BRPI0712494A2 - therapeutic combination for painful medical conditions - Google Patents

Abstract

THERAPEUTIC COMBINATION FOR PAINFUL MEDICAL CONDITIONS. The present invention relates to a therapeutic combination comprising a first agent comprising a compound as defined herein, illustratively lacosamide or a pharmaceutically acceptable salt thereof and a second agent effective in combination with it to provide intensified treatment of pain associated with or caused by a medical condition, compared to the first agent only. The combination can be supplied in a single dosage form and is illustratively useful for treating an arthritic condition and / or related pain.

Description

Patent Descriptive Report for "THERAPEUTIC COMBINATION FOR PAINFUL MEDICAL CONDITIONS".

Field of the Invention

The present invention relates to therapeutic combinations and methods of using such combinations in the treatment of medical conditions, more particularly conditions including arthritic conditions, where pain is present.

Background of the Invention

By 2020, an estimated 60 million Americans will suffer from arthritis. Arthritis is a cause of physical disability (broadly defined as needing assistance in walking or climbing stairs) and restricted daily activity in over 7 million Americans and is expected to grow to over 11, 6 million by 2020. See http://www.arthritis.org/resources/ActionPlanlnterior.pdf. It is very expensive to treat arthritis and its complications. In 1997, the total cost of arthritis and other rheumatic conditions in the United States was $ 86 billion. The direct medical costs of arthritis and other rheumatic conditions in 1997 were $ 51.1 billion. Indirect costs (due to lost wages) of arthritis and other rheumatic conditions in 1997 were $ 35.1 billion. Look

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5318a3.htm.

Rheumatoid arthritis is a chronic disease characterized mainly by inflammation of the lining or synovium of the joints. It can lead to long-term joint damage resulting in chronic pain, loss of function and disability. Rheumatoid arthritis affects about 1% of the American population or 2.1 million Americans.

Rheumatoid arthritis progresses in three stages. The first stage includes swelling of the synovial lining, causing pain, burning, stiffness, redness, and swelling around the joint. The second stage includes rapid division and growth of cells or pannus, which makes the synovium thick. In the third stage, inflamed cells release enzymes that can digest bone and cartilage, often causing the involved joint to lose its shape and alignment, plus pain and loss of movement.

Because rheumatoid arthritis is a systemic disease, it can also affect other organs in the body. Early diagnosis and treatment of rheumatoid arthritis can limit joint damage, which in turn limits movement loss, decreased ability to work, increased medical costs, and potential surgery. See http://www.arthritis.org/conditions/DiseaseCenter/RA/ra overview.asp.

Osteoarthritis is an acquired musculoskeletal disorder believed to be of noninflammatory origin, occurring when the rate of cartilage degradation exceeds that of regeneration, resulting in cartilage erosion, subchondral bone thickening, and joint damage. As the cartilage thins, its surface integrity may be lost, clumps may form, and the cartilage tends to erode more easily with joint movement. As a new cartilage is formed, it tends to be more fibrous and less able to withstand mechanical stress. Over time, the underlying bone may be exposed, which is less able to withstand mechanical stress, resulting in microfractures. Localized osteonecrosis may occur behind the bone surface, leading to cysts that may further weaken the bone support of the cartilage.

As osteoarthritis progresses, it may eventually influence structures surrounding the joint. Local inflammation, such as synovitis, may occur, for example, in response to inflammatory mediators released during degradation of the cartilage process. The joint capsule tends to thicken and the movement of nutrients in and metabolic waste products out of the joint may be restricted. Eventually, peri-articular muscle wear may become evident as osteoarthritis progresses and the joint is used less frequently or inappropriately. The pain of osteoarthritis is believed to be not due to cartilage degradation per se, but to the effects on surrounding structures, including bone, since the cartilage is aneural. According to the Centers for Disease Control and Prevention (CDC), osteoarthritis is the most common form of arthritic disease, affecting 21 million Americans. Look

http://www.cdc.gov/arthritis/data statistics / arthritis related statistics.htm # 2.

The prevalence of osteoarthritis increases with age and age is the major risk factor. A research reported by Brandt (2001) Principles of Internai Medicine. 15th ed. (Braunwald et al., Eds.), New York: McGraw-HiII, pages 1987-1994, found that only 2% of women under 45 years had evidence of osteoarthritis. In women aged 45 to 64, however, the prevalence was 30% and for those 65 and older, it was 68%. Other risk factors include excess body weight, genetics, estrogen deficiency, repetitive joint use, and trauma.

