JP2009539792A - Therapeutic combinations for medical conditions of pain - Google Patents

Abstract

  A therapeutic combination comprises a first agent comprising a compound as defined herein, specifically lacosamide, or a pharmaceutically acceptable salt thereof, and a first agent in combination with the first agent. A second agent effective to provide improved treatment of pain associated with or caused by a medical condition compared to the agent alone. This combination can be given in a single dosage form or in separate dosage forms and is particularly useful for the treatment of arthritic conditions and / or pain associated therewith.

Description

  The present invention relates to therapeutic combinations and, more particularly, to the use of such combinations in the treatment of medical conditions, such as conditions involving arthritic conditions in which pain is present.

  By 2020, it is estimated that 60 million Americans will suffer arthritis. Arthritis is a major cause of over 7 million American disabilities (defined in a broad sense as requiring help when walking or going up stairs) and limited daily activities This number is expected to increase to over 11.6 million by 2020. See http://www.arthritis.org/resources/ActionPlanInterior.pdf.

  It is very expensive to treat arthritis and its complications. In 1997, the total cost of US arthritis and other rheumatic diseases was $ 86 billion. The direct medical cost of arthritis and other rheumatic diseases in 1997 was $ 51.1 billion. In 1997, the overhead of arthritis and other rheumatic diseases (due to lost wages) was $ 35.1 billion. See http: //www.cdc.qov/mmwr/preview/mmwrhtml/mm5318a3.htm.

  Rheumatoid arthritis is a chronic disease characterized primarily by inflammation of the intima of the joint, ie the synovium. This can cause long-term joint damage and can result in chronic pain, loss of function and disability. Rheumatoid arthritis affects about 1% of the US population, or 2.1 million Americans.

  Rheumatoid arthritis progresses in stage 3. Phase 1 includes synovial intima swelling, pain, warmth, stiffness, redness, and swelling around the joint. The second phase involves the rapid division and proliferation of cells that cause the synovium to thicken, or pannus. In the third phase, inflammatory cells release enzymes that can digest bone and cartilage, often causing loss of its shape and alignment of the diseased joint, more pain, and loss of movement.

  Since rheumatoid arthritis is a systemic disease, it can affect other organs of the body. Early diagnosis and treatment of rheumatoid arthritis is important to keep a productive lifestyle. Previous studies have shown that early aggressive treatment of rheumatoid arthritis can limit joint damage and further limit loss of exercise, reduced work capacity, higher medical costs and operability. ing. See http: //www.arthritis.orq/conditions/DiseaseCenter/RA/ra overview.asp.

  Osteoarthritis is an acquired musculoskeletal disorder that is originally considered non-inflammatory and occurs when the rate of cartilage degradation exceeds the rate of regeneration, leading to cartilage erosion, subchondral bone thickening, and joint damage . As cartilage becomes thinner, its surface integrity is lost, cracks may form, and cartilage tends to erode more easily with joint motion. When new cartilage is formed, it tends to become more fibrotic and tends to reduce mechanical stress resistance. Over time, the underlying bone with reduced mechanical stress resistance is exposed, resulting in microfractures. Localized osteonecrosis may occur below the surface of the bone, causing cysts that can further weaken the cartilage bone support.

  As osteoarthritis progresses, it can ultimately affect the structures surrounding the joint. For example, local inflammation such as synovitis can occur in response to inflammatory mediators released during the cartilage degradation process. The joint capsule is prone to thickening, and the movement of nutrients into and out of metabolic joints can be limited. As a result, as osteoarthritis progresses, periarticular muscle exhaustion may become apparent, and joints are used less frequently or improperly. The pain of osteoarthritis is not due to cartilage degradation per se, because the cartilage is anervous, and is thought to be due to the action on surrounding structures including bone.

  According to the Centers for Disease Control and Prevention (CDC), 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.

  The prevalence of osteoarthritis increases with age, and age is the greatest risk factor. In a study reported by Brandt (2001) Principles of Internal Medicine, 15th edition (edited by Braunwald et al.), New York: McGraw-Hill, 1987-1994, only 2% of women younger than 45 years were evidence of osteoarthritis. It was found to show an X-ray image. However, the prevalence was 30% for women aged 45 to 64 years and 68% for women aged 65 and over. Other risk factors include overweight, genetic features, estrogen deficiency, repetitive joint use, and trauma.

  Typical patients with osteoarthritis are middle-aged or elderly and complain of knee, hip, hand or spine pain. The distal and proximal interphalangeal joints of the hand are the most common sites of osteoarthritis but are also the least prone to symptoms. The hips and knees are the second and third common joints found to be affected by X-ray, and knee pain is more likely to show symptoms.

  Pain is the most important symptom of osteoarthritis. Osteoarthritic pain can have one or both of inflammatory and non-inflammatory components. Anti-inflammatory drugs such as NSAIDs (non-steroidal anti-inflammatory drugs) and cyclooxygenase-2 inhibitors can be useful in the treatment or handling of inflammatory elements, while opioids and other analgesics are non-inflammatory It can be useful for the treatment or handling of sexual elements. However, such drug therapy is not always effective and exhibits side effects that cannot be well tolerated in all patients.

  Non-inflammatory pain is often characterized by lack of swelling or warm sensation, lack of inflammatory or systemic features, and minimal or no morning stiffness.

  Non-inflammatory osteoarthritic pain can contribute to sedentary lifestyles, depression and sleep problems, especially in the elderly. Pain is often characterized as deep, tingling pain that intensifies with movement. It is usually intermittent and often mild but can be persistent and severe. There is usually a twisting sound in the affected joint.

  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 US Pat. No. 5,378,729.

  Related peptides are disclosed in US Pat. No. 5,773,475 as being useful for treating CNS disorders.

  WO 02/074784, incorporated herein by reference in its entirety, treats different types and symptoms of acute and chronic pain, particularly non-neuropathic inflammatory pain sensations, such as rheumatoid arthritis pain or secondary inflammation The present invention relates to the use of peptide compounds having antinociceptive properties for the treatment of osteoarthritic pain.

  International Publication No. 02/074297 is a formula

Wherein Ar is a phenyl group that is unsubstituted or substituted with at least one halo substituent; R ₃ is C _1-3 alkoxy; R ₁ is methyl)
To the treatment of allodynia associated with peripheral neuropathic pain.

  Lacosamide (also called SPM927 or harcoceride) is a compound of the above formula and has a mode of action that is not well 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 ordinary antiepileptic drugs. Ion channels are not affected by these compounds in a manner comparable to other known antiepileptic drugs. For example, gamma-aminobutyric acid (GABA) induced currents are enhanced, but no direct interaction with any known GABA receptor subtype has been observed. Although the glutamate-induced current is attenuated, the compound does not interact directly with any known glutamate receptor subtype.

U.S. Pat.No. 5,378,729 U.S. Patent No. 5,773,475 International Publication No. 02/074784 International Publication No. 02/074297

A study reported by Brandt (2001) Principles of Internal Medicine, 15th edition (edited by Braunwald et al.), New York: McGraw-Hill, 1987-1994. Bialer et al. (2002) Epilepsy Res., 51: 31-71. Stohr et al. (2006) Eur. J. Pain 10 (3): 241-249. March (1985), Advanced Organic Chemistry, New York: John Wiley & Sons, 16-18 Physicians' Desk Reference (PDR), 60th edition, Montvale, NJ: Thomson (2006) Guzman et al. (2003) Toxicol. Pathol., 31 (6): 619-624. Kalbhen, (1987), J. Rheumatol., 14 (Spec.NO.): 130-131 Wheeler-Aceto & Cowan (1991) Psychopharmacology 104: 35-44

  There remains a need for improved therapies that can treat medical conditions such as arthritic conditions with pain, particularly non-inflammatory pain as a symptom thereof.

  Now, the formula (I)

(Where
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 non- Is substituted or substituted with at least one electron withdrawing group and / or at least one electron donating group;
R ₁ 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 non- May be substituted 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 ZY, 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. Cage;
Z is O, S, S (O) _a , 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 may be unsubstituted or at least Optionally substituted with one electron withdrawing group and / or at least one electron donating group, provided that when Y is halo, Z is a chemical bond, or
ZY together, 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 , PR ₄ NR ₅ R ₇ , N ⁺ R ₅ R ₆ R ₇ ,

Subject to
R ′ ₆ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl and may be unsubstituted or substituted with at least one electron withdrawing group and / or at least one electron donating group May be;
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 at least one electron sought. Substituted with an attractive group and / or 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 and / or at least one electron donating group Well;
R ₈ is hydrogen, lower alkyl, or aryl lower alkyl and may be unsubstituted or substituted with at least one electron withdrawing group and / or at least one electron donating group Well;
n is 1 to 4;
a is 1 to 3)
A first agent comprising the compound of: or a pharmaceutically acceptable salt thereof; and in combination therewith, (a) improved treatment of pain associated with or caused by a medical condition compared to the first agent alone And / or (b) a second agent effective to treat another medical symptom or root cause of the medical condition, wherein the one or more other than the compound of formula (I) A therapeutic combination is provided comprising a second agent comprising a drug.

  The medical condition in one embodiment is a condition in which non-inflammatory pain is present. For example, the medical condition can be an arthritic condition.

  The first agent and the second agent can be provided separately or in a single dosage form. Accordingly, in one embodiment, a pharmaceutical formulation is provided comprising a first agent and a second agent as defined above.

  There is further provided a method of treating a painful medical condition and / or pain associated therewith in a subject, comprising administering to the subject a therapeutic combination as defined above.

  A method of treating an arthritic condition and / or pain associated therewith in a subject comprising administering to the subject a therapeutic combination as defined above, wherein the second agent comprises one or more anti-tumor agents. Still further provided are methods comprising an arthritic agent.

  According to any of the above embodiments, a specific compound of formula (I) is lacosamide, which is (R) -2-acetamido-N-benzyl-3-methoxypropionamide.

  Other embodiments, including certain aspects of the embodiments summarized above, will be apparent from the detailed description below.

1-4, “SPM927” refers to lacosamide.
FIG. 2 is a graphic representation of the test results of Example 1 showing the effect of lacosamide at 3, 10, and 30 mg / kg on TNF-induced hyperbaric hyperalgesia. Graphic representation of the test results of Example 1 showing the maximum possible effect (MPE) of lacosamide at 3, 10, and 30 mg / kg on TNF-induced muscle hyperalgesia compared to pregabalin, gabapentin and metamizole (dipyrone) FIG. FIG. 4 is a graphic representation of the test results of Example 1 showing the effect of lacosamide at 3, 10 and 30 mg / kg on biceps grip strength after TNF-induced myalgia. Graph of test results of Example 1 showing the maximum possible effect (MPE) of lacosamide at 3, 10 and 30 mg / kg on biceps grip strength after TNF-induced myalgia compared to pregabalin, gabapentin and metamizole (dipyrone) It is a figure of a display. FIG. 4 is a graphic representation of the test results of Example 2 showing the effect of lacosamide and morpholine on the monosodium iodoacetate-induced tactile allodynia on the third day of the study. FIG. 3 is a graphic representation of the test results of Example 2 showing the effects of lacosamide and morpholine on the monosodium iodoacetate-induced tactile allodynia on day 7 of the study. FIG. 6 is a graphic representation of the test results of Example 2 showing the effect of lacosamide and morpholine on the 14 day iodoacetate monosodium-induced tactile allodynia on the 14th day of the study. FIG. 3 is a graphic representation of the test results of Example 2 showing the effect of diclofenac on monosodium iodoacetate-induced tactile allodynia on the third day of the test. FIG. 3 is a graphic representation of the test results of Example 2 showing the effect of diclofenac on the 7 day iodoacetate monosodium-induced tactile allodynia on the 7th day of the test. FIG. 3 is a graphic representation of the test results of Example 2 showing the effect of diclofenac on the monosodium iodoacetate-induced tactile allodynia on day 14 of the test. FIG. 3 is a graphic representation of the test results of Example 2 showing the effect of lacosamide and formolin on monosodium iodoacetate-induced mechanical hyperalgesia on day 3 of the study. FIG. 3 is a graphic representation of the test results of Example 2 showing the effect of lacosamide and formolin on monosodium iodoacetate-induced mechanical hyperalgesia on day 7 of the study. FIG. 6 is a graphic representation of the test results of Example 2 showing the effects of lacosamide and formolin on monosodium iodoacetate-induced mechanical hyperalgesia on day 14 of the study. FIG. 3 is a graphic representation of the test results of Example 2 showing the effect of diclofenac on monosodium iodoacetate-induced mechanical hyperalgesia on the third day of the test. FIG. 4 is a graphic representation of the test results of Example 2 showing the effect of diclofenac on monosodium iodoacetate-induced mechanical hyperalgesia on the seventh day of the test. FIG. 4 is a graphic representation of the test results of Example 2 showing the effect of diclofenac on monosodium iodoacetate-induced mechanical hyperalgesia on day 14 of the test.

  Provided are therapeutic combinations, pharmaceutical dosage forms, and methods of using such combinations and dosage forms for treating arthritic conditions and / or pain associated therewith.

  The term “therapeutic combination” refers to a plurality of agents that are co-active in providing a therapeutic benefit to a subject when administered together or separately to the subject. Such administration is referred to as “combination therapy”, “cotherapy”, “adjuvant therapy” or “additional therapy”. For example, one drug can enhance or improve the therapeutic effect of another drug, or reduce the adverse side effects of another drug, or one or more drugs than when used alone It can be effectively administered at lower doses or provide greater therapeutic benefit than when used alone, or it can complement different aspects, symptoms or etiological factors of the disease or condition.

  As used herein, a “medical condition” can typically be a clinically diagnosed disease, disorder or syndrome. The medical condition addressed by the present invention is painful or has pain as a symptom thereof and is referred to herein as a “painful medical condition”. Pain may be inflammatory or non-inflammatory in nature, or may have both inflammatory and non-inflammatory elements. For example, many arthritic conditions have non-inflammatory and inflammatory pain elements.

Non-limiting examples of medical conditions and / or pain types that may benefit from this treatment combination and method include those listed immediately below, and many of the listed conditions and pain types overlap. It is recognized that:
Acute inflammatory pain;
Acute pain;
Alcohol-related or alcoholism-induced neuropathic pain;
Allodynia (occurs independently or as a symptom of another condition);
Arthritic condition;
Back pain;
Cancer-related neuropathic pain, e.g. painful compression due to tumor growth in the adjacent nerve, brain or spinal cord;
Central neuropathic pain;
Chronic headache;
Chronic inflammatory pain;
Chronic pain;
Chronic pain from peripheral nerve injury;
Diabetes-related or diabetes-induced neuropathic pain;
Diabetic pain;
Diabetic distal sensory neuropathy;
Diabetic distal sensory polyneuropathy;
Fibromyalgia;
·headache;
Hyperalgesia (occurs independently or as a symptom of another condition);
Hypersensitivity;
Painful hypersensitivity;
Migraine (including classic and common migraine);
·muscle pain;
Fascial pain syndrome;
Neuralgia;
Neuroma;
Non-inflammatory musculoskeletal pain;
Non-inflammatory osteoarthritic pain;
Non-neuropathic inflammatory pain;
Neuropathic pain;
Chemotherapy or radiation therapy related or induced pain;
Traumatic nerve injury or compression or brain or spinal injury related or induced pain;
Painful diabetic neuropathy;
Peripheral neuropathic pain;
Persistent clinical pain;
Phantom pain;
Rheumatoid arthritis pain;
Secondary inflammatory osteoarthritic pain;
• Trigeminal neuralgia; and • Vascular headache.

  As used herein, an “arthritic condition” is a musculoskeletal disorder, usually painful, of one or more joints in a subject, including arthritis that is related or secondary to a condition that is not necessarily primarily arthritic It is. Among the most important arthritic conditions are osteoarthritis, which may be idiopathic or inherently primary, or secondary to other conditions; and rheumatoid arthritis, including juvenile rheumatoid arthritis. Other disorders encompassed herein as “arthritic conditions” include, but are not limited to, psoriatic arthritis, infectious arthritis, ankylosing spondylitis, neurogenic arthropathy and polyarthralgia. Conditions in which arthritis can be secondary include, but are not limited to, Sjogren's syndrome, Behcet's syndrome, Reiter's syndrome, systemic lupus erythematosus, rheumatic fever, gout, pseudogout, Lyme disease, sarcoidosis and ulcerative colitis.

