
  • the compound, for example lacosamide is administered in an amount ranging from about 1 mg to about 10 mg per kilogram of body weight per day.
  • a patient can be treated with the compound, for example lacosamide, at a dose of at least about 50 mg/day, for example at least about 100 mg/day, at least about 200 mg/day, at least about 300 mg/day or at least about 400 mg/day.
  • a suitable dose is not greater than about 6 g/day, for example not greater than about 1 g/day or not greater than about 600 mg/day. In some cases, however, higher or lower doses may be needed.
  • the daily dose is increased until a predetermined daily dose is reached which is maintained during further treatment.
  • several divided doses are administered daily. For example, no more than three doses per day, or no more than two doses per day, may be administered. However, it is often most convenient to administer no more than a single dose per day.
  • Doses expressed herein on a daily basis are not to be interpreted as requiring a once-a-day frequency of administration.
  • a dose of 300 mg/day can be given as 100 mg three times a day, or as 600 mg every second day.
  • an amount of the compound for example lacosamide, is administered which results in a plasma concentration of the compound of about 0.1 to about 15 ⁇ g/ml (trough) and about 5 to about 18.5 ⁇ g/ml (peak), calculated as an average over a plurality of treated subjects.
  • the compound of Formulas (I), (II) or (III), for example lacosamide can be administered in any convenient and effective manner, such as by oral, intravenous, intraperitoneal, intramuscular, intrathecal, subcutaneous or transmucosal (e.g., buccal) routes. Oral or intravenous administration is generally preferred.
  • the compound is typically administered as a component of an orally deliverable pharmaceutical composition that further comprises an inert diluent or an assimilable edible carrier, or it may be incorporated into the subject's food.
  • an orally deliverable pharmaceutical composition the compound can be incorporated together with one or more excipients and administered in the form of tablets, troches, pills, capsules, elixirs, suspensions, syrups, wafers, or the like.
  • Such compositions typically contain at least about 1%, more typically about 5% to about 80%, by weight of the compound, for example lacosamide.
  • the amount of the compound in the composition is such that, upon administration of the composition, a suitable dosage as set forth above can conveniently be provided.
  • a pharmaceutical composition useful for oral delivery of a compound of Formulas (I), (II) or (III), for example lacosamide contains about 10 mg to about 6 g, for example about 50 to about 1000 mg, or about 100 to about 600 mg, of the compound.
  • the composition is enclosed in hard or soft shell (e.g., gelatin) capsules, or is in a form of compressed or molded tablets.
  • the composition illustratively comprises as excipients one or more of a diluent such as lactose or dicalcium phosphate (in the case of capsules a liquid carrier can be present); a binding agent such as gum tragacanth, acacia, corn starch or gelatin; a disintegrating agent such as corn starch, potato starch, alginic acid or the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose or saccharin and/or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring can be added if desired.
  • a diluent such as lactose or dicalcium phosphate (in the case of capsules a liquid carrier can be present)
  • a binding agent such as gum tragacanth, acacia, corn
  • excipients may be present as coatings or otherwise modifying the physical form of the composition.
  • tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl- and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor.
  • the active compound can be incorporated into a sustained-release formulation.
  • sustained-release dosage forms are contemplated wherein the compound is bound to an ion exchange resin which, optionally, can be coated with a diffusion barrier coating to modify the release properties of the resin.
  • compositions suitable for injectable use include sterile aqueous solutions (where the compound is water soluble), dispersions, and sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions.
  • the injectable composition must be sterile and must be sufficiently fluid to permit easy syringeability.
  • the composition must be stable under the conditions of manufacture and storage and must typically be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, or the like), suitable mixtures thereof, and vegetable oils.
  • Proper fluidity can be maintained, for example, by use of a coating such as lecithin, by maintenance of a required particle size in the case of dispersions, and by use of surfactants.
  • Microbial action can be inhibited by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, or the like.
  • tonicity agents for example, sugars or sodium chloride
  • Prolonged absorption of injectable compositions can be brought about by use in the compositions of agents delaying absorption, for example aluminum monostearate or gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in a required amount in an appropriate solvent with various of the other ingredients mentioned above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating sterilized active compound into a sterile vehicle which contains the dispersion medium and other excipient ingredients such as those mentioned above.
  • Sterile powders for preparation of sterile injectable solutions can be prepared by vacuum-drying or freeze-drying a previously sterile-filtered solution or dispersion.
  • the therapeutic combination of the invention comprises, in addition to the first agent as described above, a second agent effective in combination therewith to (a) provide enhanced treatment of pain associated with or caused by a medical condition, by comparison with first agent alone; and/or (b) treat another symptom or an underlying cause of the medical condition; the second agent comprising one or more drugs other than a compound of Formula (I).
  • the second agent comprises an anti-arthritis drug other than a compound of Formula (I), and the combination is useful for treating an arthritic condition and/or pain related thereto. More than one anti-arthritis drug can optionally be present in the second agent.
  • an "anti-arthritis drug” is a drug having effectiveness in treatment (including prevention) of any aspect, symptom (e.g., pain or inflammation) and/or an underlying cause of an arthritic condition as defined herein.
  • an anti-arthritis drug included in or as the second agent can be effective for treatment of pain, i.e., analgesia.
  • Suitable analgesics include opioid and non-opioid analgesics as well as certain anti-inflammatory drugs (see immediately below).
  • a combination comprising a compound of Formulas (I), (II) or (III), for example lacosamide, and an opioid or non-opioid analgesic can be useful in any arthritic condition accompanied by pain, in particular where such pain has a non-inflammatory component as in osteoarthritis.
  • an anti-arthritis drug included in or as the second agent can be effective for treatment of inflammation and/or pain related thereto.
  • Suitable anti-inflammatories include steroidal and nonsteroidal anti-inflammatory drugs.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) include traditional NSAIDs and cyclooxygenase-2 (COX-2) selective inhibitors.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • COX-2 cyclooxygenase-2
  • a combination comprising a compound of Formulas (I), (II) or (III), for example lacosamide, and an antiinflammatory can be useful in any arthritic condition accompanied by inflammatory pain or where both inflammatory and non-inflammatory types of pain are present.
  • Nonlimiting examples of opioid and non-opioid analgesics that can be useful in the second agent include acetaminophen, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, dipyrone (metamizol), eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone,
  • Nonlimiting examples of steroidal anti-inflammatories that can be useful in the second agent include alclometasone, amcinonide, betamethasone, betamethasone 17-valerate, clobetasol, clobetasol propionate, clocortolone, cortisone, dehydrotestosterone, deoxycorticosterone, desonide, desoximetasone, dexamethasone, dexamethasone 21-isonicotinate, diflorasone, fluocinonide, fluocinolone, fluorometholone, flurandrenolide, fluticasone, halcinonide, halobetasol, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone hemisuccinate, hydrocortisone 21-lysinate, hydrocortisone sodium succinate, isoflupredone, isoflupredone acetate,
  • Nonlimiting examples of NSAIDs that can be useful in the second agent include salicylic acid derivatives (such as salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, olsalazine, salsalate and sulfasalazine), indole and indene acetic acids (such as indomethacin, etodolac and sulindac), fenamates (such as etofenamic, meclofenamic, mefenamic, flufenamic, niflumic and tolfenamic acids), heteroaryl acetic acids (such as acemetacin, alclofenac, clidanac, diclofenac, fenchlofenac, fentiazac, furofenac, ibufenac, isoxepac, ketorolac, oxipinac, tiopinac, tolmetin, zidomet
  • Nonlimiting examples of COX-2 selective inhibitors that can be useful in the second agent include celecoxib, deracoxib, valdecoxib, parecoxib, rofecoxib, etoricoxib, lumiracoxib, PAC-10549, cimicoxib, GW-406381 , LAS-34475, CS-502, pharmaceutically acceptable salts thereof, and combinations thereof.