A typical patient with osteoarthritis is of average age or elderly and conforms to pain in the knees, hip, hand or spine. The distal and proximal interphalangeal joints of the hands are the most common sites of osteoarthritis, but also the least likely to exhibit symptoms. Hip and knee are the second and third most common joints seen on x-ray as being affected, with knee pain most likely to exhibit symptoms.

Pain is the supreme symptom of osteoarthritis. Osteoarthritic pain may have one or both inflammatory and noninflammatory components. Antiinflammatory agents such as NSAIDs (non-steroidal antiinflammatory drugs) and cyclooxygenase-2 inhibitors may be useful in the treatment or management of the inflammatory component, while opioids and other analgesics may be useful in the treatment or management. of the noninflammatory component. However, such drug therapies are not always effective and have side effects that may not be well tolerated in all patients. Noninflammatory pain is often characterized by the absence of swelling or burning, absence of inflammatory or systemic features, and minimal or no stiffness in the morning. Noninflammatory osteoarthritic pain can contribute to a sedentary lifestyle, depression and sleep problems, particularly in the elderly. Pain is often characterized as a sensation of pain that intensifies with movement. It is usually intermittent and often mild, but can become persistent and severe. Crackling is usually noted in the affected joints.

Certain peptides are known to exhibit activity in the central nervous system (CNS) and are useful in the treatment of epilepsy and other CNS disorders. Such peptides are described, for example, in U.S. Patent No. 5,378,729.

Related peptides are described in U.S. Patent No. 5,773,475 as useful for treating CNS disorders.

International Patent Publication No. WO 02/074784, incorporated herein by reference in its entirety, refers to the use of such peptide compounds having anti-nociceptive properties, for the treatment of different types and symptoms of acute and chronic pain. chronic, especially non-neuropathic inflammatory, eg rheumatoid arthritic pain or secondary osteoarthritic inflammatory pain.

International Patent Publication No. WO 02/074297 refers to the treatment of peripheral neuropathic pain-related allodynia using a compound of Formula:

<formula> formula see original document page 5 </formula>

wherein Ar is a phenyl group that is unsubstituted or substituted by at least one halo substituent; R3 is C1-3 alkoxy; and Ri is methyl. Iacosamide (also called SPM 927 or harkoseride) is

a compound of the above formula having a mode of action which is not fully understood (Bialer et al. (2002) Epilepsv Res. 51: 31-71). The mode of action of Iacosamide and other peptide compounds described in the above mentioned patents and publications differs from that of common anti-epileptic drugs. Ion channels are unaffected by these compounds in a manner comparable to other known antiepileptic drugs. For example, gamma-aminobutyric acid (GABA) induced currents are potentiated, but no direct action with any known GABA receptor subtype has been observed. Glutamate induced currents are attenuated, but the compounds do not interact directly with any known glutamate receptor subtype.

There remains a need for improved therapies that can treat medical conditions, for example, arthritic conditions having pain, especially noninflammatory pain, as a symptom thereof. Summary of the Invention

Now, there is provided a therapeutic combination comprising a first agent comprising a compound of Formula (I):

<formula> formula see original document page 6 </formula> where:

R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, lower alkyl aryl, heterocyclic, lower heterocyclic alkyl, heterocyclic lower alkyl, lower cycloalkyl or lower cycloalkyl lower alkyl and R is unsubstituted or substituted by at least one group electron extraction and / or at least one electron donation group;

R1 is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, lower heterocyclic alkyl, heterocyclic lower heterocyclic, lower cycloalkyl or lower cycloalkyl lower alkyl and may be unsubstituted or substituted by at least an electron extraction group 25 and / or at least one electron donation group;

R2 and R3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkyl aryl, aryl, halo, heterocyclic, lower heterocyclic alkyl, heterocyclic lower alkyl, lower cycloalkyl, lower alkyl lower cycloalkyl or ZY where R2 and R3 are each independently unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group;

Z is O, S, S (O) a, NR 4, NR 16, PR 4 or a chemical bond;

Y is hydrogen, lower alkyl, aryl, lower alkyl aryl, lower alkenyl, lower alkynyl, halo, heterocyclic, lower heterocyclic alkyl or heterocyclic lower alkyl and may be unsubstituted or substituted by at least one electron extraction group and / or by least one electron donation group as long as when Y is halo, Z is a chemical bond or