  For example, the pain associated with arthritis in osteoarthritis can be inflammatory or non-inflammatory or both. Non-inflammatory osteoarthritic pain is a special type of non-inflammatory musculoskeletal pain from osteoarthritis-related morphological alterations such as cartilage degradation, bone changes on sensory neurons, angiogenic effects of bone remodeling Usually occurs. This refers to inflammatory osteoarthritic pain that usually results from synovial inflammation that follows pathological processes in cartilage and bone, including tissue damage and macrophage invasion (resulting in edema) associated with the classical immune system response. Are distinguished in the book.

  Stohr et al. (2006) Eur. J. Pain 10 (3): 241-249, which is incorporated herein by reference in its entirety, but does not fall within the prior art of the present invention, contains inflammatory pain. Results showing the effectiveness of lacosamide for treatment are described.

  Unless otherwise required in this context, the term “treat”, “treating” or “treatment” herein includes non-inflammatory as a combination, eg, its symptoms, eg, arthritic conditions such as osteoarthritis Preventive or prophylactic use of a combination of a first drug and a second drug as defined herein in a subject at risk for or including a medical condition having pain As well as the use of such combinations as a therapy to reduce, alleviate, reduce the intensity of or eliminate the condition or its associated pain or its root cause in a subject already experiencing such a condition.

  The term “subject” refers to a warm-blooded animal, generally a mammal, eg, a primate including a cat, dog, horse, cow, pig, mouse, rat or human. In one embodiment, the subject is a human, eg, a patient with a clinically diagnosed arthritic condition.

  The terms “synergistic”, “synergistic”, “enhanced prevention”, “enhanced alleviation” or “enhanced treatment” are stronger for a combination of two or more compounds compared to the additive effect of the compounds alone. Refers to therapeutic effect. For example, a therapeutic combination as described herein may have a synergistic effect in preventing, reducing or / and treating pain associated with or caused by a medical condition as described herein.

  A therapeutic combination as described herein may also prevent, reduce or reduce the pain associated with or caused by a medical condition as described herein or a medical condition as described herein. When administered therapeutically, and / or may have a synergistic effect on reducing side effects or / and toxicity.

  The therapeutic combination of the present invention comprises a first agent comprising a compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof. More than one such compound or salt thereof may optionally be present in the first agent. Unless otherwise stated, the terms used in the description of formula (I) and elsewhere in this specification are defined as follows.

  The term “alkyl”, alone or in combination with another term (s), typically has from 1 to about 20 carbon atoms, more typically from 1 to about 8 carbon atoms, and even more typically Means a straight or branched chain saturated hydrocarbyl substituent containing from 1 to about 6 carbon atoms.

  The term “lower alkyl” refers to an alkyl substituent containing 1 to 6 carbon atoms, particularly 1 to 3 carbon atoms, which may be straight or branched. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like and isomers thereof.

  The term “alkenyl”, alone or in combination with another term (s), includes one or more double bonds and typically 2 to about 20 carbon atoms, more typically 2 to about 8 Means a straight or branched hydrocarbyl substituent containing, more typically, 2 to about 6 carbon atoms. When asymmetric, an alkenyl group can have a cis or trans configuration.

  The term “lower alkenyl” refers to an alkenyl substituent containing from 2 to 6 carbon atoms, which may be linear or branched and may be Z-type or E-type. 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, for example 1,3- or 2,4-pentadienyl and the like are included.

  The term `` alkynyl '', alone or in combination with another term (s), includes one or more triple bonds and typically 2 to about 20 carbon atoms, more typically 2 to about 8 Means a straight or branched hydrocarbyl substituent containing carbon atoms, and even more typically 2 to about 6 carbon atoms.

  The term “lower alkynyl” refers to an alkynyl substituent containing 2 to 6 carbon atoms, which may be straight or branched. This includes ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, etc. Group is included.

  The term “cycloalkyl”, alone or in combination with another term (s), means a fully or partially saturated alicyclic hydrocarbyl group containing from 3 to about 18 ring carbon atoms. Cycloalkyl groups may be monocyclic or polycyclic. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl, cycloheptenyl, decalinyl, hydroindanyl, indanyl, fenkyl, pinenyl, adamantyl and the like. Cycloalkyl includes its cis or trans forms. The cycloalkyl group may be unsubstituted or mono- or polysubstituted with an electron withdrawing group or / and an electron donating group as described below. Furthermore, the substituent may be in either the endo- or exo-position in the bridged bicyclic system. A “lower cycloalkyl” group has 3 to 6 carbon atoms.

  The term “alkoxy”, alone or in combination with another term (s), means an alkyl ether, ie —O-alkyl, a substituent.

  The term “lower alkoxy” refers to an alkoxy substituent containing 1 to 6 carbon atoms, especially 1 to 3 carbon atoms, which may be straight or branched. Examples include methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy and the like.

  The term “aryl”, alone or in combination with another term (s), means an aromatic group containing about 6 to about 18 ring carbon atoms and includes polynuclear aromatics. The aryl group may be monocyclic or polycyclic or optionally fused. Polynuclear aromatic groups as used herein include bicyclic and tricyclic fused aromatic ring systems containing from about 10 to about 18 ring carbon atoms. Aryl groups include groups such as phenyl, polynuclear aromatic groups (eg, naphthyl, anthracenyl, phenanthrenyl, azulenyl, etc.), and ferrocenyl. The aryl group may be unsubstituted or mono- or polysubstituted with an electron withdrawing group and / or an electron donating group 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.

  The term “monosubstituted amino”, alone or in combination with another term (s), means an amino substituent in which one of the hydrogen radicals is replaced by a non-hydrogen substituent. The term “disubstituted amino”, alone or in combination with another term (s), is an amino substituent wherein both of the hydrogen atoms are substituted by non-hydrogen substituents which may be the same or different. Means.

  The term “halo” or “halogen” includes fluoro, chloro, bromo, and iodo.

  The term “carbalkoxy” refers to —CO—O-alkyl, where alkyl may be lower alkyl as defined above.

  The prefix “halo” indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, haloalkyl means an alkyl substituent in which at least one hydrogen radical is replaced with a halogen radical. Examples of haloalkyl substituents include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and the like. Illustrating further, “haloalkoxy” means an alkoxy substituent wherein at least one hydrogen radical is replaced with a halogen radical. Examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as “perfluoromethoxy”), 1,1,1-trifluoroethoxy, and the like. included. Unless stated otherwise, it should be appreciated that when a substituent is substituted with more than one halogen radical, these halogen radicals may be the same or different.

  The term “acyl” includes alkanoyl containing 1 to about 20 carbon atoms, preferably 1 to 6 carbon atoms, and may be linear or branched. Acyl groups include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, tert-butyryl, pentanoyl and isomers thereof, and hexanoyl and isomers thereof.

  The terms “electron-withdrawing” and “electron-donating” refer to the ability of a substituent to withdraw an electron, respectively, compared to the ability of a hydrogen atom to occupy the same position in the molecule, or The ability to donate electrons. These terms are well understood by those skilled in the art, for example in March (1985), Advanced Organic Chemistry, New York: John Wiley & Sons, pages 16-18, the disclosure of which is incorporated herein by reference. It is being considered. Electron withdrawing groups include halo (including fluoro, chloro, bromo, and iodo), nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamide, aryl, quaternary ammonium, haloalkyl (such as trifluoromethyl) , Aryl lower alkanoyl, carbalkoxy and the like. Electron donating groups include hydroxy, lower alkoxy (including methoxy, ethoxy, etc.), lower alkyl (including methyl, ethyl, etc.), amino, lower alkylamino, di (lower alkyl) amino, aryloxy (phenoxy, etc.) , Mercapto, lower alkylthio, lower alkylmercapto, disulfide (lower alkyldithio) and the like. One skilled in the art will appreciate that some of the above substituents can be considered electron donating or electron withdrawing under different chemical conditions. Furthermore, the present invention contemplates any combination of substituents selected from the groups identified above.

  The term “heterocyclic” means a ring substituent containing one or more sulfur, nitrogen and / or oxygen ring atoms. Heterocyclic groups include heterocyclic aromatic groups and saturated and partially saturated heterocyclic groups. The heterocyclic group may be monocyclic, bicyclic, tricyclic or polycyclic and may be a fused ring. These usually contain up to 18 ring atoms, including up to 17 ring carbon atoms, and can contain up to about 25 carbon atoms in total, but are preferably 5- to 6-membered rings. Heterocyclic groups also include so-called benzoheterocycles. Exemplary 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, pyrazolinedinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, Oxetanyl and azetidinyl groups and nitrogen-containing heterocyclic N-oxides such as pyridyl, pyrazinyl And N-oxides of pyrimidinyl groups. Heterocyclic groups may be unsubstituted or mono- or polysubstituted with electron withdrawing and / or electron donating groups.

  In one embodiment, the heterocyclic group is thienyl, furyl, pyrrolyl, benzofuryl, benzothienyl, indolyl, methylpyrrolyl, morpholinyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, and pyridazinyl, particularly furyl, pyridyl, pyrazinyl, imidazolyl, Selected from pyrimidinyl and pyridazinyl, more particularly furyl and pyridyl.

  In another embodiment, the heterocyclic group is at least one lower alkyl group (preferably having 1 to 3 carbon atoms such as methyl), pyrrolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl. And thiazolyl, in particular furyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl and thiazolyl, more particularly furyl, pyridyl, pyrimidinyl and oxazolyl.

  Specifically, in the compound of formula (I), n is 1, but di- (n = 2), tri- (n = 3) and tetrapeptide (n = 4) are also useful herein. It is planned.

  R in the compound of formula (I) is specifically aryl lower alkyl, in particular the phenyl ring is unsubstituted, or one or more electron withdrawing groups and / or electron donating groups, for example , Benzyl substituted with halo (eg, fluoro).

R ₁ in the compound of formula (I) is preferably hydrogen or lower alkyl, especially methyl.

Particularly preferred electron withdrawing and / or electron donating substituents are halo, nitro, alkanoyl, formyl, arylalkanoyl, allylyl, carboxyl, carbalkoxy, carboxamide, cyano, sulfonyl, sulfoxide, heterocycle, guanidine, quaternary ammonium Lower alkenyl, lower alkynyl, sulfonium salt, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di (lower alkyl) amino, amino lower alkyl, mercapto, mercaptoalkyl, alkylthio, and alkyldithio. The term “sulfide” includes mercapto, mercaptoalkyl and alkylthio, while the term “disulfide” includes alkylthio. Preferred electron withdrawing and / or electron donating groups are halo and lower alkoxy, especially fluoro and methoxy. These preferred substituents are any one of the groups R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ^′ ₆ , R ₇ or R ₈ as defined herein. There can be more than one.

ZY groups representing R ₂ and / or R ₃ include hydroxy, alkoxy (e.g. methoxy and ethoxy), aryloxy (e.g. phenoxy), thioalkoxy (e.g. thiomethoxy and thioethoxy), thioaryloxy (e.g. thio Phenoxy), amino, alkylamino (e.g. methylamino and ethylamino), arylamino (e.g. anilino), lower dialkylamino (e.g. dimethylamino), trialkylammonium salts, hydrazino, alkylhydrazino and arylhydrazino ( (E.g., N-methylhydrazino and N-phenylhydrazino), carbalkoxyhydrazino, aralkoxycarbonylhydrazino, aryloxycarbonylhydrazino, hydroxylamino (e.g., N-hydroxylamino (-NHOH)), lower Alkoxyami Roh (R ₁₈ is lower alkyl, for example, NHOR ₁₈ is methyl), N- lower alkyl hydroxylamino (R ₁₈ is lower alkyl _{N (R 18) OH),} N- lower alkyl -O- lower alkyl hydroxylamino (N (R ₁₈ ) OR ₁₉ , where R ₁₈ and R ₁₉ are independently lower alkyl), and o-hydroxylamino (—O—NH ₂ ), alkylamides (eg, acetamide), trifluoroacetamide, and heterocyclylamino (Eg, pyrazoylamino).

Preferred heterocyclic groups representing R ₂ and / or R ₃ are of the formula

A monocyclic 5-membered or 6-membered heterocyclic moiety, including unsaturated, partially and fully saturated forms thereof, wherein n is 0 or 1; R ₅₀ is hydrogen or electron withdrawing or electron A, E, L, J and G are independently a heteroatom selected from the group consisting of CH or N, O and S; when n is 0, G is CH or a heteroatom selected from the group consisting of N, O and S; provided that at most two of A, E, L, J and G are heteroatoms).

  When n is 0, the monocyclic heterocyclic ring is 5-membered, and when n is 1, the ring is 6-membered.

  Where the ring shown above contains a nitrogen ring atom, it is contemplated that the N-oxide form is also within the scope of the invention.

When R ₂ or R ₃ contains a heterocyclic group of the above formula, it may be linked to the main chain by a ring carbon atom. When n is 0, R ₂ or R ₃ may be further bonded to the main chain by a nitrogen ring atom.

Other preferred moieties for R ₂ and R ₃ are hydrogen, aryl (eg, phenyl), arylalkyl (eg, benzyl), and alkyl. Such moieties can be unsubstituted or mono- or polysubstituted with electron withdrawing groups and / or electron donating groups. In various embodiments, R ₂ and R ₃ are independently hydrogen; unsubstituted or one or more electron withdrawing groups and / or electron donating groups, such as lower alkoxy (eg, N-hydroxylamino; N-lower alkylhydroxyamino; N-lower alkyl-O-lower alkyl; or alkylhydroxylamino.

In some embodiments, one of R ₂ and R ₃ is hydrogen.

In one embodiment, n in formula (I) is 1 and one of R ₂ and R ₃ is hydrogen. Specifically in this embodiment, R ₂ is hydrogen, R ₃ is lower alkyl or ZY, where Z is O, NR ₄ or PR ₄ and Y is hydrogen or lower alkyl; Or ZY is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ ,

It is.

In another embodiment, n is 1, R ₂ is hydrogen, R ₃ is a lower alkyl, NR, which is unsubstituted or substituted with an electron withdrawing or electron donating group ₄ OR ₅ , or ONR ₄ R ₇ .

In yet another embodiment,
n is 1;
R is aryl lower alkyl, the aryl group is unsubstituted or substituted with an electron withdrawing group, for example, aryl is phenyl that is unsubstituted or substituted with halo. Can be;
R ₁ 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 , where R ₄ , R ₅ and R ₇ are Independently, hydrogen or lower alkyl.

In yet another embodiment, R ₂ is hydrogen and R ₃ is hydrogen, an alkyl group that is unsubstituted or substituted with at least one electron withdrawing group or electron donating group, or ZY. . In this embodiment, R ₃ is specifically an alkyl group such as hydrogen, methyl, etc., which is unsubstituted or an electron donating group such as lower alkoxy, more particularly methoxy or ethoxy. Or substituted with NR ₄ OR ₅ or ONR ₄ R ₇ , wherein R ₄ , R ₅ and R ₇ are independently hydrogen or lower alkyl.

In yet another embodiment, R ₂ and R ₃ are independently hydrogen, lower alkyl, or ZY; Z is O, NR ₄ or PR ₄ ; Y is hydrogen or lower alkyl; Or ZY is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ ,

It is.

  R is preferably 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 group or an electron donating group. When the aryl ring in R is substituted, it is most preferably substituted with an electron withdrawing group. The most preferred electron withdrawing group for R is halo, especially fluoro.

Preferred R ₁ is lower alkyl, especially methyl.

In one embodiment, R is aryl lower alkyl, such as benzyl, and R ₁ is lower alkyl, such as methyl.

Further preferred compounds are compounds of formula (I), wherein
n is 1;
R is aryl or aryl lower alkyl, e.g., benzyl, wherein the aryl group is unsubstituted or substituted with an electron withdrawing group or electron donating group;
R ₁ is lower alkyl;
R ₂ is hydrogen;
R ₃ is hydrogen, a lower alkyl group, particularly methyl substituted with an electron withdrawing group or electron donating group, or ZY.

In this embodiment, R ₃ is a lower alkyl group that is hydrogen, especially methyl [which may be substituted with an electron donating group such as lower alkoxy (eg, methoxy, ethoxy, etc.)], NR ₄ OR More preferred is ₅ or ONR ₄ R ₇ , wherein these groups are as defined above.