  • the second agent can illustratively comprise a disease- modifying osteoarthritis drug (DMOAD).
  • DMOADs disease- modifying osteoarthritis drug
  • Nonlimiting examples of DMOADs that can be useful in the second agent include methotrexate, diacerein, glucosamine, chondroitin sulfate, anakinra, MMP inhibitors, doxycycline, minocycline, misoprostol, proton pump inhibitors, non-acetylated salicylates, tamoxifen, prednisone, methylprednisolone, polysulfated glycosaminoglycan, calcitonin, alendronate, risedronate, zoledronic acid, teriparatide, VX-765, pralnacasan, SB- 462795, CPA-926, ONO-4817, S-3536, PG-530742, CP-544439, pharmaceutically acceptable salts thereof, and
  • the second agent can illustratively comprise a disease- modifying anti-rheumatic drug (DMARD).
  • DMARDs disease- modifying anti-rheumatic drug
  • Nonlimiting examples of DMARDs that can be useful in the second agent include etanercept, adalimumab, infliximab, IL-1 receptor antagonists, glucocorticoids such as prednisone and methylprednisolone, penicillamine, hydroxychloroquine sulfate, chlorambucil, cyclosphosphamide, leflunomide, cyclosporine, auranofin, aurothioglucose, azathioprine, gold sodium thiomalate, methotrexate, cyclophosphamide, minocycline, sulfasalazine, abatacept, rituximab, bucillamine, chloroquine, hydroxychloroquine, lob
  • the second agent can illustratively comprise a symptom-modifying anti-arthritis drug, not mentioned above.
  • a symptom-modifying anti-arthritis drug not mentioned above.
  • Nonlimiting examples of such drugs that can be useful in the second agent include ADL-100116, AD- 827, HOE-140, DA-5018, pharmaceutically acceptable salts thereof, and combinations thereof.
  • More than one anti-arthritis drug can be administered in combination or adjunctive therapy with a compound of Formulas (I), (II) or (III), for example lacosamide.
  • a compound of Formulas (I), (II) or (III), for example lacosamide can be included in the combination or adjunctive therapy, selected from two or more of the following classes: (i) opioid and non-opioid analgesics;
  • the two or more agents administered in combination or adjunctive therapy with a compound of Formulas (I), (II) or (III), for example lacosamide are selected from the above listed agents wherein at least one of the agents is a DMOAD or a DMARD.
  • administering is useful for treating both an arthritic condition and pain related thereto.
  • a compound of Formulas (I), (II) or (III), for example lacosamide may be used to treat pain, more particularly non-inflammatory pain, associated with an arthritic condition and at least one anti-arthritis drug, such as those listed above, may be used in combination with the compound of Formulas (I), (II) or (III) to treat an underlying process causing or contributing to the arthritic condition, or to treat another symptom, for example inflammatory pain, of the arthritic condition.
  • the second agent is present in an amount effective, in combination with the first agent, to provide enhanced treatment of pain, more particularly non-inflammatory pain, by comparison with the first agent alone.
  • Any drug that, in combination with the first agent, provides such enhanced treatment can be used as or included in the second agent, for example an opioid or non- opioid analgesic, an anticonvulsant, an antidepressant and/or an NMDA receptor antagonist.
  • first and second agent interact more than additively, but in some cases the reduction of intensity and/or duration of pain provided by the combination can be greater than would be expected based on the effectiveness of either agent alone at the same dose.
  • the second agent can comprise one or more analgesics, for example selected from those listed above.
  • the second agent comprises morphine or a pharmaceutically acceptable salt thereof.
  • the second agent can comprise one or more anticonvulsants, for example selected from acetylpheneturide, albutoin, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethadione, doxenitoin, eterobarb, ethadione, ethosuximide, ethotoin, felbamate, fluoresone, fosphenytoin, gabapentin, ganaxolone, lamotrigine, levetiracetam, lorazepam, mephenytoin, mephobarbital, metharbital, methetoin, methsuximide, midazolam, narcobarbital, nitrazepam, oxcarbazepine
  • the second agent comprises one or more anticonvulsants selected from carbamazepine, phenytoin, gabapentin, pregabalin, lamotrigine, levetiracetam and pharmaceutically acceptable salts thereof.
  • the second agent comprises gabapentin.
  • the second agent can comprise one or more antidepressants, including without limitation bicyclic, tricyclic and tetracyclic antidepressants, hydrazides, hydrazines, phenyloxazolidinones and pyrrolidones.
  • An antidepressant can for example be selected from adinazolam, adrafinil, amineptine, amitriptyline, amitriptylinoxide, amoxapine, befloxatone, bupropion, butacetin, butriptyline, caroxazone, citalopram, clomipramine, cotinine, demexiptiline, desipramine, dibenzepin, dimetacrine, dimethazan, dioxadrol, dothiepin, doxepin, duloxetine, etoperidone, femoxetine, fencamine, fenpentadiol, fluacizine, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, imipramine, imipramine N-oxide, indalpine, indeloxazine, iprindole, iproclozide, iproniazid, iso
  • the second agent can comprise one or more NMDA receptor antagonists, for example selected from amantadine, D-AP5, aptiganel, CPP, dexanabinol, dextromethorphan, dextropropoxyphene, 5,7-dichlorokynurenic acid, gavestinel, ifendopril, ketamine, ketobemidone, licostinel, LY-235959, memantine, methadone, MK-801 , phencyclidine, remacemide, selfotel, tiletamine, pharmaceutically acceptable salts thereof, and combinations thereof.
  • the second agent comprises memantine.
  • the second agent comprises one or more drugs independently selected from the group consisting of GABA analogues, thiophene propane derivatives, morphine analogues and opioids, the 2-arylpropionic acid (profen) family of NSAIDs, and amantadine (1-aminoadamantane) derivatives.
  • drugs independently selected from the group consisting of GABA analogues, thiophene propane derivatives, morphine analogues and opioids, the 2-arylpropionic acid (profen) family of NSAIDs, and amantadine (1-aminoadamantane) derivatives.
  • GABA analogue An example of a GABA analogue is gabapentin.
  • An example of a thiophene propan derivative is duloxetin.
  • An example of opioids is morphine.
  • a member of the 2-arylpropionic acid family of NSAIDs is naproxen.
  • the second agent comprises one or more drugs independently selected from the group consisting of gabapentin, duloxetine, morphine, naxproxen, and memantine.