Z-Y taken together is NR4NR5R7, NR4OR5, ONR4R7, OPR4R5, PR4OR5, SNR4R7, NR4SR7, SPR4R5, PR4SR7, NR4PR5R6, PR4NR5R7,

<formula> formula see original document page 7 </formula>

R16 is hydrogen, lower alkyl, lower alkenyl or lower alkynyl and may be unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group;

R 4, R 5 and R 6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl and are each independently unsubstituted or substituted by at least one electron extraction group and / or at least an electron donation group;

R7 is R6, COOR8 or COR8 and may be unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group;

R 8 is hydrogen, lower alkyl or aryl lower alkyl and may be unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group;

n is 1-4; and

a is 1-3;

or a pharmaceutically acceptable salt thereof; and a second agent effective in combination with it to (a) provide intensified treatment of pain associated with or caused by a medical condition as compared to the first agent alone; and / or (b) treat another symptom or underlying cause of a medical condition; the second agent comprising one or more other drugs than a compound of Formula (I).

The medical condition, in one embodiment, is a condition in which noninflammatory pain is present. The medical condition may be, for example, an arthritic condition. The first agent and the second agent may be supplied separately or in a single dosage form. Accordingly, in one embodiment, a pharmaceutical dosage form is provided comprising a first agent and a second agent as defined above.

Further provided is a method for treating a medical condition and / or related pain in an individual, the method comprising administering to the individual a therapeutic combination as described above.

Further provided is a method for treating an arthritic condition and / or pain related thereto in an individual, the method comprising administering to the individual a therapeutic combination as described above, wherein the second agent comprises one or more more anti-arthritis drugs.

According to any of the above embodiments, an illustrative compound of Formula (I) is lacosamide, (R) -2-acetamido-N-benzyl-3-methoxypropionamide.

Other embodiments, including particular aspects of the embodiments summarized above, will become apparent from the following detailed description.

Brief Description of the Drawings

In Figures 1-4, "SPM 927" refers to lacosamide.

Figure 1 is a graphical representation of the results of the study of Example 1, showing the effect of Iacosamide at 3, 10 and 30 mg / kg on TNF-induced muscle pressure hyperalgesia.

Figure 2 is a graphical representation of the results of the Example 1 study showing the possible maximum effect (MPE) of Iacosamide a3, 10 and 30 mg / kg compared to pregabalin, gabapentin and metamizole (dipyrone) on TNF-induced muscle pressure hyperalgesia.

Figure 3 is a graphical representation of the results of the study of Example 1, effect of Iacosamide at 3, 10 and 30 mg / kg on biceps muscle holding strength following TNF-induced muscle pain.

Figure 4 is a graphical representation of the results of the Example 1 study showing the maximum possible effect (MPE) of Iacosamide a3, 10 and 30 mg / kg compared to pregabalin, gabapentin and metamizole (dipyrone) on holding resistance of the biceps muscle following TNF-induced muscle pain.

Figures 5A-C are graphical representations of the results of the Example 2 study, showing the effects of Iacosamide and morphine on tactile allodynia induced monosodium iodoacetate on days 3, 7, and 14 of the study, respectively.

Figures 6A-C are graphical representations of the results of the

Example 2 study showing the effect of diclofenac on monosodium-induced tactile allodynia iodoacetamide on days 3, 7 and 14 of the study, respectively.

Figures 7A-C are graphical representations of the results of Example 2, showing the effects of Iacosamide and morphine on monosodium-induced iodoacetamide mechanical hyperalgesia on days 3, 7, and 14 of the study, respectively.

Figures 8A-C are graphical representations of the results of the Example 2 study showing the effect of diclofenac on monosodium-induced iodoacetamide mechanical hyperalgesia on days 3, 7, and 14 of the study, respectively. Detailed Description

Therapeutic combinations, pharmaceutical dosage forms and methods of using such combinations and dosage forms for treating arthritic conditions and / or pain related thereto are provided.

The term "therapeutic combination" refers to a plurality of agents which, when administered to an individual together or separately, are coercive to obtain therapeutic benefit in the individual. Such administration is referred to as "combination therapy", "co-therapy", "adjunctive therapy" or "add-on therapy". For example, one agent may potentiate or enhance the therapeutic effect of another or reduce an adverse side effect of another or one or more agents may be effectively administered at a lower dose than when used alone or may provide greater therapeutic benefit. than when used alone or can complementarily address different aspects, symptoms or etiological factors of a disease or condition.