  In one embodiment, the compound has the formula (II)

Or a pharmaceutically acceptable salt thereof, wherein
Ar is aryl, especially phenyl, which is unsubstituted or substituted with at least one halo;
R ₁ is lower alkyl, especially C _1-3 alkyl, such as methyl;
R ₃ is hydrogen or lower alkyl (which is unsubstituted or substituted with at least one electron withdrawing group or electron donating group), or ZY; for example, R ₃ is —CH ₂ -Q, where Q is lower alkoxy, in particular _C1-3 alkoxy, for example methoxy.

In another embodiment, the compound has the formula (I), wherein:
n is 1;
R is unsubstituted or substituted benzyl, especially halo-substituted benzyl;
R ₁ is lower alkyl, especially C _1-3 alkyl, such as methyl;
R ₂ is hydrogen;
R ₃ is as defined broadly herein.

  In yet another embodiment, the compound has the formula (III)

Or a pharmaceutically acceptable salt thereof, wherein
R ₄ is hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, carboxy, formyl, carboxamide, aryl, quaternary ammonium, haloalkyl, arylalkanoyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryloxy, mercapto One or more substituents independently selected from the group consisting of, alkylthio, alkyl mercapto, and disulfide;
R ₃ is selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, N-alkoxy-N-alkylamino, and N-alkoxyamino;
R ₁ is alkyl.

  The alkyl, alkoxy, alkenyl and alkynyl groups in the 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.

In certain embodiments, the R ₄ substituent in the compound of formula (III) is independently selected from a hydrogen substituent and halo, more particularly a fluoro substituent.

In certain embodiments, R ₃ in the compound of formula (III) is alkoxyalkyl, phenyl, N-alkoxy-N-alkylamino or N-alkoxyamino.

In certain embodiments, R ₁ in the compound of formula (III) is C _1-3 alkyl.

In a more particular embodiment, only one R ₄ substituent is fluoro and all others are hydrogen; R ₃ consists of methoxymethyl, phenyl, N-methoxy-N-methylamino and N-methoxyamino Selected from the group; R ₁ is methyl;

Combinations and permutations of the R ₁ , R ₂ , R ₃ and R groups and the value of n are considered to be within the scope of the present invention, even if such combinations and permutations are not explicitly described herein. It should be understood that it is contemplated. Furthermore, the present invention also encompasses therapeutic combinations comprising compounds having one or more elements of each of the Markush groups described for R ₁ , R ₂ , R ₃ and R and various combinations thereof. Thus, for example, in the present invention, R ₁ and R are independently n number of compounds of formula (I)

It is contemplated that for each of the subunits, there may be one or more of the substituents listed above in combination with any of the R ₂ and R ₃ substituents.

  The 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-Ingold system. Various enantiomers and diastereomers and various arrangements around each asymmetric carbon, including but not limited to enantiomers, diastereomers or mixtures of both, including racemic mixtures, are all contemplated by the present invention.

More particularly, in compounds of formula (I) where R ₂ and R ₃ are not identical, there is an asymmetry at the carbon atom to which the groups R ₂ and R ₃ are attached. As used herein, the term “configuration” generally refers to the configuration around the carbon atom attached to R ₂ and R ₃ , even though other chiral centers may be present in the molecule. . Thus, unless the context requires otherwise, the specific configuration, for example, when referring to D or L, the D- or L-stereoisomer at the carbon atom to which R ₂ and R ₃ are attached Should be understood to mean. However, all possible enantiomers and diastereomers at other chiral centers present in the compound, if any, are included herein.

  The compounds useful herein can include L- or D-stereoisomers as defined above, or any mixture thereof, including but not limited to racemic mixtures. The D-stereoisomer is generally preferred. In lacosamide, according to the R, S term, the D-stereoisomer corresponds to the R-enantiomer.

  In one embodiment, the compound, eg, lacosamide, is substantially enantiopure. As used herein, the term “substantially enantiopure” means an enantiomeric purity of at least 88%, preferably at least 90%, more preferably at least 95%, 96%, 97%, 98% or 99%. It means having.

Specific compounds that can be used in this 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-phenylglycine benzylamide;
D-1,2- (N, O-dimethylhydroxylamino) -2-acetamidoacetic acid benzylamide;
and
D-1,2- (O-methylhydroxylamino) -2-acetamidoacetic acid benzylamide is included.

  Depending on the substituents, some of the compounds may form salts. For example, compounds of formula (I), (II) and (III) may form salts with a wide variety of inorganic and organic acids, including pharmaceutically acceptable acids. Such salts can have increased water solubility and can be particularly useful in preparing pharmaceutical compositions for use in situations where increased water solubility is advantageous.

  Pharmaceutically acceptable salts are those that have a therapeutic effect without unacceptable toxicity. Inorganic acids such as hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid salts, and organic acids such as tartaric acid, acetic acid, citric acid, malic acid, benzoic acid, perchlorine Salts such as acid, glycolic acid, gluconic acid, succinic acid, arylsulfonic acid (for example, p-toluenesulfonic acid, benzenesulfonic acid), phosphoric acid and malonic acid can be used.

  The compounds useful herein can be any known synthetic procedure as described, for example, in the above referenced US Pat. Nos. 5,378,729 and 5,773,475, each of which is incorporated herein by reference. Can be prepared.

  The compounds as described herein are used in therapeutically effective amounts. The physician will be able to determine the preferred dose of the compound, which can vary depending on the particular compound selected, the route and method of administration, and the age and other characteristics of the individual patient. The physician may begin treatment at a small dose, eg, substantially less than the optimum dose of the compound, and increase the dose in small increments until the optimum effect under circumstances is reached. When the composition is administered orally, a greater amount of the compound may be required to produce the same therapeutic benefit as a lesser amount administered parenterally.

  In one particular embodiment, the compound, eg, lacosamide, is administered in an amount ranging from about 1 mg to about 10 mg per kilogram body weight per day. Typically, patients are treated with the compound, e.g., lacosamide, at a dose of at least about 50 mg / day, e.g., 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. be able to. In general, a suitable dose is about 6 g / day or less, such as about 1 g / day or less or about 600 mg / day or less. However, in some cases higher or lower doses may be required.

  In another embodiment, the daily dose is increased until a predetermined daily dose that is maintained during further treatment is reached.

  In yet another embodiment, several divided doses are administered daily. For example, no more than 3 doses per day, or no more than 2 doses per day may be administered. However, it is often most convenient to administer only one dose per day.

  As used herein, doses expressed on a daily basis, eg, mg / day should not be construed as requiring administration once a day. For example, a dose of 300 mg / day can be administered as 100 mg three times daily or as 600 mg every other day.

  In yet another embodiment, the plasma concentration of the compound results from about 0.1 to about 15 μg / ml (minimum) and from about 5 to about 18.5 μg / ml (maximum), calculated as an average for a plurality of treatment subjects. An amount of the compound, eg, lacosamide, is administered.

  The compound of formula (I), (II) or (III), e.g. lacosamide, is any convenient and effective method, e.g. oral, intravenous, intraperitoneal, intramuscular, intrathecal, subcutaneous or transdermal. It can be administered by mucosal (eg, buccal) route. Oral or intravenous administration is generally preferred.

  For oral administration, the compounds are usually administered as an ingredient of an orally deliverable pharmaceutical composition further comprising an inert diluent or an absorbable edible carrier, or can be incorporated into the subject's food. . In an orally deliverable pharmaceutical composition, the compound is incorporated with one or more excipients and is in the form of tablets, troches, pills, capsules, elixirs, suspensions, syrups, wafers, etc. Can be administered. Such compositions usually comprise at least about 1% by weight, more typically from about 5% to about 80% of the compound, eg, lacosamide. The amount of the compound in the composition is such that a suitable dosage as described above can be conveniently provided after administration of the composition. Specifically, pharmaceutical compositions useful for oral delivery of a compound of formula (I), (II) or (III), such as lacosamide, are about 10 mg to about 6 g, such as about 50 to about 1000 mg, or about Contains from 100 to about 600 mg of the compound.

  In certain embodiments, the composition is placed in a hard or soft shell (eg, gelatin) capsule or in the form of a compressed or molded tablet. The composition specifically includes, as an excipient, one or more diluents such as lactose or dicalcium phosphate (a liquid carrier may be present in the case of capsules); a binder such as gum tragacanth, acacia, Corn starch or gelatin; disintegrants such as corn starch, potato starch, alginic acid, etc .; lubricants such as magnesium stearate; and sweeteners such as sucrose or saccharin and / or flavoring agents such as peppermint, wintergreen Contains oil (or cherry flavoring agent may be added if necessary).

  Various other excipients may be present as coatings or otherwise altering the physical form of the composition. For instance, 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 sustained release formulations. For example, sustained release dosage forms are contemplated in which the compound is bound to an ion exchange resin that can optionally be coated with a diffusion barrier coating that modifies the release characteristics of the resin.

  Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where the compound is water-soluble), sterile dispersions, sterile injectable solutions or sterile powders for the extemporaneous preparation of dispersions. In such cases, the injectable composition must be sterile and must be fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must generally 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, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lectin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The microbial action can be suppressed by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride to provide a substantially isotonic solution for injection. Prolonged absorption of injectable compositions can be brought about by the use of agents in the composition that delay absorption, for example, aluminum monostearate or gelatin.

  Sterile injectable solutions may be prepared, if desired, by incorporating the active compound in the required amount in a suitable solvent together with various other ingredients as described above followed by filter sterilization. Generally, dispersions are prepared by incorporating the sterilized active compound into a sterile vehicle that contains a dispersion medium and other excipient components, such as those described above. Sterile powders for the preparation of sterile injectable solutions may be prepared by vacuum drying or lyophilizing a previously sterile filtered solution or dispersion.

  The therapeutic combination of the present invention comprises, in addition to the first agent as described above, in combination with (a) an improved treatment of pain associated with or caused by a medical condition compared to the first agent alone. And / or (b) a second agent effective to treat another symptom or root cause of the medical condition, wherein the one or more drugs other than the compound of formula (I) A second drug containing.

  In one embodiment, the second agent comprises an anti-arthritic agent other than a compound of formula (I), and the combination is useful for treating an arthritic condition and / or pain associated therewith. More than one anti-arthritic drug may optionally be present in the second drug.

  An “anti-arthritic agent” is a drug that has efficacy in the treatment (including prevention) of any aspect, symptom (eg, pain or inflammation) and / or root cause of an arthritic condition as defined herein. It is.

  For example, an anti-arthritic drug contained in or as a second drug can be effective in treating pain, ie, analgesia. Suitable analgesics include opioid and non-pioid analgesics, as well as certain anti-inflammatory drugs (see immediately below). A combination comprising a compound of formula (I), (II) or (III), e.g. lacosamide, and an opioid or non-opioid analgesic is suitable for any arthritic condition involving pain, particularly as such pain is in osteoarthritis. It may be useful if it has a non-inflammatory element.

  Alternatively or in addition, an anti-arthritic agent included in or as the second agent may be effective in treating inflammation and / or pain associated therewith. Suitable anti-inflammatory drugs include steroidal and non-steroidal anti-inflammatory drugs. Non-steroidal anti-inflammatory drugs (NSAIDs) include traditional NSAIDs and cyclooxygenase-2 (COX-2) selective inhibitors. A combination comprising a compound of formula (I), (II) or (III), e.g. lacosamide, and an anti-inflammatory drug is any combination with inflammatory pain or in which both inflammatory and non-inflammatory types of pain are present May be useful in other arthritic conditions.

  Non-limiting examples of opioid and non-opioid analgesics that may be useful for the second drug include acetaminophen, alfentanil, allylprozine, alphaprozin, anilellidine, benzylmorpholine, vegitramide, buprenorphine, butorphanol, clonitazen, Codeine, Cyclazosin, Desomorphin, Dextromoramide, Dextropropoxyphene, Dezocine, Diampromide, Dimorphone, Dihydrocodeine, Dihydromorphine, Dimenoxadol, Dimefeptanol, Dimethylthianbutene, Dioxafetilbutyrate, Dipipanone, Dipyrone (Metamizole) , Eptazosin, etoheptadine, ethyl methyl thianbutene, ethyl morphene, etonitazen, fentanyl, heroin, hydrocodone, hyphen Lomorphone, hydroxypetidin, isomethadone, ketobemidone, levalorphan, levorphanol, levofenacil-morphane, lofentanil, meperidine, meptazinol, metazosin, methadone, methopone, morphine, mirofin, nalbuphine, nalolphine, narcein, nicomorphine, norlevorphanol, normethordon , Normorphin, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazodine, phenadoxone, phenazosin, phenomorphan, phenoperidine, pimidine, pyritramide, proheptadine, promedol, properidine, propilam, propoxyphene, sufentanil, thyridine, tramadol, NO Naproxen, NCX-701, ALGRX-4975, pharmaceutically acceptable These salts, and combinations thereof.

  Non-limiting examples of steroidal anti-inflammatory drugs that may be useful for the second drug include alcromethasone, amsinonide, betamethasone, betamethasone 17-valerate, clobetasol, clobetasol propionate, crocortron, cortisone, dehydrotestosterone, deoxycortis Costerone, Desonide, Desoximethasone, Dexamethasone, Dexamethasone 21-isonicotinate, Diflorazone, Fluocinonide, Fluocinolone, Fluorometron, Fluland Lenolide, Fluticasone, Halsinonide, Halobetasol, Hydrocortisone, Hydrocortisone Acetate, Hydrocortisone Cypionate, Hydrocortisone Cypionate -Hydrocortisone ricinate, sodium hydrocortisone succinate, isoflupredone, isoflupredone acetate, methylpred Nizolone, methylprednisolone acetate, sodium methylprednisolone succinate, methylprednisolone streptanoate, mometasone, prednisocarbate, prednisolone, prednisolone acetate, prednisolone hemisuccinate, sodium prednisolone phosphate, sodium prednisolone nicotinate Triamcinolone, triamcinolone acetonide, their pharmaceutically acceptable salts, and combinations thereof are included.

  Non-limiting examples of NSAIDs that may be useful in the second agent include salicylic acid derivatives (e.g., salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, olsalazine, salsalate and sulfasalazine), indole and indene acetic acid ( (E.g., indomethacin, etodolac and sulindac), phenamates (e.g. etofenamic acid, meclofenamic acid, mefenamic acid, flufenamic acid, niflumic acid and tolfenamic acid), heteroaryl acetic acids (e.g. acemetacin, alclofenac, clidanac, diclofenac, fenclofenac) Nac, Fenthiazac, Flofenac, Ibufenac, Isoxepak, Ketorolac, Oxypinac, Thiopinac, Tolmetine, Zidometacin and Zomepi ), Arylacetic acid and propionic acid derivatives (e.g., aluminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, Miloprofen, naproxen, oxaprozin, pyrprofen, pranoprofen, suprofen, thiaprofenic acid and thiooxaprofen), enolic acid (e.g. oxicam derivatives ampiroxicam, synoxicam, droxicam, lornoxicam, meloxicam, piroxicam, sudoxicam and tenoxicam, and pyrazolone derivatives Aminopyrine, antipyrine, apazone, dipyrone, oxyphenbutazone and phenylbutazone), alkanone (Eg, nabumetone), nimesulide, proquazone, MX-1094, lycoferon, and pharmaceutically acceptable salts thereof, and combinations thereof.

  Non-limiting examples of COX-2 selective inhibitors that may be useful for the second agent include celecoxib, deracoxib, valdecoxib, parecoxib, rofecoxib, etlicoxib, luminacoxib, PAC-10549, cimicoxib, GW-406381, LAS -34475, CS-502, pharmaceutically acceptable salts thereof, and combinations thereof.

  Alternatively or additionally, the second agent may specifically include a disease modifying osteoarthritic agent (DMOAD). Non-limiting examples of DMOAD (s) that may be useful for a second agent include methotrexate, diacerein, glucosamine, chondroitin sulfate, anakinra, MMP inhibitor, doxycycline, minocycline, misoprostol, proton pump inhibitor, Non-acetylated salicylate, tamoxifen, prednisone, methylprednisolone, polysulfated glycosaminoglycan, calcitonin, alendronate, risedronate, zoledronic acid, teriparatide, VX-765, prarnacasan, SB-462795, CPA-926, ONO-4817 , S-3536, PG-530742, CP-544439, pharmaceutically acceptable salts thereof, and combinations thereof.