  • the second agent comprises one or more drugs independently selected from the group consisting of duloxetine, morphine, naxproxen, and memantine.
  • the first agent comprises lacosamide.
  • the first agent comprises lacosamide
  • the second agent comprises gabapentin
  • the first agent comprises lacosamide
  • the second agent comprises duloxetine
  • the first agent comprises lacosamide
  • the second agent comprises morphine
  • the first agent comprises lacosamide
  • the second agent comprises naxproxen
  • the first agent comprises lacosamide
  • the second agent comprises memantine
  • the combination of the present invention provides enhanced treatment of pain associated with or caused by a medical condition, wherein the medical condition is accompanied by or has, as a symptom thereof, non-inflammatory pain.
  • the combination of the present invention provides enhanced treatment of pain, wherein the pain related to the medical condition comprises non-inflammatory pain.
  • the combination of the present invention provides enhanced treatment of pain associated with or caused by a medical condition, wherein the medical condition is an arthritic condition and/or pain related thereto.
  • the arthritic condition may comprise osteoarthritis.
  • the first agent and the second agent may be present in absolute and relative amounts effective to treat an arthritic condition and/or pain related thereto.
  • the first agent and the second agent may be present in absolute and relative amounts effective to treat both noninflammatory and inflammatory components of pain associated with or caused by the arthritic condition.
  • the first and the second agent may be present in absolute and relative amounts effective to treat non-inflammatory pain related to an arthritic condition.
  • the first and the second agent may be present in absolute and relative amounts effective to treat non inflammatory osteoarthritic pain.
  • the first and the second agent may be present in absolute and relative amounts effective to treat inflammatory pain related to an arthritic condition.
  • the first agent and the second agent may be present in absolute and relative amounts effective to treat inflammatory osteoarthritic pain.
  • Osteoarthritic pain may be associated with cartilage degradation, structural bone changes, and or vascularization of areas of osteoarthritic remodeling.
  • the arthritic condition may comprise one or more disorders selected from the group consisting of idiopathic osteoarthritis, secondary osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, infectious arthritis, ankylosing spondylitis, neurogenic arthropathy, polyarthralgia, and arthritis associated with Sjogren's syndrome, Behcet's syndrome, Reiter's syndrome, systemic lupus erythematosus, rheumatic fever, gout, pseudogout, Lyme disease, sarcoidosis and ulcerative colitis.
  • disorders selected from the group consisting of idiopathic osteoarthritis, secondary osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, infectious arthritis, ankylosing spondylitis, neurogenic arthropathy, polyarthralgia, and arthritis associated with Sjogren's syndrome, Beh
  • the arthritic condition may comprise rheumatoid arthritis or juvenile rheumatoid arthritis.
  • the combination of the present invention provides enhanced treatment of pain associated with or caused by a medical condition, wherein the medical condition is pain in painful diabetic neuropathy.
  • the painful diabetic neuropathy may be diabetic distal sensory polyneuropathy.
  • the first and the second agent may be effective for treatment of an aspect of pain selected from the group consisting of average daily pain, overall pain, present pain intensity, pain interference with sleep, the subjects' perception of pain interference with general activity, the patients' global impression of change in pain, clinical global impression of change in pain, the subject's perception of different neuropathic pain qualities, quality of life and proportion of pain-free days.
  • the painful diabetic neuropathy may be associated with Diabetes mellitus Type I or Type II.
  • the painful diabetic neuropathy may also be associated with Diabetes mellitus Type II.
  • the combination of the present invention provides enhanced treatment of pain associated with or caused by a medical condition, wherein the medical condition or pain related thereto is selected from the group consisting of acute inflammatory pain; acute pain; alcoholism-associated or alcoholism-induced neuropathic pain; allodynia; arthritic conditions; back pain; cancer-related neuropathic pain; central neuropathic pain; chronic headache; chronic inflammatory pain; chronic pain; chronic pain due to peripheral nerve injury; diabetes-associated or diabetes-induced neuropathic pain; diabetic distal sensory neuropathy; diabetic distal sensory polyneuropathy; diabetic pain; fibromyalgia; headache; hyperalgesia; hyperesthesia; hyperpathia; migraine; myalgia; myofascial pain syndrome; neuralgia; neuroma; noninflammatory osteoarthritic pain; non-neuropathic inflammatory pain; neuropathic pain; pain associated with or induced by chemotherapy or radiation therapy; pain associated with or induced by traumatic nerve injury or compression or
  • the second agent may be present in an amount effective, in combination with the first agent, to provide enhanced treatment of pain by comparison with the first agent alone.
  • Yet another aspect of the present invention is a method for treating a painful medical condition and/or pain related thereto in a subject, the method comprising administering to the subject the therapeutic combination of the present invention.
  • the painful medical condition or/and pain related thereto is selected from the conditions as described herein.
  • the medical condition or pain related thereto is selected from the group consisting of acute inflammatory pain; acute pain; alcoholism-associated or alcoholism-induced neuropathic pain; allodynia; arthritic conditions; back pain; cancer-related neuropathic pain; central neuropathic pain; chronic headache; chronic inflammatory pain; chronic pain; chronic pain due to peripheral nerve injury; diabetes-associated or diabetes-induced neuropathic pain; diabetic distal sensory neuropathy; diabetic distal sensory polyneuropathy; diabetic pain; fibromyalgia; headache; hyperalgesia; hyperesthesia; hyperpathia; migraine; myalgia; myofascial pain syndrome; neuralgia; neuroma; noninflammatory osteoarthritic pain; non-neuropathic inflammatory pain; neuropathic pain; pain associated with or induced by chemotherapy or radiation therapy; pain associated with or induced by traumatic nerve injury or compression or by traumatic injury to the brain or spinal cord; painful diabetic neuropathy; peripheral neuropathic pain;
  • the method of the present invention employs in said combination a first agent comprising lacosamide.
  • Yet another aspect of the present invention is the use of a combination as defined herein for the preparation of a medicament for the enhanced prevention, alleviation or/and treatment of pain associated with or caused by a medical condition, by comparison with the compound of Formula (I) alone; said second agent comprising one or more drugs other than a compound of Formula (I).
  • the painful medical condition or/and pain related thereto is selected from the conditions as described herein.
  • the first agent comprises lacosamide.
  • Suitable regimens including doses and routes of administration for particular drugs useful in or as the second agent can be determined from readily-available reference sources relating to these drugs, for example Physicians' Desk Reference (PDR), 60th edition, Montvale, NJ: Thomson (2006) and various internet sources known to those of skill in the art.
  • PDR Physicians' Desk Reference
  • a drug useful in or as the second agent can be used at a full dose, but the physician may elect to administer less than a full dose of such a drug, at least initially.
  • the first agent and second agent can be provided in one pharmaceutical preparation (single dosage form) for administration to the subject at the same time, or in two or more distinct preparations (separate dosage forms) for administration to the subject at the same or different times, e.g., sequentially, and/or at the same or different frequencies.
  • the two distinct preparations can be provided in forms adapted for administration by the same route or by different routes.
  • kits comprising, in a first container, a compound of Formulas (I), (II) or (III), for example lacosamide, and, in a second container, a second agent as described herein.