A "medical condition" here may be a disease, disorder or syndrome, typically one that has been clinically diagnosed. Medical conditions directed by the present invention are accompanied by or have pain as a symptom thereof and are referred to herein as "painful medical conditions". The pain may be inflammatory or noninflammatory in nature or may have inflammatory and noninflammatory components. Many arthritic conditions, for example, have noninflammatory and inflammatory pain components.

Non-limiting examples of medical conditions and / or types of pain for which the present therapeutic combinations and methods may be useful include those listed immediately below, recognizing that many of the listed conditions and types of pain overlap:

• acute inflammatory pain;

• acute pain;

· Neuropathic pain associated with alcoholism or induced by alcoholism;

• allodynia (occurring independently or as a symptom of another condition); • arthritic conditions;

• back pain;

• cancer-related neuropathic pain, for example, painful compression by tumor growth of adjacent nerves, the brain or spinal column;

• central neuropathic pain;

• chronic headache;

• chronic inflammatory pain;

• chronic pain;

· Chronic pain due to peripheral nerve injury;

• diabetes-associated or diabetes-induced neuropathic pain;

• diabetic pain;

• diabetic distal sensory neuropathy;

• diabetic distal sensory polyneuropathy; · Fibromyalgia;

• Headache;

• hyperalgesia (occurring independently or as a symptom of another condition);

• hyperesthesia; · Hyperpathy;

• migraine; including classic migraine and common migraine;

• myalgia;

• myofascial pain syndrome;

• neuralgia; · Neuroma;

• noninflammatory musculoskeletal pain;

• noninflammatory osteoarthritic pain;

• non-neuropathic inflammatory pain;

• neuropathic pain;

· Pain associated with or induced by chemotherapy or radiation therapy;

• pain associated with or induced by traumatic injury or nerve compression or traumatic injury to the brain or spinal column; • painful diabetic neuropathy;

• peripheral neuropathic pain;

• persistent clinical pain;

• phantom pain;

· Pain from rheumatoid arthritis;

• secondary osteoarthritic inflammatory pain;

• trigeminal neuralgia; and

• vascular headache.

An "arthritic condition" here is a musculoskeletal disorder, usually accompanied by pain, in one or more joints of an individual and includes arthritis associated with or secondary to conditions that are not necessarily primarily arthritic. Among the most important arthritic conditions are osteoarthritis, which may be of idiopathic origin or primary or secondary to other conditions; and rheumatoid arthritis, including juvenile rheumatoid arthritis. Other disorders encompassed herein as "arthritic conditions" include, without limitation, psoriatic arthritis, infectious arthritis, ankylosing spondylitis, neurogenic arthropathy, and polyarthralgia. Conditions to which arthritis may be secondary include, but are not limited to, Sjogren's syndrome, Behcet's syndrome, Reiter's syndrome, systemic Iupus erythematosus, rheumatic fever, gout, pseudogout, Lyme disease, sarcoidosis, and ulcerative colitis.

Arthritis-related pain, for example osteoarthritis, may be inflammatory or noninflammatory or both. Noninflammatory osteoarthritic pain is a specific type of specific musculoskeletal pain that typically arises from the effects of osteoarthritis-related morphological changes, such as cartilage degradation, bone changes in sensory neurons, and bone remodeling vascularization. It is distinguished from arthritic inflammatory pain which typically occurs from synovial inflammation following pathological processes in cartilage and damage involving bone tissue and macrophage infiltration (resulting in edema) associated with a classical response. of the immune system.

Stohr et al. (2006) Eur. J. Pain 10 (3): 241-249, incorporated herein by reference in its entirety but not accepted as prior art to the present invention, describes the results, showing the efficacy of Iacosamide for treatment of inflammatory pain.

Unless the context otherwise requires, the term "treating" or "treatment" herein includes preventive or prophylactic use of a combination, for example, a combination, for example, a combination of a first agent and a second agent, as defined herein, wherein an individual at risk of or having a prognosis including a medical condition having noninflammatory pain as a symptom thereof, for example an arthritic condition such as osteoarthritis as well as use of such a combination - an individual already experiencing such a condition as a therapy to relieve, reduce the intensity of or eliminate the condition or pain associated with it or an underlying cause thereof.

The term "individual" refers to a warm-blooded animal, generally a mammal such as, for example, a cat, dog, horse, cow, pig, mouse, rat or primate, including a human being. In one embodiment, the individual is a human being, for example, a patient having a clinically diagnosed arthritic condition.