  Alternatively or additionally, the second agent may specifically include a disease modifying anti-rheumatic drug (DMARD). Non-limiting examples of DMARDs that may be useful for secondary agents include etanercept, adalimumab, infliximab, IL-1 receptor antagonists, glucocorticoids such as prednisone and methylprednisolone, penicillamine, hydroxychloroquine sulfate, chlorambucil, Cross phosphamide, leflunoid, cyclosporine, auranofin, aurothioglucose, azathiopyrine, gold thiomalate, methotrexate, cyclophosphamide, minocycline, sulfasalazine, abatacept, rituximab, bucylamine, chloroquine, hydroxychloroquine, lobenzalit, misopro Stalls, pharmaceutically acceptable salts thereof, and combinations thereof are included.

  Alternatively or additionally, the second agent may specifically include a symptom modifying anti-rheumatic drug not described above. Non-limiting examples of such drugs that may be useful for the second agent include ADL-100116, AD-827, HOE-140, DA-5018, pharmaceutically acceptable salts thereof, and Is included.

Two or more anti-arthritic agents may be administered in combination or adjuvant therapy with a compound of formula (I), (II) or (III), eg, lacosamide. In one embodiment, two or more such agents are in the following class:
(i) opioid and non-opioid analgesics;
(ii) steroidal anti-inflammatory drugs;
(iii) NSAIDs and COX-2 selective inhibitors;
(iv) DMOADS; and
(v) DMARD (multiple)
It is included in combination therapy or adjuvant therapy selected from two or more of these.

  In certain embodiments, two or more agents administered in combination or adjuvant therapy with a compound of formula (I), (II) or (III), such as lacosamide, wherein at least one of the agents is DMOAD or DMARD Selected from certain of the above listed drugs.

  In one embodiment, administration of the therapeutic combination is useful for treating both arthritic conditions and associated pain. Specifically, compounds of formula (I), (II) or (III), such as lacosamide, may be used to treat pain associated with arthritic conditions, more particularly non-inflammatory pain, and are listed above. At least one anti-arthritic drug, such as one, to treat the underlying process that causes or causes the arthritic condition, or to treat another symptom of the arthritic condition, such as inflammatory pain You may use together with the compound of a formula (I), (II) or (III).

  In another embodiment, present in an effective amount in combination with the first agent to provide improved treatment of pain, more particularly non-inflammatory pain, as compared to the first agent alone. Any drug that provides such improved treatment in combination with a first drug is a second drug, such as an opioid or non-opioid analgesic, an anticonvulsant, an antidepressant and / or an NMDA receptor antagonist. Can be used or included in them.

`` Improved pain treatment '' in this context refers to the following points:
(a) a greater reduction in pain intensity and / or duration;
(b) allow for dose reduction of either the first drug or the second drug or both compared to the normal effective dose when used in monotherapy;
(c) reduction of harmful side effects; and / or
(d) means that the combination is superior to the first agent alone in at least one of the improved treatable ratios.

  The first and second agents are not required to interact more than additively, but in some cases, the reduction in pain intensity and / or duration provided by the combination may be at the same dose. It can be greater than expected based on the effectiveness of either drug alone.

  According to this embodiment, the second drug can include, for example, one or more analgesics selected from those listed above. In a specific example, the second agent comprises morphine or a pharmaceutically acceptable salt thereof.

  Alternatively or in addition, the second agent can be, for example, acetylphenethylide, arbutoin, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactoamide, bechramid, bramate, carbamazepine, sylromido, clomethiazole, clonazepam , Decimemide, Diethadione, Dimethadione, Doxenitoin, Eterovalve, Etadione, Ethoximid, Etotoin, Ferbamate, Fluoresson, Phosphenytoin, Gabapentin, Ganaxolone, Lamotrigine, Levetiracetam, Lorazepam, Mefentotemetomitometomidometomidome Narcobarbital, nitrazepam, oxcarbazepine, parameterdione, phenacemide, phenetalbital, phenethylide, Nobarbital, fenceximide, phenylmethylbarbituric acid, phenytoin, phenethylate, pregabalin, primidone, progabide, remasemide, rufinamide, suclophenide, sultiam, thalene panel, tetratoin, tiagabine, topiramate, trimethadione, valproic acid, valpromide, nigabamide One or more anticonvulsants selected from pharmaceutically acceptable salts thereof, and combinations thereof.

  In a more specific embodiment, the second agent comprises one or more anticonvulsants selected from carbamazepine, phenytoin, gabapentin, pregabalin, lamotrigine, levetiracetam, and pharmaceutically acceptable salts thereof. In a specific example, the second agent includes gabapentin.

  Alternatively or in addition, the second agent includes one or more antidepressants, including but not limited to bicyclic, tricyclic and tetracyclic antidepressants, hydrazide, hydrazine, phenyloxazolidinone and pyrrolidone. sell. Antidepressants include, for example, azinazolam, adrafinil, amineptin, amitriptyline, amitriptyline oxide, amoxapine, befloxatone, bupropion, butacetin, buttriptyline, caloxazone, citalopram, clomipramine, cotinine, demexeptiline, decipramine, dioxadoline, dimetacrine, Dothiepine, doxepin, duloxetine, etoperidone, femoxetine, fencamine, fenpentadiol, fluacidin, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, imipramine, imipramine N-oxide, indalpine, indeloxazine, iprindole, iproclodide, iproxid De, levofacetoperan, Fepramine, maprotiline, medifoxamine, melitracene, metapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, moclobemide, nefazodone, nefopam, niaramide, nomifensine, nortriptyline, noxiptylline, octamoxine, opipramol, oxafurozan, oxytriptan, oxytriptan Phenelzine, piberalin, pizotirin, prolintan, propizepine, protriptyline, priscodanol, quinupramine, reboxetine, ritanserin, roxindole, rubidium chloride, sertraline, sulpiride, tandospirone, thiazesim, tozalinone, tianeptine, tofenacin, toloxaton, tolamine , Trazodone , Trimipramine, tryptophan, venlafaxine, viloxazine, dimerzine, pharmaceutically acceptable salts thereof, and combinations thereof. In a specific example, the second agent comprises duloxetine.

  Alternatively or in addition, the second agent can be, for example, amantadine, D-AP5, aptiganel, CPP, dexanabinol, dextromethorphan, dextropropoxyphene, 5,7-dichloroquinurenic acid, gavestinel, ifendopril, ketamine One or more selected from: ketobemidon, lycostinel, LY-235959, memantine, methadone, MK-801, phencyclidine, remademid, serfotel, tiretamine, pharmaceutically acceptable salts thereof, and combinations thereof An NMDA receptor antagonist may be included. In a specific example, the second agent comprises memantine.

  In another embodiment, the second agent is from a GABA analog, thiophenepropane derivative, morphine analog and opioid, NSAIDs 2-arylpropionic acid (profen) family, and amantadine (1-aminoadamantane) derivatives. One or more drugs independently selected from the group consisting of:

  An example of a GABA analog is gabapentin. An example of a thiophenepropane derivative is duloxetine. An example of an opioid is morphine. A member of the 2-arylpropionic acid family of NSAIDs is naproxen. The derivative of amantadine is memantine.

  In another embodiment, the second agent comprises one or more drugs independently selected from the group consisting of gabapentin, duloxetine, morphine, naxproxen, and memantine.

  In yet another embodiment, the second agent comprises one or more drugs independently selected from the group consisting of duloxetine, morphine, naxproxen, and memantine.

  In another embodiment, in the combination of the present invention, the first agent comprises lacosamide.

  In yet another embodiment, in the combination of the present invention, the first agent comprises lacosamide and the second agent comprises gabapentin.

  In yet another embodiment, in the combination of the invention, the first agent comprises lacosamide and the second agent comprises duloxetine.

  In yet another embodiment, in the combination of the invention, the first agent comprises lacosamide and the second agent comprises morphine.

  In yet another embodiment, in the combination of the invention, the first agent comprises lacosamide and the second agent comprises naxproxen.

  In yet another embodiment, in the combination of the invention, the first agent comprises lacosamide and the second agent comprises memantine.

  In one embodiment of the invention, the combination of the present invention provides an improved treatment of pain associated with or caused by a medical condition, the medical condition being accompanied by or having non-inflammatory pain as a symptom thereof .

  In one embodiment of the invention, the combination of the invention provides an improved treatment of pain, wherein the pain associated with a medical condition includes non-inflammatory pain.

  In one embodiment of the invention, the combination of the invention provides an improved treatment of pain associated with or caused by a medical condition, wherein the medical condition is an arthritic condition and / or pain associated therewith. The arthritic condition can include osteoarthritis. In this embodiment, in the combination, the first and second agents may be present in absolute and relative amounts effective to treat the arthritic condition and / or pain associated therewith. In the combination, the first and second agents may be present in absolute and relative amounts effective to treat both the non-inflammatory and inflammatory components of pain associated with or caused by the arthritic condition.

  In the combination, the first and second agents may be present in absolute and relative amounts effective to treat non-inflammatory pain associated with an arthritic condition. The first and second agents may be present in absolute and relative amounts effective to treat non-inflammatory osteoarthritic pain.

  In the combination, the first and second agents may be present in absolute and relative amounts effective to treat inflammatory pain associated with an arthritic condition. The first and second agents may be present in absolute and relative amounts effective to treat inflammatory osteoarthritic pain.

  Osteoarthralgia can involve angiogenesis in areas of cartilage degradation, structural bone changes, and / or osteoarthritis remodeling.

  Arthritic conditions include idiopathic osteoarthritis, secondary osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, infectious arthritis, ankylosing spondylitis, neurogenic arthropathy, polyarthralgia, and Sjogren's syndrome, It may include one or more disorders selected from the group consisting of Behcet syndrome, Reiter syndrome, systemic lupus erythematosus, rheumatic fever, gout, pseudogout, Lyme disease, sarcoidosis and arthritis associated with ulcerative colitis.

  The arthritic condition can include rheumatoid arthritis or juvenile rheumatoid arthritis.

  In another embodiment of the invention, the combination of the invention provides an improved 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. In the combination, the first and second drugs are: average daily pain, total pain, current pain intensity, pain sleep disturbance, patient perception of pain general activity disturbance, patient general impression of pain change, clinical overall pain change It may be effective in the treatment of an aspect of pain selected from the group consisting of impression, patient perception of different neuropathic pain qualities, quality of life and percentage of days without pain.

  In the present invention, painful diabetic neuropathy can be associated with type 1 diabetes or type II diabetes. Painful diabetic neuropathy can also accompany type II diabetes.

  In another embodiment of the invention, the combination of the invention provides an improved treatment of pain associated with or caused by a medical condition, wherein the medical condition or pain associated therewith is acute Inflammatory pain; acute pain; alcoholism-related 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-related or diabetes-induced neuropathic pain; Diabetic distal sensory neuropathy; Diabetic distal sensory polyneuropathy; Diabetic pain; Fibromyalgia; Headache; Hyperalgesia; Hypersensitivity; hyperalgesia; migraine; muscle pain; fascial pain syndrome; neuralgia; neuroma; non-inflammatory osteoarthritic pain; non-neuropathic inflammatory pain; neuropathic pain; associated with chemotherapy or radiation therapy Or induced pain Pain associated with or caused by traumatic nerve injury or compression or traumatic injury to the brain or spinal cord; painful diabetic neuropathy; peripheral neuropathic pain; persistent clinical pain; phantom pain; rheumatoid arthritis pain; Secondary inflammatory osteoarthritic pain; trigeminal neuralgia; vascular headache; and combinations thereof.

  The second agent may be present in an effective amount in combination with the first agent alone to provide improved treatment of pain compared to the first agent.

  Yet another embodiment of the present invention is a method of treating a painful medical condition and / or pain associated therewith in a subject, the method comprising administering to the subject a therapeutic combination of the present invention. It is a method including. In the methods of the present invention, the painful medical condition or / and pain associated therewith is selected from the conditions as described herein.

  In another embodiment of the method, the medical condition or pain associated therewith is acute inflammatory pain; acute pain; alcoholism-related or alcoholism-induced neuropathic pain; allodynia; arthritic condition; back Pain; Cancer-related neuropathic pain; Central neuropathic pain; Chronic headache; Chronic inflammatory pain; Chronic pain; Chronic pain due to peripheral nerve injury; Diabetes-related or diabetes-induced neuropathic pain; Diabetic distal sensory neuropathy Diabetic distal sensory polyneuropathy; diabetic pain; fibromyalgia; headache; hyperalgesia; hypersensitivity; hyperalgesia; migraine; muscle pain; fascial pain syndrome; neuralgia; neuroma; non-inflammatory Osteoarthritic pain; non-neuropathic inflammatory pain; neuropathic pain; pain associated with or induced by chemotherapy or radiation therapy; associated with or induced traumatic nerve injury or compression or traumatic injury to the brain or spinal cord Pain Painful diabetic neuropathy; peripheral neuropathic pain; persistent clinical pain; phantom pain; rheumatoid arthritis pain; secondary inflammatory osteoarthritic pain; trigeminal neuralgia; vascular headache; and combinations thereof Selected.

  In yet another embodiment, the methods of the invention employ a first agent that comprises lacosamide in the combination.

  Yet another aspect of the present invention is a book for the preparation of a medicament for improved prevention, alleviation or / and treatment of pain associated with or caused by a medical condition compared to a compound of formula (I) alone. Use of a combination as defined in the specification; the second agent comprises one or more drugs other than the compound of formula (I).

  In one embodiment of the use of the present invention, the painful medical condition or / and pain associated therewith is selected from conditions as described herein.

  In another embodiment of the use of the invention, in the combination, the first agent comprises lacosamide.

  Suitable dosing schedules including the dosage and route of administration for a second drug or as a second drug useful as a second drug are readily available reference sources for these drugs, such as the Physicians' Desk Reference (PDR), 60th edition, Montvale, NJ: Thomson (2006) and various Internet sources known to those skilled in the art. When administered in combination or in adjunct therapy with a compound of formula (I), (II) or (III), such as a compound of lacosamide, the total amount of drug useful as or as a second drug is However, the physician may choose to administer less than the total amount of such drugs at least initially.

  The first agent and the second agent may be in one pharmaceutical preparation (single dosage form) for simultaneous administration to a subject, or at the same or different times, e.g., sequentially and / or the same Alternatively, it can be given in two or more separate preparations (separate dosage forms) for administration to a subject at different frequencies. The two separate preparations can be given in a form adapted for administration by the same route or by different routes.

  Separate dosage forms can optionally be co-packaged in, for example, a single container or multiple containers within a single sheath, or can co-exist ("co-present") in separate packages. . As an example of co-packaging or co-presentation, a compound of formula (I), (II) or (III), such as lacosamide, in a first container and a second as described herein in a second container. Kits comprising the agents are contemplated. In another example, a compound of formula (I), (II) or (III), for example lacosamide, and a second agent are packaged separately and are available for sale independently of each other, but the use according to the invention Are either marketed together or promoted together. For use in accordance with the present invention, separate dosage forms may be provided to the subject separately and independently.

  Depending on the dosage form, which may be the same or different, for example a rapid release dosage form, a controlled release dosage form or a depot dosage form, a compound of formula (I), (II) or (III), for example The lacosamide, and the second agent can be administered on the same or different schedule, eg on a daily, weekly or monthly basis.

  In one embodiment, administration of the therapeutic combination is useful for treating non-inflammatory osteoarthritic pain. Such administration is particularly useful when non-inflammatory osteoarthritic pain is associated with cartilage degradation, structural bone changes, and / or angiogenesis in the area of bone remodeling. The bone is continuously reshaped. Remodeling is a process in which old bone is replaced with new bone to maintain peak bone density. Angiogenesis is caused by the growth of capillaries during the remodeling process and can be increased in conditions such as osteoarthritis.

  In one embodiment, administration of the therapeutic combination suppresses pain transmission. Inhibition of pain transmission, a commonly contributing effect of compounds of formula (I), (II) or (III), for example lacosamide, is that spinal neurons respond to neurotransmitters such as glutamate released by nociceptors Can be achieved by hindering.

(Example)
(Example 1)
This example demonstrates the suppression of mechanical hyperalgesia, as measured by paw withdrawal threshold for muscle pressure, which occurs in TNF-induced musculoskeletal pain in rats, and mechanical strength as measured by biceps grip strength. Described is a study showing the antinociceptive efficacy of lacosamide in suppressing allodynia. The model used in this example can be applied to musculoskeletal pain that occurs in fibromyalgia, fascial pain syndrome, back pain or osteoarthritis. For comparison purposes, the non-opioid analgesic agent dipyrone (methamizole) and the anticonvulsants pregabalin and gabapentin were included in this study.