  • a compound of Formulas (I), (II) or (III), for example lacosamide, and a second agent are separately packaged and available for sale independently of one another, but are co-marketed or co-promoted for use according to the invention.
  • the separate dosage forms may also be presented to a subject separately and independently, for use according to the invention.
  • the compound of Formulas (I), (II) or (III), for example lacosamide, and the second agent may be administered on the same or on different schedules, for example on a daily, weekly or monthly basis.
  • administration of the therapeutic combination is useful for treating non-inflammatory osteoarthritic pain.
  • such administration is useful when non-inflammatory osteoarthritic pain is associated with cartilage degradation, structural bone changes, and/or vascularization of areas of bone remodeling. Bone continually undergoes remodeling. Remodeling is a process in which old bone is replaced with new bone to maintain peak bone density. Vascularization occurs by the proliferation of capillaries during the remodeling process and can be increased in conditions such as osteoarthritis.
  • administration of the therapeutic combination inhibits transmission of pain.
  • Inhibition of transmission of pain typically a contributory effect of the compound of Formulas (I), (II) or (III), for example lacosamide, may be accomplished by preventing spinal neurons from responding to neurotransmitters, such as glutamate, released by nociceptors.
  • neurotransmitters such as glutamate
  • This example describes a study demonstrating antinociceptive effectiveness of lacosamide in inhibiting mechanical hyperalgesia, as measured by paw withdrawal threshold to muscle pressure, and mechanical allodynia, as measured by biceps muscle grip strength, occurring in musculoskeletal pain induced by TNF in rats.
  • the model used in this example is applicable to musculoskeletal pain which occurs in fibromyalgia, myofascial pain syndrome, back pain or osteoarthritis.
  • the non-opioid analgesic dipyrone (metamizol) and the anticonvulsants pregabalin and gabapentin were included in the study.
  • TNF Recombinant rat tumor necrosis factor alpha
  • R&D Systems Recombinant rat tumor necrosis factor alpha
  • TNF was obtained from R&D Systems, Minneapolis, MN, U.S.A.
  • TNF was diluted in 0.9% NaCI and used in a concentration of 1 ⁇ g in 50 ⁇ l.
  • Injections were performed in short halothane narcosis with a 30 g needle bilaterally into the gastrocnemius or into the biceps brachii muscle. All rats were used to the behavioral tests before injections and baseline values were recorded over three test days.
  • Rats were injected with TNF into the gastrocnemius muscle at 2 pm. Eighteen hours later, rats were tested for pressure hyperalgesia pre- and post- administration of the test drug. Rats were tested for pressure hyperalgesia 30 to 60 minutes after drug administration.
  • Rats were injected with TNF into the biceps brachii muscle at 8 am. Six hours later, grip strength of the forelimbs was tested with a digital grip force meter. Test drug was administered, and grip strength was again tested after 30 to 60 minutes.
  • the rats initially 10 per group, were treated with either 3, 10 or 30 mg/kg lacosamide, 2 mg/kg metamizol, 30 or 100 mg/kg pregabalin, 100 mg/kg gabapentin, or the NaCI vehicle, i.p. (intraperitoneal ⁇ ). Volume of i.p. injections was 0.5 ml. A pilot study was performed to confirm that i.m. (intramuscular) injection of 1 ⁇ g TNF into the gastrocnemius muscle was sufficient to induce pressure hyperalgesia.
  • Fig. 1 shows absolute values of withdrawal thresholds to pressure.
  • the MPE (Fig. 2) was significantly different from vehicle for lacosamide at 10 and 30 mg/kg, for pregabalin at 30 and 100 mg/kg, for gabapentin at 100 mg/kg, and for metamizol at 2 mg/kg. The vehicle had no effect.
  • Fig. 3 shows absolute values of grip strength.
  • the MPE (Fig. 4) was significantly different from vehicle for lacosamide at 10 and 30 mg/kg, for pregabalin at 100 mg/kg, for gabapentin at 100 mg/kg, and for metamizol at 2 mg/kg.
  • the vehicle had no effect.
  • lacosamide had a stronger effect on muscle pain.
  • pregabalin nor gabapentin led to a full reversal of the muscle hyperalgesia.
  • lacosamide reversed the effect of TNF on the muscle at 10 mg/kg. Again lacosamide was more potent than pregabalin and gabapentin, which improved grip strength at 100 mg/kg.
  • lacosamide was effective in reducing the muscular hyperalgesia and mechanical allodynia induced by TNF injected into muscle.
  • lacosamide illustratively of compounds of Formulas (I), (II) and (III), is concluded to have therapeutic efficacy in the treatment, in particular systemic treatment, of specific manifestations of non-inflammatory musculoskeletal pain, such as muscular hyperalgesia and allodynia, occurring for example in fibromyalgia, myofascial pain syndrome, back pain or osteoarthritis.
  • This example describes a study demonstrating antinociceptive effectiveness of lacosamide in an iodoacetate rat model.
  • the model used in this example is applicable to non-inflammatory osteoarthritic pain.
  • the opioid analgesic morphine and the NSAID diclofenac was included in the study.
  • One of the best characterized rat models for osteoarthritis is injection of the metabolic inhibitor monosodium iodoacetate into a joint, for example a knee joint, which inhibits activity of glyceraldehyde-3-phosphate dehydrogenase in chondrocytes, resulting in disruption of glycolysis and eventually in cell death (Guzman et al. (2003) Toxicol. Pathol. 31 (6):619-624; Kalbhen (1987) J, Rheumatol. 14(Spec. No.):130-131).
  • the progressive loss of chondrocytes results in histological and morphological changes of the articular cartilage, closely resembling those seen in human osteoarthritis patients.
  • mice Male Wistar rats (Janview, France) weighing 170-200 g at the start of the study were used. The animals were group-housed (3 animals per cage) in a room with controlled temperature (21-22 0 C), and a reversed light-dark cycle (12 h/12 h), and had free access to food and water.
  • Osteoarthritis was induced by intra-articular injection in 50 ⁇ l of 3 mg monosodium iodoacetate (MIA) (Sigma) through the intrapatellar ligament of the right knee. Control rats were injected with an equivalent volume of saline. Up to five days after the iodoacetate injection a substantial inflammation of synovial joints was observed in this model. The general health of the animals was monitored. No signs of distress were seen.
  • MIA monosodium iodoacetate
  • Diclofenac (30 mg/kg, s.c.) was tested in a separate experiment by the same scientists under the same conditions at about the same time.
  • the non- iodoacetate treated control group received p.o. injection of saline 45 minutes prior to the pain assessment.
  • Lacosamide, diclofenac and morphine were injected 60 minutes prior to implementation of behavioral tests. Each group was examined blind. Evaluation of tactile allodynia and mechanical hyperalgesia
  • nociceptive flexion reflexes were quantified using the Randall-Selitto paw pressure device (Bioseb, France), which applied a linearly increasing mechanical force to the dorsum of the rat's hind paw.
  • the paw withdrawal threshold was defined as the force at which the rat withdrew its paw.
  • the cutoff pressure was set to 250 g.