The term "synergism", "synergistic effect", "intensified prevention", "intensified relief" or "intensified treatment" refers to a stronger therapeutic effect of a combination of two or more compounds compared to the additive effects of the compounds alone. For example, a therapeutic combination as described herein may have a synergistic effect in preventing, relieving and / or treating pain associated with or caused by a medical condition as described herein.

A therapeutic combination as described herein may also have a synergistic effect in reducing side effects and / or toxicity if administered to prevent, relieve and / or treat a medical condition as described herein, or pain associated with or caused by for a medical condition as described here.

The therapeutic combination of the present invention comprises a first agent comprising a compound of Formula (I) as set forth above or a pharmaceutically acceptable salt thereof. More than one of such compound or salt thereof may optionally be present in the first agent. Terms used in the description of Formula (I) and elsewhere in this specification, unless otherwise indicated, are defined as follows.

The term "alkyl", alone or in combination with other term (s), means a straight or branched saturated hydrocarbyl substituent preferably containing from 1 to about 20 carbon atoms plus typically from 1 to about 8 carbon atoms and even more typically from 1 to about 6 carbon atoms. The term "lower alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms, especially 1 to 3 carbon atoms, which may be straight or branched chain. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, hexyl and the like and isomers thereof. The term "alkenyl", alone or in combination with other

term (s) means a straight or branched chain hydrocarbyl substituent containing one or more double bonds and typically from 2 to about 20 carbon atoms, more typically from 2 to about 8 carbon atoms and even more typically from 2 to about 6 carbon atoms. Alkenyl groups, where asymmetric, may have the useful or trans configuration.

The term "lower alkenyl" refers to an alkenyl substituent containing from 2 to 6 carbon atoms which may be straight or branched and in Z or E form. Examples include vinyl, propenyl, 1-butenyl, isobutenyl , 2-butenyl, 1-pentenyl, (Z) -2-pentenyl, (E) -2-pentenyl, (Z) -4-methyl-2-pentenyl, (E) -4-methyl-2-pentenyl, pentadienyl for example 1, 3 or 2,4-pentadienyl and the like.

The term "alkynyl", alone or in combination with other term (s), means a straight or branched chain hydrocarbyl substituent containing one or more triple bonds and typically from 2 to about 20 carbon atoms plus typically from 2 to about 8 carbon atoms and even more typically from 2 to about 6 carbon atoms.

The term "lower alkynyl" refers to an alkynyl substituent containing from 2 to 6 carbon atoms which may be straight or branched. It includes groups such as ethinyl, propynyl, 1-butynyl, 2-butynyl, 1-pentinyl, 2-pentinyl, 3-methyl-1-pentinyl, 3-pentinyl, 1-hexinyl, 2-hexinyl, 3-hexinyl and the like. .

The term "cycloalkyl", alone or in combination with other 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, fenchyl, pinenyl, adamantyl and the like. Cycloalkyl includes useful or trans forms. Cycloalkyl groups may be unsubstituted or mono- or polysubstituted by electron extraction and / or electron donation groups as described below. In addition, the substituents may be in the endo- or exo- positions in bridged bicyclic systems. "Lower cycloalkyl" groups have 3 to 6 carbon atoms.

The term "alkoxy", alone or in combination with other term (s), means an alkyl ether, that is, -O-alkyl substituent.

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

The term "aryl", alone or in combination with other term (s), means an aromatic group which contains from about 6 to about 18 carbon atoms and includes polynuclear aromatics. Aryl groups may be monocyclic or polycyclic and optionally fused. A polynuclear aromatic group, as used herein, encompasses bicyclic and tricyclic fused aromatic ring systems containing from about 10 to about 18 carbon atoms in the ring. Aryl groups include phenyl, pollen aromatic groups (e.g. naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like) such as ferrocenyl. Aryl groups may be unsubstituted or mono- or polysubstituted by electron extraction and / or electron extraction groups as described below.

"Aryl lower alkyl" groups include, for example, benzyl, phenylethyl, phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl, 1,1-diphenylethyl, 1,2-diphenylethyl and the like.

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

The term "halo" or "halogen" includes fluorine, chlorine, bromine and iodine.