Animals, induction of myalgia Adult male Sprague Dawley rats (body weight 250-300 g) were used (supplier: Charles River, Sulzfeld, Germany). Animals were housed (3 animals per cage) and maintained in a room with controlled temperature (21-22 ° C) and inverted light-dark cycle (12 hours / 12 hours) with freely available food and water . All experiments were approved by the Bavarian State Animal Experiment Committee and conducted in accordance with its regulations.

  Recombinant rat tumor necrosis factor alpha (referred to herein as TNF) was obtained from R & D Systems, Minneapolis, MN, U.S.A. TNF was diluted in 0.9% NaCl and used at a concentration of 1 μg in 50 μl. Injections were made with a short halothane anesthesia with a 30 g needle in both the gastrocnemius or biceps. All rats were used for behavioral testing, after which injection values and baseline values were recorded over three test days.

Behavioral readout: Randall-Selitto
The mechanical withdrawal threshold for muscle pressure was measured with an analgesimeter (Ugo Basile, Comerio, Italy). Rats were placed in socks that helped to relax the rats. The hind limb was placed so that increasing pressure could be applied on the gastrocnemius muscle (up to 250 g). The pressure required to cause retraction was recorded. The average of three trials was calculated for each hindlimb (interval between stimuli over 30 seconds). Only animals with significant TNF effects were included for further analysis.

  At 2 pm, rats were injected with TNF into the gastrocnemius muscle. After 18 hours, the rats were tested for tenderness before and after administration of the test drug. Rats were tested for hyperalgesia 30 to 60 minutes after drug administration.

Behavioral readout: grip strength The grip strength of the forelimbs was tested with a digital grip strength meter (DFIS series, Chatillon, Greensboro, NC, USA). The rat was placed to grip the grid with its forelimbs and gently pulled to record its grip strength. The average of 3 trials was calculated. The effect of TNF treatment was calculated individually for each animal and only animals with significant TNF effects were included in further analysis.

  At 8 am, rats were injected with TNF into the biceps. After 6 hours, the grip strength of the forelimbs was tested with a digital dynamometer. Test drugs were administered and grip strength was tested again 30-60 minutes later.

Administration protocol
ip (intraperitoneally) with either 10, 10 or 30 mg / kg lacosamide, 2 mg / kg metamizole, 30 or 100 mg / kg pregabalin, 100 mg / kg gabapentin, or NaCl vehicle initially at 10 per group One rat was treated. The ip injection volume was 0.5 ml. Preliminary experiments were performed to confirm that im (intramuscular) injection of 1 μg TNF into the gastrocnemius muscle was sufficient to induce tenderness.

  Tables 1 and 2 summarize groups and treatments for TNF gastrocnemius and biceps injections, respectively.

Data presentation and statistics The data are shown in a graph displaying the mean and standard error of the mean (SEM). ANOVA (Analysis of Variance) and Tukey post hoc test were used to compare pre- and post-treatment data. One-way ANOVA and Dunnett's post hoc test were used to compare the treatment group means. The maximum possible effect (MPE) was calculated for all types of treatment.

Result: Muscle hyperalgesia
Only rats with significantly reduced withdrawal thresholds after TNF injection were included. In about 13% of the rats, there was no TNF effect. FIG. 1 shows the absolute value of the withdrawal threshold versus pressure.

  A complete reversal of muscle mechanical hyperalgesia was seen with lacosamide 30 mg / kg and metamizole 2 mg / kg.

  Significant reversal of muscle mechanical hyperalgesia was also seen for pregabalin 30 and 100 mg / kg, and gabapetin 100 mg / kg.

  MPE (Figure 2) was significantly different from vehicle for lacosamide 10 and 30 mg / kg, pregabalin 30 and 100 mg / kg, gabapentin 100 mg / kg, and metamizole 2 mg / kg. The vehicle had no effect.

Result: biceps grip strength
Only rats with significantly reduced grip strength after TNF injection were included. In about 13% of the rats, there was no TNF effect. FIG. 3 shows the absolute value of the grip strength.

  A significant reversal of TNF-induced decrease in grip strength was seen with lacosamide 10 and 30 mg / kg. Significant reversals were also seen for pregabalin 100 mg / kg, gabapentin 100 mg / kg and metamizole 2 mg / kg.

  MPE (FIG. 4) was significantly different from vehicle for lacosamide 10 and 30 mg / kg, pregabalin 100 mg / kg, gabapentin 100 mg / kg, and metamizole 2 mg / kg. The vehicle had no effect.

Discussion Lacosamide dose-dependently improved myalgesia induced by TNF injection in the foot pressure test reached a complete reversal at 30 mg / kg. Compared to the anticonvulsants pregabalin and gabapentin, lacosamide had a stronger effect on myalgia. Neither pregabalin nor gabapentin resulted in a complete reversal of myalgesia. In a grip strength test showing mechanical allodynia, lacosamide reversed the effect of TNF on muscle at 10 mg / kg. Again, lacosamide was more potent than pregabalin and gabapentin, which improved grip strength at 100 mg / kg.

  In conclusion, lacosamide was effective in reducing myalgesia and mechanical allodynia induced by TNF injected into muscle. Thus, specifically, lacosamide, a compound of formulas (I), (II) and (III), for example, non-inflammatory musculoskeletal pain caused by fibromyalgia, fascial pain syndrome, back pain or osteoarthritis, For example, it is concluded that it has therapeutic effects in the treatment of specific expression of myalgesia and allodynia, in particular systemic treatment.

(Example 2)
This example describes a study showing the antinociceptive efficacy of lacosamide in an iodoacetate rat model. The model used in this example can be applied to non-inflammatory osteoarthritic pain. For comparative purposes, the opioid analgesic morphine and NSAID diclofenac were included in this study.

  One of the best characterized rat models for osteoarthritis is the injection of the metabolic inhibitor monosodium iodoacetate into joints such as the knee joint, which is glyceraldehyde-3-phosphate in chondrocytes Inhibits the activity of dehydrogenase, leading to the breakdown of glycolysis and resulting 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 in articular cartilage, much like those seen in human osteoarthritic patients.

Male Wistar rats (Janview, France) (weight 170-200 g) were used at the start of the animal study. Animals were housed in groups (3 animals per cage) in a room with controlled temperature (21-22 ° C.) and inverted light-dark cycle (12 hours / 12 hours) and allowed free access to food and water.

Induction of osteoarthritis Osteoarthritis was induced by intra-articular injection with 50 μl of 3 mg monosodium iodoacetate (MIA) (Sigma) through the intrapatellar ligament of the right knee.

  Control rats were injected with an equal volume of saline. By day 5 after iodoacetate injection, substantial inflammation of synovial connections was observed in this model. The general health of the animals was monitored. There were no signs of tightness.

Histology Four animals were sacrificed for histological examination on days 3, 7 and 14 after iodoacetate treatment, respectively. Knees were harvested and fixed overnight in 10% formalin, followed by decalcification with 10% formic acid for 72 hours and then embedded in paraffin. Sections 10 μm thick were prepared every 250 μm. Hematoxylin / eosin staining was performed to assess the extent of inflammatory infiltrates in joints and surrounding tissues, and safranin-O rapid green staining was performed to measure cartilage degeneration.

Assessment of the effects of compounds on nociception In the first round of the experiment, iodoacetate-treated rats were randomized into 6 experimental groups (12 animals per group) on the day of pain assessment (3 days after iodoacetate treatment). Eyes, days 7 and 14) received the following treatments (po = oral; sc = subcutaneous):
Po injection of saline (vehicle);
Po injection of lacosamide 3mg / kg;
Po injection of lacosamide 10 mg / kg;
Po injection of lacosamide 30 mg / kg;
Sc injection of morphine 3 mg / kg.

  Diclofenac (30 mg / kg, s.c.) was tested in separate experiments by the same scientist under the same conditions at about the same time. A non-iodoacetate treated control group (control) received a p.o. injection of saline 45 minutes prior to pain assessment. Lacosamide, diclofenac and morphine were injected 60 minutes before the conduct of the behavioral test. Each group was investigated blindly.

Evaluation of tactile allodynia and mechanical hyperalgesia To test tactile allodynia, rats were placed on a metal grid floor. A nociceptive test was performed by inserting a von Frey filament (Bioseb, France) through the lattice floor and applying it to the plantar surface of the hind paw. The test consisted of several applications of different von Frey filaments (at a frequency of about 1 Hz). The von Frey filament was applied at 10 to 100 g filament. As soon as the animal subsequently removed its paw, the test was stopped and the number of filaments was recorded to represent the paw withdrawal threshold.

  To test for mechanical hyperalgesia, the nociceptive flexion reflex was quantified using a Randall-Selitto paw pressure device (Bioseb, France) that exerts a linearly increasing mechanical force on the dorsal back of the rat. . The paw withdrawal threshold was defined as the force with which the rat retracts its paw. The cut-off pressure was set at 250 g.

Drugs and Reagents Lacosamide (Schwarz BioScience GmbH) and morphine sulfate (Francopia, France) were dissolved in saline. Monosodium iodoacetate and diclofenac were purchased from Sigma (France). Drug administration was performed at a volume of 1 ml / kg.

Data analysis and statistics
ANOVA was used to compare groups of behavioral data at different time points, followed by post-hoc analysis (Dunnett's test).

Results Joint lesions were evaluated on days 3, 7 and 14 after intra-articular injection of iodoacetate. On day 3, there was a substantial initial inflammatory response. This inflammation was characterized by swelling of the synovium that could be most caused by fibrin with proteinous edema fluid and infiltrating macrophages, neutrophils, plasma cells and leukocytes. The cartilage remained unchanged. By day 7, the inflammation in the synovium and surrounding tissue was mostly resolved. On the 14th day, proteoglycan disappeared over the deep part of the cartilage. The synovium appeared normal and did not contain any inflammatory cells.

  Tactile allodynia was assessed in iodoacetate treated rats compared to control rats by testing with von Frey filaments on days 3, 7 and 14. Treatment with lacosamide (30 mg / kg) and morphine (3 mg / kg) improved tactile allodynia in iodoacetate treated rats on days 3 (Figure 5A) and 7 (Figure 5B), but on day 14. There was no improvement in (FIG. 5C) and the lower dose of lacosamide showed a trend of such improvement. Diclofenac (30 mg / kg) had no effect on tactile allodynia on day 3 (FIG. 6A), day 7 (FIG. 6B) or day 14 (FIG. 6C).

  There was significant mechanical hyperalgesia as evidenced by a decrease in paw pressure withdrawal threshold in iodoacetate / vehicle treated animals compared to control / vehicle treated animals. Treatment of iodoacetate-treated rats with 3 mg / kg of lacosamide, 3 mg / kg of morphine and 30 mg / kg of diclofenac in each case, paw pressure compared to iodoacetate / vehicle-treated animals on day 3 (Figures 7A, 8A) An increase in withdrawal threshold was induced. On day 7, lacosamide, morphine and diclofenac at all doses tested (3, 10 and 30 mg / kg) decreased mechanical hyperalgesia, respectively (FIGS. 7B, 8B). Similar results were seen 14 days after iodoacetate treatment, except that the group treated with lacosamide 10 mg / kg had no statistically significant effect (FIGS. 7C, 8C). Interestingly, mechanical hyperalgesia progressed from day 3 and continued for at least 14 days in iodoacetate treated animals compared to antennal allodynia that was more intense during the early stages of arthritis progression, which continued for at least 14 days after iodoacetate treatment. Reflected the continuing progression of pain sensitization based on different molecular mechanisms during 14 days.

  The results show that lacosamide inhibited mechanical nociception during the post-inflammatory period, indicating the effectiveness of lacosamide for treating non-inflammatory osteoarthritic pain.

(Example 3)
This example demonstrates the use of lacosamide alone and in combination with gabapentin in the rat formalin paw test (late stage) to detect analgesia, as described in Wheeler-Aceto & Cowan (1991) Psychopharmacology 104: 35-44. The test that shows the effectiveness is described.

Materials and Methods Rats received an intraplantar injection of 5% formalin (50 μl) into the rear left paw. This treatment induces a discernable, dull and licking response of the affected paw in control animals. Starting 20 minutes after formalin injection, the number of winches was counted for 15 minutes. The time for licking the affected foot was also recorded.

  Male Rj: Wistar (Han) rats, 10 per group, body weight 100-130 g at the start of the experiment were tested for each group. The test was performed blind.

  Lacosamide (20 mg / kg), gabapentin (50 and 100 mg / kg), a combination of lacosamide (20 mg / kg) and gabapentin (50 and 100 mg / kg), and vehicle were administered i.p. 10 minutes prior to formalin injection.

Results The results of the test are shown in Table 3 (number of winches) and Table 4 (Licking time).

  Compared to the vehicle control, lacosamide alone at 20 mg / kg tended to reduce the number of winks by 33%. This also tended to reduce licking time by 34% compared to vehicle control (p = 0.0962).

  Compared to the vehicle control, gabapentin alone at 50 and 100 mg / kg reduced the number of winches overall, but not significantly, by 24% and 31%, respectively. Gabapentin reduced dose-dependent licking time by 28% (50 mg / kg) and 60% (100 mg / kg), and was significantly so at 100 mg / kg (p <0.05).

  Compared to the vehicle control, lacosamide 20 mg / kg in combination with gabapentin 50 and 100 mg / kg reduced the number of winches by 64% and 76%, respectively, clearly and dose-dependently (p <0.01). The combination reduced licking time by 74% (p <0.01) and 82% (p <0.001), respectively. The effect of lacosamide in combination with gabapentin on the number of winches and licking time was significantly more pronounced than the effect of lacosamide alone (p <0.05 or p <0.01).

(Example 4)
This example describes a study showing the effectiveness of lacosamide alone and in combination with morphine in the rat formalin paw test (late stage) as described in Wheeler-Aceto & Cowan (1991) above.

Materials and Methods Test methods were similar to those of Example 3. Lacosamide (10 and 20 mg / kg), morphine (2 and 4 mg / kg), a combination of lacosamide (10 and 20 mg / kg) and morphine (2 and 4 mg / kg), and vehicle 10 minutes prior to formalin injection ip administered.

Results The results of the test are shown in Table 5 (number of winches) and Table 6 (Licking time).

  Compared to the vehicle control, lacosamide alone at 10 and 20 mg / kg did not significantly affect the number of shininess (22% increase and 35% decrease, respectively), but the trend towards a decrease at 20 mg / kg was statistical (P = 0.0961). Lacosamide reduced licking time in a dose-dependent manner by 28% at 10 mg / kg (p <0.05) and 56% at 20 mg / kg (p <0.001).

  Compared to the vehicle control, morphine alone at 2 and 4 mg / kg reduced the number of winches and licking time in a dose-dependent manner. Nevertheless, these effects did not reach statistical significance.

  Compared to vehicle control, lacosamide 10 mg / kg in combination with morphine 4 mg / kg clearly reduced the number of shininess by 86% (p <0.001) and licking time by 48% (p <0.01). Not so with morphine 2mg / kg. The effect of lacosamide 10 mg / kg in combination with morphine 4 mg / kg on the number of winches was more pronounced than the effect of lacosamide alone at the same dose p <0.001), but not for licking time. There wasn't.

  Lacosamide 20 mg / kg in combination with morphine 2 and 4 mg / kg produces a clear and dose-dependent, 70% (p <0.01) and 87% (p <0.001) number of winches compared to the vehicle control, respectively. Decreased. This combination reduced licking time by 69% and 94%, respectively, clearly and dose-dependently (p <0.001). The effect of lacosamide 20 mg / kg in combination with morphine on the number of winches and licking time was significantly more pronounced than the effect of lacosamide alone at the same dose (p <0.05 or p <0.01). However, licking time at 2mg / kg dose of morphine is excluded.

(Example 5)
This example describes a study showing the effectiveness of lacosamide alone and in combination with the antidepressant duloxetine in the rat formalin paw test (late stage) as described by Wheeler-Aceto & Cowan (1991), supra.

Materials and Methods Test methods were similar to those of Example 3. Lacosamide (10 mg / kg), duloxetine (8 mg / kg), a combination of lacosamide (10 mg / kg) and duloxetine (8 mg / kg) was administered ip 10 minutes before formalin injection.

Results The results of the test are shown in Table 7 (number of winches) and Table 8 (Licking time).

  Lacosamide 10 mg / kg alone had no significant effect, but tended to reduce the licking time (30% reduction, p = 0.0538).