  • Lacosamide (Schwarz BioSciences GmbH) and morphine sulfate (Francopia, France) were dissolved in saline. Monosodium iodoacetate and diclofenac were purchased from Sigma (France). Drug administration was made in a volume of 1 ml/kg.
  • Tactile allodynia tested with von Frey filaments, was assessed at day 3, 7, and 14 in iodoacetate-treated rats compared to control rats.
  • Treatment with lacosamide (30 mg/kg) and morphine (3 mg/kg) improved tactile allodynia of iodoacetate- treated rats at day 3 (Fig. 5A) and 7 (Fig. 5B) but not on day 14 (Fig. 5C), and lower doses of lacosamide showed a trend for such improvement.
  • Diclofenac (30 mg/kg) had no effect on tactile allodynia at day 3 (Fig. 6A), day 7 (Fig. 6B) or day 14 (Fig. 6C).
  • Rats were given an intraplantar injection of 5% formalin (50 ⁇ l) into the posterior left paw. This treatment induces a recognizable flinching and licking response of the affected paw in control animals. The number of flinches was counted for 15 minutes, beginning 20 minutes after injection of formalin. The time spent licking the affected paw was also recorded.
  • Lacosamide (20 mg/kg), gabapentin (50 and 100 mg/kg), combinations of lacosamide (20 mg/kg) with gabapentin (50 and 100 mg/kg), and vehicle were administered i.p. 10 minutes before injection of formalin.
  • the effects of lacosamide combined with gabapentin on the number of flinches and the time spent licking were significantly more marked than the effects of lacosamide alone (p ⁇ 0.05 or p ⁇ 0.01 ).
  • Test methods were similar to those of Example 3.
  • Lacosamide (10 and 20 mg/kg), morphine (2 and 4 mg/kg), combinations of lacosamide (10 and 20 mg/kg) with morphine (2 and 4 mg/kg), and vehicle were administered i.p. 10 minutes before injection of formalin.
  • Lacosamide 20 mg/kg combined with morphine 2 and 4 mg/kg clearly and dose- dependently decreased the number of flinches by 70% (p ⁇ 0.01) and 87% (p ⁇ 0.001) respectively, as compared with vehicle controls.
  • the combination clearly and dose-dependently decreased the time spent licking by 69% and 94%, respectively (p ⁇ 0.001).
  • the effects of lacosamide 20 mg/kg combined with morphine on the number of flinches and the time spent licking were significantly more marked than the effects of lacosamide alone at the same dose (p ⁇ 0.05 or p ⁇ 0.01 ), except for the time spent licking at the 2 mg/kg dose of morphine.
  • Test methods were similar to those of Example 3.
  • Lacosamide (10 mg/kg), duloxetine (8 mg/kg), a combination of lacosamide (10 mg/kg) with duloxetine (8 mg/kg), and vehicle were administered i.p. 10 minutes before injection of formalin.
  • Lacosamide 10 mg/kg alone had no significant effects although it tended to decrease the time spent licking (30% decrease, p 0.0538).
  • Test methods were similar to those of Example 3.
  • Lacosamide (10 and 20 mg/kg), memantine (4 and 8 mg/kg), combinations of lacosamide (10 and 20 mg/kg) with memantine (4 and 8 mg/kg), and vehicle were administered i.p. 10 minutes before injection of formalin.
  • Memantine alone at 4 and 8 mg/kg did not clearly affect the number of flinches, as compared with vehicle controls. Memantine dose-dependently increased the time spent licking (25% increase, p 0.0537 and 35% increase, p ⁇ 0.05).
  • the effects of lacosamide combined with memantine on the number of flinches and the time spent licking were not different from the effects of lacosamide alone.
  • Lacosamide at 20 mg/kg combined with memantine at 4 and 8 mg/kg clearly decreased the number of flinches, as compared with vehicle controls, by 74% and 64% respectively (p ⁇ 0.001 ).
  • the combination clearly decreased the time spent licking, although in a manner inversely related to the dose of memantine (69% decrease, p ⁇ 0.001 and 49% decrease, p ⁇ 0.05, respectively).
  • the effects of lacosamide combined with memantine at 4 mg/kg on the number of flinches but not on the time spent licking were significantly more marked than the effects of lacosamide alone (p ⁇ 0.05).
  • Test methods were similar to those of Example 3.
  • Lacosamide (10 and 20 mg/kg), naproxen (8 and 16 mg/kg), combinations of lacosamide (10 and 20 mg/kg) with memantine (8 and 16 mg/kg), and vehicle were administered i.p. 10 minutes before injection of formalin.
  • Morphine (8 mg/kg) was included as a comparative treatment.
  • Lacosamide alone at 10 and 20 mg/kg did not clearly affect the number of flinches, as compared with vehicle controls. It clearly decreased the time spent licking at 20 mg/kg, by 59% (p ⁇ 0.001 ), but had no clear effects at 10 mg/kg.
  • Naproxen alone at 8 and 16 mg/kg did not clearly affect the number of flinches or the time spent licking, as compared with vehicle controls.
  • Lacosamide 10 mg/kg combined with naproxen 8 and 16 mg/kg did not clearly affect the number of flinches, as compared with vehicle controls.
  • Lacosamide 10 mg/kg combined with naproxen at 16 but not at 8 mg/kg significantly decreased the time spent licking, by 38% (p ⁇ 0.05).
  • the effects of lacosamide 10 mg/kg combined with naproxen on the number of flinches and the time spent licking were not different from the effects of lacosamide alone.
  • Lacosamide 20 mg/kg combined with naproxen 8 and 16 mg/kg did not clearly affect the number of flinches, as compared with vehicle controls.
  • Lacosamide 20 mg/kg combined with naproxen at 16 but not 8 mg/kg significantly decreased the time spent licking, by 53% (p ⁇ 0.01 ).
  • the effects of lacosamide 20 mg/kg combined with naproxen on the number of flinches and the time spent licking were not different from the effects of lacosamide alone.
  • Examples 3 to 7 demonstrate synergistic effects between lacosamide and a compound selected from gabapentin, duloxetine, morphine, naproxen and memantine. All patents and publications cited herein are incorporated by reference into this application in their entirety.