  Duloxetine 8 mg / kg alone had no obvious effect.

  Compared to the vehicle control, lacosamide 10 mg / kg in combination with duloxetine 8 mg / kg significantly reduced the number of winches by 31% (p <0.05). This combination reduced licking time by 63% (p <0.001). The effect of lacosamide in combination with duloxetine on the number of looseness and licking time was more prominent than the effect of lacosamide alone (p <0.05 to p <0.01).

(Example 6)
This example describes a study showing the efficacy of lacosamide alone and in combination with the NMDA receptor antagonist memantine in the rat formalin paw test (late stage) as described in Wheeler-Aceto & Cowan (1991) above.

Materials and Methods Test methods were similar to those of Example 3. Lacosamide (10 and 20 mg / kg), memantine (4 and 8 mg / kg), a combination of lacosamide (10 and 20 mg / kg) and memantine (4 and 8 mg / kg), and vehicle 10 minutes prior to formalin injection ip administered.

Results The results of the test are shown in Table 9 (number of winches) and Table 10 (time of licking).

  Compared to the vehicle control, lacosamide alone at 10 and 20 mg / kg reduced the number of winches by 31% and 48%, respectively, and was significantly so at 20 mg / kg (p <0.05). ). Lacosamide clearly reduced the licking time at 20 mg / kg (52% reduction, p <0.01), but showed no apparent effect at 10 mg / kg.

  Compared to the vehicle control, memantine alone at 4 and 8 mg / kg did not clearly affect the number of winks. Memantine increased licking time in a dose-dependent manner (25% increase, p = 0.0537 and 35% increase, p <0.05).

  Compared to the vehicle control, lacosamide at 10 mg / kg combined with memantine at 4 and 8 mg / kg reduced the number of winches by 36% and 50%, respectively, in a dose-dependent manner (p <0.05). This combination significantly reduced licking time at 8 mg / kg memantine (35% reduction, p <0.05), but not at 4 mg / kg memantine. The effect of lacosamide in combination with memantine on the number of winches and licking time was not different from the effect of lacosamide alone.

  Lacosamide at 20 mg / kg in combination with memantine at 4 and 8 mg / kg clearly reduced the number of shininess by 74% and 64%, respectively, compared to the vehicle control (p <0.001). This combination clearly reduced the time of licking, but in the opposite manner with respect to memantine dose (69% reduction, p <0.001 and 49% reduction, p <0.05, respectively). The effect of lacosamide in combination with memantine at 4 mg / kg on the number of winches was significantly more pronounced than the effect of lacosamide alone (p <0.05), but not for the time of licking .

(Example 7)
This example describes a test that demonstrates the effectiveness of lacosamide alone and in combination with naproxen in the rat formalin paw test (late stage) as described by Wheeler-Aceto & Cowan (1991) above.

Materials and Methods Test methods were similar to those of Example 3. Lacosamide (10 and 20 mg / kg), naproxen (8 and 16 mg / kg), combination of lacosamide (10 and 20 mg / kg) and memantine (8 and 16 mg / kg), and vehicle 10 minutes prior to formalin injection ip administered. Morphine (8 mg / kg) was included as a comparative treatment.

Results The results of the test are shown in Table 11 (number of winches) and Table 12 (time of licking).

  Compared to the vehicle control, lacosamide alone at 10 mg / kg and 20 mg / kg did not clearly affect the number of winks. Licking time at 20 mg / kg was clearly reduced by 59% (p <0.001), but did not show a clear effect at 10 mg / kg.

  Compared to the vehicle control, naproxen alone at 8 mg / kg and 16 mg / kg had no apparent effect on the number of winks or licking time.

  Compared to the vehicle control, lacosamide 10 mg / kg in combination with naproxen 8 and 16 mg / kg did not clearly affect the number of winches. Lacosamide 10 mg / kg combined with naproxen at 16 mg / kg significantly reduced licking time by 38% (p <0.05), but not at 8 mg / kg. The effect of 10 mg / kg lacosamide in combination with naprokin on the number of winches and licking time was not different from the effect of lacosamide alone.

  Compared to the vehicle control, lacosamide 20 mg / kg in combination with naproxen 8 and 16 mg / kg did not clearly affect the number of winches. Lacosamide 20 mg / kg combined with naproxen at 16 mg / kg significantly reduced licking time by 53% (p <0.01), but not at 8 mg / kg. The effect of 20 mg / kg lacosamide in combination with naproxen on the number of winches and licking time was not different from the effect of lacosamide alone.

  Compared to the vehicle control, morphine alone at 8 mg / kg administered under the same experimental conditions eliminated the time used for winking and licking (p <0.001).

  In summary, Examples 3-7 show a synergistic effect between lacosamide and a compound selected from gabapentin, duloxetine, morphine, naproxen and memantine.

  All patents and publications cited herein are hereby incorporated by reference in their entirety into this application.

  The words “comprise”, “comprises”, and “including” are to be interpreted inclusively rather than exclusively.

  The subject of the present invention is the following embodiments:

  Item 1 Formula (I)

(Where:
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 non- Is substituted or substituted with at least one electron withdrawing group and / or at least one electron donating group;
R ₁ 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 non- Is substituted 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 ZY, 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. Cage;
Z is O, S, S (O) _a , 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 at least one electron Substituted with an attractive group and / or at least one electron donating group, provided that when Y is halo, Z is a chemical bond, or
ZY together, 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 , PR ₄ NR ₅ R ₇ , N ⁺ R ₅ R ₆ R ₇ ,

Subject to
R ′ ₆ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl and is unsubstituted or substituted with at least one electron withdrawing group and / or 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 at least one electron sought. Substituted with an attractive group and / or 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 and / or 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 and / or at least one electron donating group;
n is 1 to 4;
a is 1 to 3)
Or a first agent comprising a pharmaceutically acceptable salt thereof; and in combination therewith (a) improved pain associated with or caused by a medical condition compared to a compound of formula (I) alone One or more other than the compound of formula (I), effective for providing treatment and / or (b) treating another symptom or underlying cause of the medical condition A therapeutic combination comprising a second agent comprising a drug.

Item 2 In the compound of formula (I) present in the first agent, one or both of R ₂ and R ₃ is 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, pyrazolinedinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl, methyl Drill, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl, and N in the heterocycle If present, is a heterocycle independently selected from the group consisting of its N-oxide; the heterocycle is independently unsubstituted or at least one electron withdrawing group and / or at least 1 A combination according to item 1, substituted with two electron donating groups.

  Item 3 The first drug is represented by formula (III)

(Where:
R ₄ is hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, carboxy, formyl, carboxamide, aryl, quaternary ammonium, haloalkyl, arylalkanoyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryloxy, mercapto One or more substituents independently selected from the group consisting of, alkylthio, alkyl mercapto, and disulfide;
R ₃ is selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, N-alkoxy-N-alkylamino, and N-alkoxyamino;
R ₁ is alkyl)
Or a pharmaceutically acceptable salt thereof.

Item 4 In the compound of the formula (III) or a 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;
Item 4. The combination according to Item 3, wherein R ₁ is lower alkyl.

Item 5 The combination according to Item 4, wherein in the compound of formula (III) or a salt thereof, R ₃ is lower alkoxy-lower alkyl.

Item 6 In the compound of formula (III) or a salt thereof:
R ₄ is hydrogen;
R ₃ is methoxymethyl;
R ₁ is methyl, A combination according to claim 3.

Item 7 The first drug is
(R) -2-acetamido-N-benzyl-3-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-phenylglycine benzylamide;
D-1,2- (N, O-dimethylhydroxylamino) -2-acetamidoacetic acid benzylamide;
and
Item 4. The combination according to Item 3, comprising a compound selected from the group consisting of D-1,2- (O-methylhydroxylamino) -2-acetamidoacetic acid benzylamide.

  Item 8 The combination according to Item 3, wherein the compound of the 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 an amount of lacosamide that provides a dose of about 100 to about 6000 mg / day.

  Item 11 The combination of Item 9, comprising an amount of lacosamide that provides a dose of about 200 to about 1000 mg / day.

  Item 12. The combination of item 9, comprising an amount of lacosamide that provides a dose of about 300 to about 600 mg / day.

  Item 13 The combination according to Item 1, wherein the medical condition is accompanied by or has non-inflammatory pain as a symptom thereof.

  Item 14 The combination according to 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-arthritic agents.

  Item 16 In item 15, wherein the one or more anti-arthritic drugs are independently selected from the group consisting of opioid and non-opioid analgesics, steroidal and non-steroidal anti-inflammatory drugs, DMOAD (s) and DMARD (s) Combination of descriptions.

  Item 17 The second drug is acetaminophen, alfentanil, allylprozin, alphaprozin, anileridine, benzylmorpholine, vegitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphin, dextromoramide, dextropropoxyphene, dezocine , Diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthianbutene, dioxafetilbutyrate, dipipanone, eptazocine, etoheptadine, ethylmethylthianbutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, Hydromorphone, hydroxypetidin, isomethadone, ketobemidone, levalorphan, levo Fanol, levofenacil-morphane, lofentanil, meperidine, meptazinol, metazosin, methadone, methopone, morphine, myrophin, nalbuphine, nalolphine, narcein, nicomorphin, norlevorphanol, normethadone, normorphin, norpipanone, opium, oxycodone, oxymorphone, papaberetum , Pentazodine, phenadoxone, phenazosin, phenomorphan, phenoperidine, pimidine, pyritramide, proheptadine, promedol, properidine, propyram, propoxyphene, sufentanil, thyridine, tramadol, NO-naproxen, NCX-701, ALGRX-4975, and pharmaceutical 16. A combination according to item 15, comprising one or more analgesics selected from the group consisting of those salts acceptable in.

  Item 18 , Diflorazone, flusinonide, fluocinolone, fluorometholone, flulandrenolide, fluticasone, halcinonide, halobetasol, hydrocortisone, hydrocortisone acetate, hydrocortisone hepionate, hydrocortisone hemicuccinate, hydrocortisone 21-ricinate, hydrofludonone succinate hydrofludonone acetate Isoflupredone, methylprednisolone, methylprednisolone acetate, sodium succinate Lithium methylprednisolone, methylprednisolone streptanoate, mometasone, prednisocarbate, prednisolone, prednisolone acetate, prednisolone hemisuccinate, sodium prednisolone phosphate, prednisolone succinate, prednisolone valerate-prednisolone, triamcinolone, triamcinolone, triamcinolone 16. A combination according to item 15, comprising one or more steroidal anti-inflammatory drugs selected from the group consisting of pharmaceutically acceptable salts thereof.

  Item 19 The second drug is 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, acemetacinic acid , Alclofenac, Cridanac, Diclofenac, Fenclofenac, Fenthiazac, Flofenac, Ibufenac, Isoxepak, Ketorolac, Oxypinac, Thiopinac, Tolmetine, Zidometacin, Zomepilac, Aluminoprofen, Benoxaprofen, Buclofenic acid, Carprofen, Fenbufen , Fenoprofen, fluprofen, flurbiprofen, ibuprofen Indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pyrprofen, pranoprofen, suprofen, thiaprofenic acid, thioxaprofen, ampiroxicam, cinoxicam, droxicam, lornoxicam, meloxicam, piroxicam, sudoxicam, tenoxicam, aminopyrine, antipyrine, parin One or more non-steroidal anti-inflammatory selected from the group consisting of: dipyrone, oxyphenbutazone, phenylbutazone, nabumetone, nimesulide, proquazone, MX-1094, lycoferon, and pharmaceutically acceptable salts thereof The combination according to item 15, comprising a medicine.

  Item 20 The second drug is celecoxib, delacoxib, valdecoxib, parecoxib, rofecoxib, etoroxixib, lumiracoxib, PAC-10549, cimicoxib, GW-406381, LAS-34475, CS-502, and pharmaceutically acceptable salts thereof 16. A combination according to item 15, comprising one or more COX-2 selective inhibitors selected from the group consisting of.

  Item 21 The second drug is methotrexate, diacerein, glucosamine, chondroitin sulfate, anakinra, MMP inhibitor, doxycycline, minocycline, misoprostol, proton pump inhibitor, nonacetylated salicylate, tamoxifen, prednisone, methylprednisolone, polysulfate Glycosaminoglycan, calcitonin, alendronate, risedronate, zoledronic acid, teriparatide, VX-765, prarnacasan, SB-462795, CPA-926, ONO-4817, S-3536, PG-530742, CP-544439, and 16. A combination according to item 15, comprising one or more DMOAD (s) selected from the group consisting of pharmaceutically acceptable salts thereof.

  Item 22 The second drug is etanercept, adalimumab, infliximab, IL-1 receptor antagonist, prednisone, methylprednisolone, penicillamine, hydroxychloroquine sulfate, chlorambucil, cyclosphosphamide, leflunomide, cyclosporine, auranofin, aurothio Group consisting of glucose, azathioprine, gold sodium thiomalate, methotrexate, cyclophosphamide, minocycline, sulfasalazine, abatacept, rituximab, bucillamine, chloroquine, hydroxychloroquine, robenzalit, misoprostol, and their pharmaceutically acceptable salts 16. A combination according to item 15, comprising one or more DMARD (s) selected from.

  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 the arthritic condition and / or pain associated therewith.

  Item 24 The combination of Item 14, wherein the second agent comprises an anti-inflammatory agent in an amount effective to treat inflammation that occurs in an arthritic condition.

  Item 25. The first and second agents are present in absolute and relative amounts effective to treat both non-inflammatory and inflammatory components of pain associated with or caused by an arthritic condition. The combination described in 14.

  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 an improved treatment of pain compared to the first agent alone.

  Item 27 The combination of Item 26, wherein the improved 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 second drug is acetaminophen, alfentanil, allylprozin, alphaprozin, anileridine, benzylmorphine, vegitramide, buprenorphine, butorphanol, clonitazen, codeine, cyclazocine, desomorphin, dextromoramide, dextropropoxyphene, dezocine , Diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthianbutene, dioxafetilbutyrate, dipipanone, eptazocine, etoheptadine, ethylmethylthianbutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, Hydromorphone, hydroxypetidin, isomethadone, ketobemidone, levalorphan, levo Fanol, levofenacil-morphane, lofentanil, meperidine, meptazinol, metazosin, methadone, methopone, morphine, myrophin, nalbuphine, nalolphine, narcein, nicomorphin, norlevorphanol, normethadone, normorphin, norpipanone, opium, oxycodone, oxymorphone, papaberetum , Pentazodine, phenadoxone, phenazosin, phenomorphan, phenoperidine, pimidine, pyritramide, proheptadine, promedol, properidine, propyram, propoxyphene, sufentanil, thyridine, tramadol, NO-naproxen, NCX-701, ALGRX-4975, and pharmaceutical 27. A combination according to item 26, comprising one or more analgesics selected from the group consisting of those salts acceptable in.

  Item 30. Doxenitoin, eterobulb, etadione, ethosuximide, ethotoin, ferbamate, fluoresson, phosphenytoin, gabapentin, ganazolone, lamotrigine, levetiracetam, lorazepam, mephenytoin, mefobarbital, metalbital, mettezomcoside Zepin, parameterdione, phenacemide, phenetal bital, pheneturide, phenobarbital, phen Nsuccimide, phenylmethylbarbituric acid, phenytoin, phenethylate, pregabalin, primidone, progabide, remasemide, rufinamide, scrofenide, sultiam, thalunpanel, tetrantin, tiagabine, topiramate, trimetadione, valproic acid, valpromide, vigabatrin, and zonisamide 27. A combination according to item 26 comprising one or more anticonvulsants selected from the group consisting of acceptable salts thereof.

  Item 31. Dioxadorol, dothiepine, doxepin, duloxetine, etoperidone, femoxetine, fencamine, fenpentadiol, fluacidin, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, imipramine, imipramine N-oxide, indalpine, indeloxazine, ipridolid, iprodidol , Isocarboxazide, levofacetoperan, Lof Epramine, maprotiline, medifoxamine, melitracene, metapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, moclobemide, nefazodone, nefopam, niaramide, nomifensine, nortriptyline, noxiptylline, octamoxine, opipramol, oxafurozan, oxytriptan Phenelzine, piberalin, pizotirin, prolintan, propizepine, protriptyline, piriscideanol, quinupramine, reboxetine, ritanserin, roxindole, rubidium chloride, sertraline, sulpiride, tandospirone, thiazesim, tozalinone, tianeptine, tofenacin, toloxatone, tolamine , Trazodone, tho Mipuramin, tryptophan, venlafaxine, viloxazine, zimeldine, and a pharmaceutically including acceptable one or more antidepressants selected from the group consisting of salts, the combination of claim 26.