  • Item 1 A therapeutic combination comprising a first agent that comprises a compound of Formula (I)
  • R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl or lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group, and/or at least one electron donating group;
  • Ri is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, lower alkyl heterocyclic, heterocyclic, lower cycloalkyl, or lower cycloalkyl lower alkyl, and is unsubstituted or substituted with at least one electron-withdrawing group and/or at least one electron- donating group;
  • R 2 and R 3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, or Z-Y, wherein R 2 and R 3 are each independently unsubstituted or substituted with at least one electron-withdrawing group and/or at least one electron-donating group;
  • Z is O, S, S(O) 3 , NR 4 , NR' 6) PR 4 or a chemical bond;
  • Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, or lower alkyl heterocyclic, and is unsubstituted or substituted with at least one electron-withdrawing group and/or at least one electron-donating group, provided that when Y is halo, Z is a chemical bond, or
  • Z-Y taken together is NR4NR5R7, NR 4 OR 5 , ONR 4 R 7 , OPR 4 R 5 , PR 4 OR 5 , SNR 4 R 7 , NR 4 SR 7 , SPR 4 R 5 , PR 4 SR 7 , NR 4 PR 5 R 6 , PR4NR5R7, N + R 5 R 6 R 7 ,
  • R' 6 is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl, and is unsubstituted or substituted with at least one electron-withdrawing group or/and at least one electron-donating group;
  • R 4 , R 5 and R 6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, and are each independently unsubstituted or substituted with at least one electron-withdrawing group or/and at least one electron-donating group;
  • R 7 is R 6 , COOR 8 , or COR 8 , and is unsubstituted or substituted with at least one electron-withdrawing group or/and at least one electron-donating group;
  • R 8 is hydrogen, lower alkyl, or aryl lower alkyl, and is unsubstituted or substituted with at least one electron-withdrawing group or/and at least one electron-donating group;
  • n 1-4;
  • a 1-3;
  • a second agent effective in combination therewith to (a) provide enhanced treatment of pain associated with or caused by a medical condition, by comparison with the compound of Formula (I) alone; and/or (b) treat another symptom or an underlying cause of the medical condition; said second agent comprising one or more drugs other than a compound of Formula (I).
  • Item 2 The combination of Item 1 , wherein, in the compound of Formula (I) present in the first agent, one or both of R2 and R 3 are heterocycles independently selected from the group consisting of furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl, furazanyl, N
  • Item 3 The combination of Item 1 , wherein the first agent comprises a compound of Formula (III)
  • R 4 is one or more substituents independently selected from the group consisting of hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, carboxy, formyl, carboxyamido, aryl, quaternary ammonium, haloalkyl, aryl alkanoyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryloxy, mercapto, alkylthio, alkylmercapto and disulfide;
  • R 3 is selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, N-alkoxy-N-alkylamino and N-alkoxyamino; and
  • Ri is alkyl
  • Item 4 The combination of Item 3, wherein, in the compound of Formula (III) or salt thereof:
  • R 4 is one or more substituents independently selected from the group consisting of hydrogen and halo;
  • R 3 is selected from the group consisting of lower alkoxy-lower alkyl, aryl, N- lower alkoxy-N-lower alkylamino, and N-lower alkoxyamino;
  • Ri is lower alkyl.
  • Item 5 The combination of Item 4, wherein, in the compound of Formula (III) or salt thereof, R 3 is lower alkoxy-lower alkyl.
  • Item 6 The combination of Item 3, wherein, in the compound of Formula (III) or salt thereof:
  • R 4 is hydrogen
  • R 3 is methoxymethyl
  • R 1 is methyl
  • Item 7 The combination of Item 3, wherein the first agent comprises a compound selected from the group consisting of (R ⁇ -acetamido-N-benzyl-S-methoxypropionamide; (R)-2-acetamido-N-benzyl-3-ethoxypropionamide; O-methyl-N-acetyl-D-serine-m-fluorobenzylamide; O-methyl-N-acetyl-D-serine-p-fluorobenzylamide; N-acetyl-D-phenylglycinebenzylamide;
  • Item 8 The combination of Item 3, wherein the compound of Formula (III) is substantially enantiopure.
  • Item 9 The combination of Item 3, wherein the first agent comprises lacosamide.
  • Item 10 The combination of Item 9, comprising lacosamide in an amount providing a dose of about 100 to about 6000 mg/day.
  • Item 11 The combination of Item 9, comprising lacosamide in an amount providing a dose of about 200 to about 1000 mg/day.
  • Item 12 The combination of Item 9, comprising lacosamide in an amount providing a dose of about 300 to about 600 mg/day.
  • Item 13 The combination of Item 1 , wherein the medical condition is accompanied by or has, as a symptom thereof, non-inflammatory pain.
  • Item 14 The combination of Item 1 , wherein the medical condition is an arthritic condition.
  • Item 15 The combination of Item 14, wherein the second agent comprises one or more anti-arthritis drugs.
  • Item 16 The combination of Item 15, wherein the one or more anti-arthritis drugs are independently selected from the group consisting of opioid and non-opioid analgesics, steroidal and non-steroidal anti-inflammatory drugs, DMOADs and DMARDs.
  • Item 17 The combination of Item 15, wherein the second agent comprises one or more analgesics selected from the group consisting of acetaminophen, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone,
  • Item 18 The combination of Item 15, wherein the second agent comprises one or more steroidal anti-inflammatory drugs selected from the group consisting of alclometasone, amcinonide, betamethasone, betamethasone 17-valerate, clobetasol, clobetasol propionate, clocortolone, cortisone, dehydrotestosterone, deoxycorticosterone, desonide, desoximetasone, dexamethasone, dexamethasone 21-isonicotinate, diflorasone, fluocinonide, fluocinolone, fluorometholone, flurandrenolide, fluticasone, halcinonide, halobetasol, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone hemisuccinate, hydrocortisone 21-lysinate, hydrocortisone sodium succinate, isoflupredone, is
  • Item 19 The combination of Item 15, wherein the second agent comprises one or more non-steroidal anti-inflammatory drugs selected from the group consisting of salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, olsalazine, salsalate, sulfasalazine, indomethacin, etodolac, sulindac, etofenamic acid, meclofenamic acid, mefenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, acemetacin, alclofenac, clidanac, diclofenac, fenchlofenac, fentiazac, furofenac, ibufenac, isoxepac, ketorolac, oxipinac, tiopinac, tolmetin, zidometacin, zomepirac, alminoprofen, benoxapro
  • Item 20 The combination of Item 15, wherein the second agent comprises one or more COX-2 selective inhibitors selected from the group consisting of celecoxib, deracoxib, valdecoxib, parecoxib, rofecoxib, etoricoxib, lumiracoxib, PAC-10549, cimicoxib, GW-406381 , LAS-34475, CS-502, and pharmaceutically acceptable salts thereof.
  • COX-2 selective inhibitors selected from the group consisting of celecoxib, deracoxib, valdecoxib, parecoxib, rofecoxib, etoricoxib, lumiracoxib, PAC-10549, cimicoxib, GW-406381 , LAS-34475, CS-502, and pharmaceutically acceptable salts thereof.
  • Item 21 The combination of Item 15, wherein the second agent comprises one or more DMOADs selected from the group consisting of methotrexate, diacerein, glucosamine, chondroitin sulfate, anakinra, MMP inhibitors, doxycycline, minocycline, misoprostol, proton pump inhibitors, non- acetylated salicylates, tamoxifen, prednisone, methylprednisolone, polysulfated glycosaminoglycan, calcitonin, alendronate, risedronate, zoledronic acid, teriparatide, VX-765, pralnacasan, SB-462795, CPA-926, ONO-4817, S-3536, PG-530742, CP-544439, and pharmaceutically acceptable salts thereof.
  • DMOADs selected from the group consisting of methotrexate, diacerein, glucosamine,
  • Item 22 The combination of Item 15, wherein the second agent comprises one or more DMARDs selected from the group consisting of etanercept, adalimumab, infliximab, IL-1 receptor antagonists, prednisone, methylprednisolone, penicillamine, hydroxychloroquine sulfate, chlorambucil cyclosphosphamide, leflunomide, cyclosporine, auranofin, aurothioglucose azathioprine gold, sodium thiomalate, methotrexate, cyclophosphamide, minocycline, sulfasalazine, abatacept, rituximab, bucillamine, chloroquine hydroxychloroquine, lobenzarit, misoprostol, and pharmaceutically acceptable salts thereof.