  Item 32. Including one or more NMDA receptor antagonists selected from the group consisting of LY-235959, memantine, methadone, MK-801, phencyclidine, remademid, serfotel, tiretamine, and pharmaceutically acceptable salts thereof, The combination according to item 26.

  Item 33 The combination of item 1, wherein the first agent and the second agent are given 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 given in a dosage form adapted for oral or parenteral administration.

  Item 35 The combination of Item 34, wherein the first agent is given 1 to 3 doses per day in a dosage form adapted for oral administration.

  Item 36 The combination of item 34, wherein the second agent is given in a dosage form that is orally bioavailable and 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 according to Item 37, which is adapted for oral or parenteral administration.

  Item 40. A method of treating a painful medical condition and / or pain associated therewith in a subject, comprising administering to the subject the therapeutic combination of Item 1.

  Item 41 The medical condition or pain associated therewith is acute inflammatory pain; acute pain; alcoholism-related 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 from peripheral nerve injury; diabetes-related or diabetes-induced neuropathic pain; diabetic distal sensory neuropathy; diabetic distal sensory polyneuropathy Disability; Diabetic pain; Fibromyalgia; Headache; Hyperalgesia; Hypersensitivity; Hyperalgesia; Migraine; Muscle pain; Fascial pain syndrome; Neuralgia; Neuroma; Non-inflammatory musculoskeletal pain; Non-inflammatory osteoarthritis Pain; non-neuropathic inflammatory pain; neuropathic pain; pain associated with or induced by chemotherapy or radiation therapy; associated with or induced by traumatic nerve injury or compression or traumatic injury to the brain or spinal cord Pain; painful Urinary neuropathy; peripheral neuropathic pain; persistent clinical pain; phantom pain; rheumatoid arthritis pain; secondary inflammatory osteoarthritis pain; trigeminal neuralgia; vascular headache; and combinations thereof The method according to item 40.

  Item 42 The method of Item 40, wherein the pain associated with the medical condition comprises non-inflammatory pain.

  Item 43. A method of treating an arthritic condition and / or pain associated therewith in a subject, 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 associated therewith are treated.

  Item 45 The method of Item 43, wherein in the combination, the first agent comprises lacosamide.

  Item 46 The method of item 45, wherein the lacosamide is administered according to a dosing schedule in which the daily dose is increased until a predetermined daily dose that is maintained during further treatment is reached.

  Item 47 The method according to Item 45, wherein lacosamide is administered orally.

  Item 48 Lacosamide is effective to give a plasma concentration of lacosamide of about 0.1 to about 15 μg / ml (minimum) and about 5 to about 18.5 μg / ml (maximum), calculated as an average across multiple treatment subjects 48. The method of item 47, wherein the method is administered in an amount that provides a daily dose.

  Item 49 The arthritic condition is idiopathic osteoarthritis, secondary osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, infectious arthritis, ankylosing spondylitis, neurogenic arthropathy, polyarthralgia, and Items comprising one or more disorders selected from the group consisting of Sjogren's syndrome, Behcet's syndrome, Reiter's syndrome, systemic lupus erythematosus, rheumatic fever, gout, pseudogout, Lyme disease, sarcoidosis and arthritis associated with ulcerative colitis 43 combinations.

  Item 50 The method of item 43, wherein the arthritic condition comprises osteoarthritic pain.

  Item 51 The method of item 43, wherein the arthritic condition comprises rheumatoid arthritis or juvenile rheumatoid arthritis.

Item 52 Formula (I)
(Where
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 non- Is substituted or substituted with at least one electron withdrawing group and / or at least one electron donating group;
R ₁ 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 non- Is substituted 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 ZY, 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. Cage;
Z is O, S, S (O) _a , 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 at least one electron Substituted with an attractive group and / or at least one electron donating group, provided that when Y is halo, Z is a chemical bond, or
ZY together, 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 , PR ₄ NR ₅ R ₇ , N ⁺ R ₅ R ₆ R ₇ ,
Subject to
R ′ ₆ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl and is unsubstituted or substituted with at least one electron withdrawing group and / or 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 at least one electron sought. Substituted with an attractive group and / or 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 and / or 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 and / or at least one electron donating group;
n is 1 to 4;
a is 1 to 3)
A first agent comprising a compound of: or a pharmaceutically acceptable salt thereof; and in combination, provides an improved treatment of pain associated with or caused by a medical condition compared to a compound of formula (I) alone A therapeutic combination comprising a second agent effective for the treatment, wherein the second agent comprises one or more drugs other than the compound of formula (I).

Item 53 In the compound of formula (I) present in the first agent, one or both of R ₂ and R ₃ is 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, pyrazolinedinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl, methyl Drill, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl, and N in the heterocycle If present, is a heterocycle independently selected from the group consisting of its N-oxides; said heterocycle is independently unsubstituted or at least one electron withdrawing group and / or at least 1 53. A combination according to item 52, which is substituted with two electron donating groups.

Item 54 The first drug is represented by the formula (III)
(Where:
R ₄ is hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, carboxy, formyl, carboxamide, aryl, quaternary ammonium, haloalkyl, arylalkanoyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryloxy, mercapto One or more substituents independently selected from the group consisting of, alkylthio, alkyl mercapto, and disulfide;
R ₃ is selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, N-alkoxy-N-alkylamino, and N-alkoxyamino;
R ₁ is alkyl)
53. A combination according to item 52 comprising a compound of: or a pharmaceutically acceptable salt thereof.

Item 55 In the compound of the formula (III) or a 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;
55. A combination according to item 54, wherein R ₁ is lower alkyl.

Item 56 The combination according to Item 55, wherein in the compound of Formula (III) or a salt thereof, R ₃ is lower alkoxy-lower alkyl.

Item 57 In the compound of the formula (III) or a salt thereof:
R ₄ is hydrogen;
R ₃ is methoxymethyl;
55. A combination according to item 54, wherein R ₁ is methyl.

Item 58 The first drug is
(R) -2-acetamido-N-benzyl-3-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-phenylglycine benzylamide;
D-1,2- (N, O-dimethylhydroxylamino) -2-acetamidoacetic acid benzylamide;
and
55. A combination according to item 54, comprising a compound selected from the group consisting of D-1,2- (O-methylhydroxylamino) -2-acetamidoacetic acid benzylamide.

  Item 59 The combination according to any of Items 54 to 58, wherein the compound of formula (III) is substantially enantiopure.

  Item 60 The combination of Item 54, wherein the first agent comprises lacosamide.

  Item 61 The combination of item 60, comprising an amount of lacosamide that provides a dose of about 100 to about 6000 mg / day.

  Item 62 The combination of item 60, comprising an amount of lacosamide that provides a dose of about 200 to about 1000 mg / day.

  Item 63 The combination of Item 60, comprising an amount of lacosamide that provides a dose of about 300 to about 600 mg / day.

  Item 64. Any of Items 52 to 63, wherein the second agent comprises one or more drugs independently selected from the group consisting of analgesics, anticonvulsants, antidepressants and NMDA receptor antagonists. combination.

  Item 65 The second drug is acetaminophen, alfentanil, allylprozin, alphaprozin, anilellidine, benzylmorphine, vegitramide, buprenorphine, butorphanol, clonitazen, codeine, cyclazocine, desomorphin, dextromoramide, dextropropoxyphene, dezocine , Diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthianbutene, dioxafetilbutyrate, dipipanone, eptazocine, etoheptadine, ethylmethylthianbutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, Hydromorphone, hydroxypetidin, isomethadone, ketobemidone, levalorphan, levo Fanol, levofenacil-morphane, lofentanil, meperidine, meptazinol, metazosin, methadone, methopone, morphine, myrophin, nalbuphine, nalolphine, narcein, nicomorphin, norlevorphanol, normethadone, normorphin, norpipanone, opium, oxycodone, oxymorphone, papaberetum , Pentazodine, phenadoxone, phenazosin, phenomorphan, phenoperidine, pimidine, pyritramide, proheptadine, promedol, properidine, propyram, propoxyphene, sufentanil, thyridine, tramadol, naproxen, NO-naproxen, NCX-701, ALGRX-4975, and In item 64, comprising one or more analgesics selected from the group consisting of pharmaceutically acceptable salts thereof Combination of descriptions.

  Item 66. Doxenitoin, eterobulb, etadione, ethosuximide, ethotoin, ferbamate, fluoresson, phosphenytoin, gabapentin, ganazolone, lamotrigine, levetiracetam, lorazepam, mephenytoin, mefobarbital, metalbital, mettezomcoside Zepin, parameterdione, phenacemide, phenetal bital, pheneturide, phenobarbital, phen Nsuccimide, phenylmethylbarbituric acid, phenytoin, phenethylate, pregabalin, primidone, progabide, remasemide, rufinamide, scrofenide, sultiam, thalunpanel, tetrantin, tiagabine, topiramate, trimetadione, valproic acid, valpromide, vigabatrin, and zonisamide 66. A combination according to item 64 or 65, comprising one or more anticonvulsants selected from the group consisting of acceptable salts thereof.

  Item 67. Dioxadorol, dothiepine, doxepin, duloxetine, etoperidone, femoxetine, fencamine, fenpentadiol, fluacidin, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, imipramine, imipramine N-oxide, indalpine, indeloxazine, ipridolid, iprodidol , Isocarboxazide, levofacetoperan, Lof Epramine, maprotiline, medifoxamine, melitracene, metapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, moclobemide, nefazodone, nefopam, niaramide, nomifensine, nortriptyline, noxiptylline, octamoxine, opipramol, oxafurozan, oxytriptan Phenelzine, piberalin, pizotirin, prolintan, propizepine, protriptyline, piriscideanol, quinupramine, reboxetine, ritanserin, roxindole, rubidium chloride, sertraline, sulpiride, tandospirone, thiazesim, tozalinone, tianeptine, tofenacin, toloxatone, tolamine , Trazodone, tho A combination according to any of items 64 to 66, comprising one or more antidepressants selected from the group consisting of mipramine, tryptophan, venlafaxine, viloxazine, dimerzine, and pharmaceutically acceptable salts thereof. .

  Item 68. Comprising one or more NMDA receptor antagonists selected from the group consisting of LY-235959, memantine, methadone, MK-801, phencyclidine, remasemide, serfotel, tiretamine, and pharmaceutically acceptable salts thereof, 68. A combination according to any of items 64 to 67.

  Item 69 The combination of any of Items 52 to 68, wherein the second agent comprises one or more drugs independently selected from the group consisting of gabapentin, duloxetine, morphine, naxproxen, and memantine.

  Item 70 The combination of item 69, wherein the second agent comprises one or more drugs independently selected from the group consisting of duloxetine, morphine, naxproxen, and memantine.

  Item 71 The combination according to any of Items 52 to 70, wherein the medical condition is accompanied by or has non-inflammatory pain as a symptom thereof.

  Item 72 The combination of any of Items 52 to 71, wherein the pain associated with the medical condition comprises non-inflammation.

  Item 73 The combination of any of Items 52 to 72, wherein the medical condition is an arthritic condition and / or associated pain.

  Item 74 The combination of item 73, wherein the arthritic condition comprises osteoarthritis.

  Item 75. The combination of item 73 or 74, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat the arthritic condition and / or pain associated therewith.

  Item 76.From Item 73, 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 an arthritic condition The combination according to any one of 75.

  Item 77. Any of Items 73 to 76, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat non-inflammatory pain associated with an arthritic condition. combination.

  Item 78 The combination of any of Items 73 to 77, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat non-inflammatory osteoarthritic pain.

  Item 79 The combination of any of Items 73 to 76, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat inflammatory pain associated with an arthritic condition .

  Item 80 The combination of any of Items 73 to 76 and 79, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat inflammatory osteoarthritic pain.

  Item 81 The combination of items 78 or 80, wherein the osteoarthritic pain is associated with angiogenesis in the area of cartilage degradation, structural bone changes, and / or osteoarthritis remodeling.

  Item 82 The arthritic condition is idiopathic osteoarthritis, secondary osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, infectious arthritis, ankylosing spondylitis, neurogenic arthropathy, polyarthralgia, and Sjogren Item 73, including one or more disorders selected from the group consisting of syndrome, Behcet syndrome, Reiter syndrome, systemic lupus erythematosus, rheumatic fever, gout, pseudogout, Lyme disease, sarcoidosis, and arthritis associated with ulcerative colitis, 82. The combination according to any one of to 81.

  Item 83 The combination according to any of items 73 to 82, wherein the arthritic condition comprises rheumatoid arthritis or juvenile rheumatoid arthritis.

  Item 84 The combination of any of Items 52 to 70, wherein the medical condition is pain in painful diabetic neuropathy.

  Item 85 The combination of Item 84, wherein the painful diabetic neuropathy is diabetic distal sensory polyneuropathy.

  Item 86 1st and 2nd drugs combined, mean daily pain, total pain, current pain intensity, pain sleep disturbance, patient perception of pain general activity disturbance, patient general impression of pain change, pain change 86. Effective in treating a pain aspect selected from the group consisting of a clinical general impression of, a patient perception of different neuropathic pain qualities, a quality of life and a ratio of days without pain, combination.

  Item 87 The combination according to any of Items 84 to 86, wherein the painful diabetic neuropathy is associated with type 1 diabetes or type II diabetes.

  Item 88 Any of Items 52-87, wherein the second agent is present in an amount effective to provide an improved treatment of pain compared to the first agent alone in combination with the first agent. Combination of descriptions.

  Item 89 The medical condition or pain associated therewith is acute inflammatory pain; acute pain; alcoholism-related 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 from peripheral nerve injury; diabetes-related or diabetes-induced neuropathic pain; diabetic distal sensory neuropathy; diabetic distal sensory polyneuropathy Disability; Diabetic pain; Fibromyalgia; Headache; Hyperalgesia; Sensory hypersensitivity; Abnormal hypersensitivity; Migraine; Muscle pain; Fascial pain syndrome; Neuralgia; Neuroma; Non-inflammatory osteoarthritic pain; Nonneuropathic inflammation Pain associated with or induced by chemotherapy or radiation therapy; pain associated with or induced by traumatic nerve injury or compression or traumatic injury to the brain or spinal cord; painful diabetic Neuropathy; Any of items 52 through 70, selected from the group consisting of neuropathic pain; persistent clinical pain; phantom pain; rheumatoid arthritis pain; secondary inflammatory osteoarthritic pain; trigeminal neuralgia; vascular headache; and combinations thereof Combination of crab.

  Item 90 The combination of any of Items 52 to 89, wherein the first agent and the second agent are given in separate dosage forms for administration by the same or different routes, at the same or different times.

  Item 91 The combination of any of Items 52 to 90, wherein at least the first agent is provided in a dosage form adapted for oral or parenteral administration.

  Item 92 The combination of any of Items 52 to 91, wherein the first agent is given 1 to 3 doses per day in a dosage form adapted for oral administration.

  Item 93 The combination of any of claims 52 to 92, wherein the second agent is given in a dosage form that is orally bioavailable and adapted for oral administration.

  Item 94 A pharmaceutical dosage form comprising the combination of items 52 to 70 and at least one pharmaceutically acceptable excipient.

  Item 95 The dosage form of item 94, wherein the first agent comprises lacosamide.

  Item 96 The dosage form according to Item 94 or 95, which is adapted for oral or parenteral administration.

  Item 97. A method of treating a painful medical condition and / or pain associated therewith in a subject, comprising administering to the subject a treatment combination according to any of items 52 to 70.

  Item 98. The method of item 97, wherein the painful medical condition or / and pain associated therewith is selected from the condition described in any of items 71 to 99.

  Item 99 The medical condition or pain associated therewith is acute inflammatory pain; acute pain; alcoholism-related 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 from peripheral nerve injury; diabetes-related or diabetes-induced neuropathic pain; diabetic distal sensory neuropathy; diabetic distal sensory polyneuropathy Disability; Diabetic pain; Fibromyalgia; Headache; Hyperalgesia; Sensory hypersensitivity; Abnormal hypersensitivity; Migraine; Muscle pain; Fascial pain syndrome; Neuralgia; Neuroma; Non-inflammatory osteoarthritic pain; Nonneuropathic inflammation Pain associated with or induced by chemotherapy or radiation therapy; pain associated with or caused by traumatic nerve injury or compression or traumatic injury to the brain or spinal cord; painful diabetic nerve Disability; peripheral god Fault pain; persistent clinical pain; phantom pain; rheumatoid arthritis pain; secondary inflammatory osteoarthritic pain; trigeminal neuralgia; vascular headaches; is selected from the group consisting of: The method of claim 97.