  • DMARDs selected from the group consisting of etanercept, adalimum
  • Item 23 The combination of Item 14, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat an arthritic condition and/or pain related thereto.
  • Item 24 The combination of Item 14, wherein the second agent comprises an anti-inflammatory drug in an amount effective to treat inflammation occurring in the arthritic condition.
  • Item 25 The combination of Item 14, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat both non-inflammatory and inflammatory components of pain associated with or caused by the arthritic condition.
  • Item 26 The combination of Item 1 , wherein the second agent is present in an amount effective, in combination with the first agent, to provide enhanced treatment of pain by comparison with the first agent alone.
  • Item 27 The combination of Item 26, wherein said enhanced treatment is of non-inflammatory pain.
  • Item 28 The combination of Item 26, wherein the second agent comprises one or more drugs independently selected from the group consisting of analgesics, anticonvulsants, antidepressants and NMDA receptor antagonists.
  • Item 29 The combination of Item 26, wherein the second agent comprises one or more analgesics selected from the group consisting of acetaminophen, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone,
  • Item 30 The combination of Item 26, wherein the second agent comprises one or more anticonvulsants selected from the group consisting of acetylpheneturide, albutoin, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, carbamazepine, cinromide, clomethiazole, clonazepam, decimemide, diethadione, dimethadione, doxenitoin, eterobarb, ethadione, ethosuximide, ethotoin, felbamate, fluoresone, fosphenytoin, gabapentin, ganaxolone, lamotrigine, levetiracetam, lorazepam, mephenytoin, mephobarbital, metharbital, methetoin, methsuximide, midazolam, narcobarbital, nitrazepam,
  • Item 31 The combination of Item 26, wherein the second agent comprises one or more antidepressants selected from the group consisting of adinazolam, adrafinil, amineptine, amitriptyline, amitriptylinoxide, amoxapine, befloxatone, bupropion, butacetin, butriptyline, caroxazone, citalopram, clomipramine, cotinine, demexiptiline, desipramine, dibenzepin, dimetacrine, dimethazan, dioxadrol, dothiepin, doxepin, duloxetine, etoperidone, femoxetine, fencamine, fenpentadiol, fluacizine, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, imipramine, imipramine N-oxide, indalpine, indeloxazine, iprindole
  • Item 32 The combination of Item 26, wherein the second agent comprises one or more NMDA receptor antagonists selected from the group consisting of amantadine, D-AP5, aptiganel, CPP, dexanabinol, dextromethorphan, dextropropoxyphene, 5,7-dichlorokynurenic acid, gavestinel, ifendopril, ketamine, ketobemidone, licostinel, LY-235959, memantine, methadone, MK-801 , phencyclidine, remacemide, selfotel, tiletamine, and pharmaceutically acceptable salts thereof.
  • NMDA receptor antagonists selected from the group consisting of amantadine, D-AP5, aptiganel, CPP, dexanabinol, dextromethorphan, dextropropoxyphene, 5,7-dichlorokynurenic acid, gavestinel, ifendopril, ketamine, ketobemidone
  • Item 33 The combination of Item 1 , wherein the first agent and the second agent are provided in separate dosage forms for administration by the same or different routes at the same or different times.
  • Item 34 The combination of Item 1 , wherein at least the first agent is provided in a dosage form adapted for oral or parenteral administration.
  • Item 35 The combination of Item 34, wherein the first agent is provided in a dosage form adapted for oral administration one to three doses per day.
  • Item 36 The combination of Item 34, wherein the second agent is orally bioavailable and is provided in a dosage form adapted for oral administration.
  • Item 37 A pharmaceutical dosage form comprising the combination of Item 1 and at least one pharmaceutically acceptable excipient.
  • Item 38 The dosage form of Item 37, wherein the first agent comprises lacosamide.
  • Item 39 The dosage form of Item 37 that is adapted for oral or parenteral administration.
  • Item 40 A method for treating a painful medical condition and/or pain related thereto in a subject, the method comprising administering to the subject the therapeutic combination of Item 1.
  • Item 41 The method of Item 40, wherein the medical condition or pain related thereto is selected from the group consisting of acute inflammatory pain; acute pain; alcoholism-associated or alcoholism-induced neuropathic pain; allodynia; arthritic conditions; back pain; cancer-related neuropathic pain; central neuropathic pain; chronic headache; chronic inflammatory pain; chronic pain; chronic pain due to peripheral nerve injury; diabetes- associated or diabetes-induced neuropathic pain; diabetic distal sensory neuropathy; diabetic distal sensory polyneuropathy; diabetic pain; fibromyalgia; headache; hyperalgesia; hyperesthesia; hyperpathia; migraine; myalgia; myofascial pain syndrome; neuralgia; neuroma; noninflammatory musculoskeletal pain; non-inflammatory osteoarthritic pain; non-neuropathic inflammatory pain; neuropathic pain; pain associated with or induced by chemotherapy or radiation therapy; pain associated with or induced by traumatic nerve injury or compression or by traumatic injury to the brain or
  • Item 42 The method of Item 40, wherein the pain related to the medical condition comprises non-inflammatory pain.
  • Item 43 A method for treating an arthritic condition and/or pain related thereto in a subject, the method comprising administering to the subject the therapeutic combination of Item 15.
  • Item 44 The method of Item 43, wherein both the arthritic condition and pain related thereto are treated.
  • Item 45 The method of Item 43, wherein, in said combination, the first agent comprises lacosamide.
  • Item 46 The method of Item 45, wherein the lacosamide is administered according to a regimen wherein daily doses are increased until a predetermined daily dose is reached which is maintained during further treatment.
  • Item 47 The method of Item 45, wherein the lacosamide is administered orally.
  • Item 48 The method of Item 47, wherein the lacosamide is administered in an amount providing a daily dose effective to provide a plasma concentration of lacosamide of about 0.1 to about 15 ⁇ g/ml (trough) and about 5 to about 18.5 ⁇ g/ml (peak), calculated as an average over a plurality of treated subjects.
  • Item 49 The method of Item 43, wherein the arthritic condition comprises one or more disorders selected from the group consisting of idiopathic osteoarthritis, secondary osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, infectious arthritis, ankylosing spondylitis, neurogenic arthropathy, polyarthralgia, and arthritis associated with Sjogren's syndrome, Behget's syndrome, Reiter's syndrome, systemic lupus erythematosus, rheumatic fever, gout, pseudogout, Lyme disease, sarcoidosis and ulcerative colitis.
  • the arthritic condition comprises one or more disorders selected from the group consisting of idiopathic osteoarthritis, secondary osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, infectious arthritis, ankylosing spondylitis, neurogenic arthropathy
  • Item 50 The method of Item 43, wherein the arthritic condition comprises osteoarthritis.
  • Item 51 The method of Item 43, wherein the arthritic condition comprises rheumatoid arthritis or juvenile rheumatoid arthritis.