  Item 100 The method of any of items 97 to 99, wherein, in the combination, the first agent comprises lacosamide.

  Item 101. The method of any of items 97 to 100, wherein the lacosamide is administered according to a dosing schedule in which the daily dose is increased until a predetermined daily dose that is maintained during further treatment is reached.

  Item 102 The method of any of items 97 to 101, wherein lacosamide is administered orally.

  Item 103 Lacosamide is effective to give a plasma concentration of lacosamide of about 0.1 to about 15 μg / ml (minimum) and about 5 to about 18.5 μg / ml (maximum), calculated as an average across multiple treatment subjects 105. A method according to any of items 97 to 102, wherein the method is administered in an amount that provides a daily dose.

  Item 104 Any of items 52 to 70 for the preparation of a medicament for improved prevention, reduction or / and treatment of pain associated with or caused by a medical condition compared to a compound of formula (I) alone Use of a combination.

  Item 105. Use according to item 104, wherein the medical condition is selected from the condition according to any of items 71 to 99.

  Item 106 The use of item 104 or 105, wherein in the combination, the first agent comprises lacosamide.

Claims (55)

Formula (I)
(Where
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 non- Is substituted or substituted with at least one electron withdrawing group and / or at least one electron donating group;
R ₁ 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 non- Is substituted 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 ZY, 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. Cage;
Z is O, S, S (O) _a , 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 at least one electron Substituted with an attractive group and / or at least one electron donating group, provided that when Y is halo, Z is a chemical bond, or
ZY together, 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 , PR ₄ NR ₅ R ₇ , N ⁺ R ₅ R ₆ R ₇ ,
Subject to
R ′ ₆ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl and is unsubstituted or substituted with at least one electron withdrawing group and / or 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 at least one electron sought. Substituted with an attractive group and / or 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 and / or 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 and / or at least one electron donating group;
n is 1 to 4;
a is 1 to 3)
A first agent comprising a compound of: or a pharmaceutically acceptable salt thereof; and in combination, provides an improved treatment of pain associated with or caused by a medical condition compared to a compound of formula (I) alone A therapeutic combination comprising a second agent effective for the treatment, wherein the second agent comprises one or more drugs other than the compound of formula (I). In the compound of formula (I) present in the first agent, one or both of R ₂ and R ₃ is 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, pyrazolinedinyl, imidazolinyl, imidazolinedinyl, pyrrolidinyl, infradolyl, N-methyl Methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl, and N are present in the heterocycle A heterocycle independently selected from the group consisting of N-oxides; the heterocycle is independently unsubstituted or at least one electron withdrawing group and / or at least one 2. A combination according to claim 1 substituted with an electron donating group. The first drug is of formula (III)
(Where:
R ₄ is hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, carboxy, formyl, carboxamide, aryl, quaternary ammonium, haloalkyl, arylalkanoyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryloxy, mercapto One or more substituents independently selected from the group consisting of, alkylthio, alkyl mercapto, and disulfide;
R ₃ is selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, N-alkoxy-N-alkylamino, and N-alkoxyamino;
R ₁ is alkyl)
Or a pharmaceutically acceptable salt thereof. In a compound of formula (III) or a 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;
4. A combination according to claim 3, wherein R ₁ is lower alkyl. 5. The combination according to claim 4, wherein in the compound of formula (III) or a salt thereof, R ₃ is lower alkoxy-lower alkyl. In the compound of formula (III) or salt thereof:
R ₄ is hydrogen;
R ₃ is methoxymethyl;
R ₁ is methyl, A combination according to claim 3. The first drug is
(R) -2-acetamido-N-benzyl-3-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-phenylglycine benzylamide;
D-1,2- (N, O-dimethylhydroxylamino) -2-acetamidoacetic acid benzylamide;
and
4. The combination according to claim 3, comprising a compound selected from the group consisting of D-1,2- (O-methylhydroxylamino) -2-acetamidoacetic acid benzylamide.   8. A combination according to any one of claims 3 to 7, wherein the compound of formula (III) is substantially enantiopure.   4. A combination according to claim 3, wherein the first agent comprises lacosamide.   10. The combination of claim 9, comprising an amount of lacosamide that provides a dose of about 100 to about 6000 mg / day.   10. The combination of claim 9, comprising an amount of lacosamide that provides a dose of about 200 to about 1000 mg / day.   10. The combination of claim 9, comprising an amount of lacosamide that provides a dose of about 300 to about 600 mg / day.   The combination according to any of claims 1 to 12, wherein the second agent comprises one or more drugs independently selected from the group consisting of analgesics, anticonvulsants, antidepressants and NMDA receptor antagonists. .   The second drug is acetaminophen, alfentanil, allylprozin, alphaprozin, anileridine, benzylmorphine, vegitramide, buprenorphine, butorphanol, clonitazen, codeine, cyclazocine, desomorphin, dextromoramide, dextropropoxyphene, dezocine, dianpromide , Diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthianbutene, dioxafetilbutyrate, dipipanone, eptazocine, etoheptazine, ethylmethylthianbutene, ethylmorphine, etonithazene, fentanyl, heroin, hydrocodone, hydromorphone, Hydroxypetidin, isomethadone, ketobemidone, levalorphan, levorfano , Levofenacil-morphane, lofentanil, meperidine, meptazinol, methazosin, methadone, methopone, morphine, mirophine, nalbuphine, nalolphine, narcein, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, Papaveretum, pentazodine, phenadoxone, phenazosin, phenomorphan, phenoperidine, pimidine, pyritramide, proheptadine, promedol, properidine, propyram, propoxyphene, sufentanil, thyridine, tramadol, naproxen, NO-naproxen, NCX-701, ALGRX-4975 And one or more analgesics selected from the group consisting of pharmaceutically acceptable salts thereof. Combination.   The second drug is acetylpheneturide, arbutoin, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, bechramid, bramate, carbamazepine, cinromide, clomethiazole, clonazepam, decimemid, dietadione, dimethadione, doxenitoin, Eterobulb, etadione, ethosuximide, ethotoin, ferbamate, fluoresson, phosphenytoin, gabapentin, ganaxolone, lamotrigine, levetiracetam, lorazepam, mephenytoin, mefobarbital, metalbital, methotein, methosuximide, midazotal oxybalt , Parameterdione, phenacemide, phenetal bital, pheneturide, phenobarbital, fence Mido, phenylmethylbarbituric acid, phenytoin, phenethylate, pregabalin, primidone, progabide, remasemide, rufinamide, suclophenide, sultiam, thalnepanel, tetrantin, tiagabine, topiramate, trimetadione, valproic acid, valpromid, vigabatrin, zonisamide, and pharmaceutically 15. A combination according to claim 13 or 14, comprising one or more anticonvulsants selected from the group consisting of acceptable salts thereof.   The second drug is azinazolam, adrafinil, amineptin, amitriptyline, amitriptylinoxide, amoxapine, befloxatone, bupropion, butacetin, buttriptyline, caloxazone, citalopram, clomipramine, cotinine, demexeptiline, desipramine, dimethazine, dimetacrine, dimetacrine, Drol, dothiepine, doxepin, duloxetine, etoperidone, femoxetine, fencamine, fenpentadiol, fluacidin, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, imipramine, imipramine N-oxide, indalpine, indeloxazine, ipridolid, iproudid Carboxazide, levofacetoperan, rofepra , Maprotiline, medifoxamine, melitracene, metapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, moclobemide, nefazodone, nefopam, niaramide, nomifensine, nortriptyline, noxoptiline, octamoxine, opipramol, oxafrozan, oxytriptan, oxytriptan Phenelzine, piberalin, pizotirin, prolintan, propizepine, protriptyline, piriscideanol, quinupramine, reboxetine, ritanserin, roxindole, rubidium chloride, sertraline, sulpiride, tandospirone, thiazesim, tozalinone, tianeptine, tofenacin, toloxatone, tolamine , Trazodone, trimip 16. One or more antidepressants selected from the group consisting of min, tryptophan, venlafaxine, viloxazine, dimerzine, and pharmaceutically acceptable salts thereof, according to any of claims 13 to 15. combination.   The second drug is amantadine, D-AP5, aptiganel, CPP, dexanabinol, dextromethorphan, dextropropoxyphene, 5,7-dichloroquinurenic acid, gavestinel, ifendpril, ketamine, ketobemidon, ricosttinel, LY- 235959, comprising one or more NMDA receptor antagonists selected from the group consisting of memantine, methadone, MK-801, phencyclidine, remasemide, serfotel, tiretamine, and pharmaceutically acceptable salts thereof. The combination according to any one of 13 to 16.   18. A combination according to any of claims 1 to 17, wherein the second agent comprises one or more drugs independently selected from the group consisting of gabapentin, duloxetine, morphine, naxproxen, and memantine.   19. The combination of claim 18, wherein the second agent comprises one or more drugs independently selected from the group consisting of duloxetine, morphine, naxproxen, and memantine.   20. A combination according to any of claims 1 to 19, wherein the medical condition is accompanied by or has non-inflammatory pain as a symptom thereof.   21. A combination according to any one of claims 1 to 20, wherein the pain associated with the medical condition comprises non-inflammation.   22. A combination according to any one of claims 1 to 21, wherein the medical condition is an arthritic condition and / or associated pain.   23. A combination according to claim 22, wherein the arthritic condition comprises osteoarthritis.   24. The combination of claim 22 or 23, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat the arthritic condition and / or pain associated therewith.   25. The first and second agents are present in absolute and relative amounts effective to treat both non-inflammatory and inflammatory components of pain associated with or caused by an arthritic condition. A combination described in any of the above.   26. A combination according to any of claims 22 to 25, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat non-inflammatory pain associated with an arthritic condition. .   27. A combination according to any of claims 22 to 26, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat non-inflammatory osteoarthritic pain.   26. A combination according to any of claims 22 to 25, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat inflammatory pain associated with an arthritic condition.   29. A combination according to any of claims 22 to 25 and 28, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat inflammatory osteoarthritic pain.   30. A combination according to claim 27 or 29, wherein the osteoarthritic pain is associated with angiogenesis in the area of cartilage degradation, structural bone changes and / or osteoarthritic remodeling.   Arthritic conditions include idiopathic osteoarthritis, secondary osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, infectious arthritis, ankylosing spondylitis, neurogenic arthropathy, polyarthralgia, and Sjogren's syndrome, From one or more disorders selected from the group consisting of arthritis associated with Behcet syndrome, Reiter syndrome, systemic lupus erythematosus, rheumatic fever, gout, pseudogout, Lyme disease, sarcoidosis and ulcerative colitis The combination according to any one of 30.   32. A combination according to any of claims 22 to 31, wherein the arthritic condition comprises rheumatoid arthritis or juvenile rheumatoid arthritis.   20. A combination according to any of claims 1 to 19, wherein the medical condition is pain in painful diabetic neuropathy.   34. The combination of claim 33, wherein the painful diabetic neuropathy is diabetic distal sensory polyneuropathy.   1st and 2nd drugs combined, mean daily pain, total pain, current pain intensity, pain sleep disturbance, patient perception of pain general activity disturbance, patient general impression of pain change, pain change clinical 35. Combination according to claim 33 or 34, effective for the treatment of a pain aspect selected from the group consisting of general impression, patient perception of different neuropathic pain qualities, quality of life and ratio of days without pain .   36. A combination according to any of claims 33 to 35, wherein the painful diabetic neuropathy is associated with type 1 diabetes or type II diabetes.   37. The second agent according to any of claims 1-36, wherein the second agent is present in an amount effective in combination with the first agent to provide an improved treatment of pain compared to the first agent alone. Combination.   The medical condition or pain associated with it is acute inflammatory pain; acute pain; alcoholism-related or alcoholism-induced neuropathic pain; allodynia; arthritic condition; back pain; cancer-related neuropathic pain; central nervous system Impaired pain; Chronic headache; Chronic inflammatory pain; Chronic pain; Chronic pain due to peripheral nerve injury; Diabetes-related or diabetes-induced neuropathic pain; Diabetic distal sensory neuropathy; Diabetic distal sensory polyneuropathy; Diabetic pain; fibromyalgia; headache; hyperalgesia; hypersensitivity; hyperalgesia; migraine; muscle pain; fascial pain syndrome; neuralgia; neuroma; non-inflammatory osteoarthritic pain; non-neuropathic inflammatory pain Pain associated with or induced by chemotherapy or radiation therapy; pain associated with or caused by traumatic nerve injury or compression or traumatic injury to the brain or spinal cord; painful diabetic neuropathy ; Peripheral nerve 21. Any one of claims 1 to 19, selected from the group consisting of harmful pain; persistent clinical pain; phantom pain; rheumatoid arthritis pain; secondary inflammatory osteoarthritic pain; trigeminal neuralgia; vascular headache; and combinations thereof Combination of crab.   39. The combination of any of claims 1-38, wherein the first agent and the second agent are given in separate dosage forms for administration by the same or different routes, at the same or different times.   40. A combination according to any of claims 1 to 39, wherein at least the first agent is given in a dosage form adapted for oral or parenteral administration.   41. A combination according to any of claims 1 to 40, wherein the first agent is given 1 to 3 doses per day in a dosage form adapted for oral administration.   42. A combination according to any of claims 1-41, wherein the second agent is given in a dosage form that is orally bioavailable and adapted for oral administration.   20. A pharmaceutical dosage form comprising the combination according to claims 1-19 and at least one pharmaceutically acceptable excipient.   44. The dosage form of claim 43, wherein the first agent comprises lacosamide.   45. A dosage form according to claim 43 or 44, adapted for oral or parenteral administration.   20. A method of treating a painful medical condition and / or pain associated therewith in a subject, comprising administering to the subject a therapeutic combination according to any of claims 1-19.   49. The method of claim 46, wherein the painful medical condition or / and pain associated therewith is selected from the condition of any of claims 20-38.   The medical condition or pain associated with it is acute inflammatory pain; acute pain; alcoholism-related or alcoholism-induced neuropathic pain; allodynia; arthritic condition; back pain; cancer-related neuropathic pain; central nervous system Impaired pain; Chronic headache; Chronic inflammatory pain; Chronic pain; Chronic pain due to peripheral nerve injury; Diabetes-related or diabetes-induced neuropathic pain; Diabetic distal sensory neuropathy; Diabetic distal sensory polyneuropathy; Diabetic pain; fibromyalgia; headache; hyperalgesia; hypersensitivity; hyperalgesia; migraine; muscle pain; fascial pain syndrome; neuralgia; neuroma; non-inflammatory osteoarthritic pain; non-neuropathic inflammatory pain Pain associated with or induced by chemotherapy or radiotherapy; pain associated with or induced by traumatic nerve injury or compression or traumatic injury to the brain or spinal cord; painful diabetic neuropathy; Peripheral neuropathy Pain; persistent clinical pain; phantom pain; rheumatoid arthritis pain; secondary inflammatory osteoarthritic pain; trigeminal neuralgia; vascular headaches; is selected from the group consisting of: The method of claim 46.   49. A method according to any of claims 46 to 48, wherein, in the combination, the first agent comprises lacosamide.   50. The method of any of claims 46 to 49, wherein lacosamide is administered according to a dosage regime in which the daily dose is increased until a predetermined daily dose that is maintained during further treatment is reached.   51. The method according to any of claims 46 to 50, wherein lacosamide is administered orally.   One effective lacosamide is to give a plasma concentration of lacosamide of about 0.1 to about 15 μg / ml (minimum) and about 5 to about 18.5 μg / ml (maximum), calculated as an average across multiple subjects. 52. The method of any one of claims 46 to 51, wherein the method is administered in an amount that provides a daily dose.   A method according to any of claims 1 to 19 for the preparation of a medicament for improved prevention, reduction or / and treatment of pain associated with or caused by a medical condition compared to a compound of formula (I) alone. Use of combinations.   54. Use according to claim 53, wherein the medical condition is selected from the condition according to any of claims 20 to 38.   56. The use according to claim 54 or 55, wherein, in the combination, the first agent comprises lacosamide.