Abstract

La présente invention concerne une combinaison thérapeutique qui comprend un premier agent comprenant un composé tel que défini ici, à titre d'exemple un lacosamide ou un de ses sels pharmaceutiquement acceptable, et un second agent plus efficace en combinaison avec le premier agent pour assurer un traitement amélioré de la douleur associée à un état médical ou causée par lui que le premier agent utilisé seul. Selon l'invention, la combinaison peut être proposée sous la forme d'une dose unitaire ou sous la forme de doses séparées et elle est utilisable par exemple pour le traitement d'un état arthritique et/ou de la douleur causée par cet état.
PCT/EP2007/005036 2006-06-08 2007-06-06 Combinaison thérapeutique pour états médicaux douloureux WO2007141018A1 (fr)

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Application Number Priority Date Filing Date Title
CA002652667A CA2652667A1 (fr) 2006-06-08 2007-06-06 Combinaison therapeutique pour etats medicaux douloureux
AU2007256352A AU2007256352A1 (en) 2006-06-08 2007-06-06 Therapeutic combination for painful medical conditions
MX2008015341A MX2008015341A (es) 2006-06-08 2007-06-06 Combinacion terapeutica para condiciones medicas dolorosas.
JP2009513597A JP2009539792A (ja) 2006-06-08 2007-06-06 疼痛の医学的状態のための治療組合せ
EP07725884A EP2026788B1 (fr) 2006-06-08 2007-06-06 Combinaison thérapeutique pour états médicaux douloureux
BRPI0712494-5A BRPI0712494A2 (pt) 2006-06-08 2007-06-06 combinação terapêutica para consições médicas dolorosas
AT07725884T ATE530175T1 (de) 2006-06-08 2007-06-06 Therapeutische kombination für schmerzhafte medizinische zustände
EA200802412A EA200802412A1 (ru) 2006-06-08 2007-06-06 Терапевтические комбинации для сопровождающихся болью медицинских состояний

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US81185906P 2006-06-08 2006-06-08
US81184006P 2006-06-08 2006-06-08
US60/811,840 2006-06-08
US60/811,859 2006-06-08
US11/506,524 US20070043120A1 (en) 2005-08-18 2006-08-18 Therapeutic combination for painful medical conditions
US11/506577 2006-08-18
EPPCT/EP2006/008171 2006-08-18
US11/506524 2006-08-18
US11/506,577 US20070042969A1 (en) 2004-03-26 2006-08-18 Combination therapy for pain in painful diabetic neuropathy
US11/506,523 2006-08-18
PCT/EP2006/008171 WO2007020103A2 (fr) 2005-08-18 2006-08-18 Nouvelle utilisation de composes peptidiques pour traiter une douleur musculaire
US11/506,578 US20070048372A1 (en) 2005-08-18 2006-08-18 Method for treating non-inflammatory osteoarthritic pain
US11/506,523 US20070197657A1 (en) 2005-08-18 2006-08-18 Method for treating non-inflammatory musculoskeletal pain
US11/506578 2006-08-18

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BR (1) BRPI0712494A2 (fr)
CA (1) CA2652667A1 (fr)
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EP2329824A1 (fr) * 2008-09-11 2011-06-08 Astellas Pharma Inc. Nouvelle composition pharmaceutique pour le traitement de la douleur nociceptive
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Publication number Priority date Publication date Assignee Title
EP2123642A1 (fr) * 2007-03-15 2009-11-25 Astellas Pharma Inc. Nouvel agent prophylactique et/ou thérapeutique servamt à traiter une douleur neurogénique
EP2123643A1 (fr) * 2007-03-15 2009-11-25 Astellas Pharma Inc. Nouvel agent prophylactique et/ou thérapeutique servant à traiter une neuropathie diabétique
EP2123643A4 (fr) * 2007-03-15 2011-12-07 Astellas Pharma Inc Nouvel agent prophylactique et/ou thérapeutique servant à traiter une neuropathie diabétique
EP2123642A4 (fr) * 2007-03-15 2011-12-07 Astellas Pharma Inc Nouvel agent prophylactique et/ou thérapeutique servamt à traiter une douleur neurogénique
US9914705B2 (en) 2008-04-25 2018-03-13 Laboratorios Del Dr. Esteve, S.A. 1-aryl-3-aminoalkoxy pyrazoles as sigma ligands enhancing analgesic effect of opioids and attenuating the dependency thereof
EP2329824A4 (fr) * 2008-09-11 2013-01-16 Astellas Pharma Inc Nouvelle composition pharmaceutique pour le traitement de la douleur nociceptive
EP2329824A1 (fr) * 2008-09-11 2011-06-08 Astellas Pharma Inc. Nouvelle composition pharmaceutique pour le traitement de la douleur nociceptive
US8198268B2 (en) 2008-10-31 2012-06-12 Janssen Biotech, Inc. Tianeptine sulfate salt forms and methods of making and using the same
US9844516B2 (en) 2010-02-04 2017-12-19 Laboratorios De Dr. Esteve Sigma ligands for use in the prevention and/or treatment of post-operative pain
US9757358B2 (en) 2010-02-04 2017-09-12 Laboratorios Del Dr. Esteve, S.A. Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof
US9782483B2 (en) 2010-05-21 2017-10-10 Laboratories Del Dr. Esteve, S.A. Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy
US10813890B2 (en) 2010-06-15 2020-10-27 Grünenthal GmbH Pharmaceutical combination
US9789115B2 (en) 2010-08-03 2017-10-17 Laboratorios Del Dr. Esteve, S.A. Use of sigma ligands in opioid-induced hyperalgesia
US9789117B2 (en) 2011-05-18 2017-10-17 Laboratorios Del Dr. Esteve, S.A. Use of sigma ligands in diabetes type-2 associated pain
EP2524694A1 (fr) * 2011-05-19 2012-11-21 Laboratorios Del. Dr. Esteve, S.A. Utilisation de ligands sigma dans la douleur liée au diabète de type 2
KR101937255B1 (ko) 2011-05-19 2019-01-11 에스테베 파마슈티칼스 에스에이 제 2형 당뇨병 관련 통증에서 시그마 리간드의 이용
WO2012156497A1 (fr) * 2011-05-19 2012-11-22 Laboratorios Del Dr. Esteve, S.A. Utilisation de ligands sigma dans une douleur associée au diabète de type 2
US9931346B2 (en) 2013-12-17 2018-04-03 Laboratorios Del Dr. Esteve S.A. Serotonin-norepinephrine reuptake inhibitors (SNRIs) and Sigma receptor ligands combinations
CN114306346A (zh) * 2021-12-14 2022-04-12 四川大学华西医院 拉莫三嗪在治疗系统性红斑狼疮中的应用

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AU2007256352A1 (en) 2007-12-13
BRPI0712494A2 (pt) 2012-10-09
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CA2652667A1 (fr) 2007-12-13
KR20090018863A (ko) 2009-02-23
EA200802412A1 (ru) 2009-06-30
JP2009539792A (ja) 2009-11-19
MX2008015341A (es) 2009-02-10
AR061250A1 (es) 2008-08-13

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