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 replaced by one or more independently selected halogen radicals. For example, haloalkyl means an alkyl substituent wherein at least one hydrogen radical is substituted by a halogen radical. Examples of haloalkyl substituents include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like. Still illustrating, "haloalkoxy" means an alkoxy substituent wherein at least one hydrogen radical is substituted by a halogen radical. Examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), 1,1,1, -trifluoroethoxy and the like. It should be recognized that if a substituent is substituted by more than one halogen radical, these halogen radicals may be identical or different unless otherwise stated.

The term "acyl" includes alkanoyl containing from 1 to about 20 carbon atoms, preferably 1 to 6 carbon atoms and may be straight or branched chain. Acyl groups include, without limitation, formyl, acetyl, propionyl, butyryl, isobutyryl, tertiary butyryl, pentanoyl and isomers thereof and hexanoyl and isomers thereof.

The terms "electron extraction" and "electron donation" refer to the ability of a substituent to extract or donate electrons, respectively, with respect to that of hydrogen, if the hydrogen atom occupies the same position in the molecule. These terms are well understood by those skilled in the art and are discussed in Advanced Organic Chemistry, by J. March, John Wiley and Sons, New York, NY, pages 16-18 (1985) and discussion thereof is incorporated herein. by reference. Electron extraction groups include halo (including bromine, fluorine, chlorine and iodine); nitro, carboxy, alkenyl, alkynyl, formyl, carboxyamido, aryl, quaternary ammonium, haloalkyl (such as trifluoromethyl), aryl alkanoyl, carbalkoxy and the like. Electron donation groups include groups such as hydroxy, alkoxy (including methoxy, ethoxy and the like); lower alkyl (including methyl, ethyl and the like); amino, lower alkylamino, di (lower alkyl) amino, aryloxy (such as phenoxy), mercapto, lower alkylthio, lower alkylmercapto, disulfide (lower alkylditio) and the like. Those skilled in the art will appreciate that some of the aforementioned substituents may be considered as electron donation groups or electron extraction under different chemical conditions. Further, the present invention contemplates any combination of substituents selected from the groups identified above.

The term "heterocyclic" means a ring substituent that contains one or more ring sulfur, nitrogen and / or oxygen atoms. Heterocyclic groups include heteroaromatic groups and saturated and partially saturated heterocyclic groups. Heterocyclic groups may be monocyclic, bicyclic, tricyclic or polycyclic and may be fused rings. They typically contain up to 18 ring atoms, including up to 17 ring carbon atoms, and contain in total up to about 25 carbon atoms but preferably are 5 to 6 membered rings. Heterocyclic groups also include the so-called benzoheterocyclic groups. Representative heterocyclic groups include furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolidin, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinyl benzylyl benzylyl benzylyl benzyl benzyl benzyl benzyl benzyl , tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl, imadazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridine, epoxy, oxyethylethoxyethoxyethoxyazoline, of nitrogen-containing heterocycles such as N-oxides of pyridyl, pyrazinyl and pyrimidinyl groups and the like. Heterocyclic groups may be unsubstituted or mono- or polysubstituted by electron extraction and / or electron donation groups.

In one embodiment, a heterocyclic group is selected from thienyl, furyl, pyrrolyl, benzofuryl, benzothienyl, indolyl, methylpyrrolyl, morpholinyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl and pyridazinyl, especially furyl, pyridyl, pyrazinyl, imidazolyl, pyrazinyl, pyrimidinyl , especially furila and pyridyl.

In another embodiment, a heterocyclic group is selected from furyl, optionally with at least one lower alkyl group (preferably one having 1-3 carbon atoms, for example methyl), pyrrolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl and thiazolyl, especially furyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl and thiazolyl, more especially furyl, pyridyl, pyrimidinyl and oxazolyl.

Illustratively, in the compound of Formula (I) η is 1, but di- (n = .2), tri- (n = 3) and tetrapeptides (n = 4) are also considered to be useful herein.

R in the compound of Formula (I) is illustratively lower alkyl aryl, especially benzyl, where the phenyl ring thereof is unsubstituted or substituted by one or more electron and / or group donation groups. electron extraction such as halo (eg fluorine).

R1 in the compound of Formula (I) is preferably hydrogen or lower alkyl, especially methyl.

Electron extraction and / or electron donation substituents are halo, nitro, alkanoyl, formyl, arylalkanoyl, aryloyl, carboxyl, carbalcoxy, carboxamido, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, salts sulfonium, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di (lower alkyl) amino, amino lower alkyl, mercapto, mercaptoalkyl, alkylthio and alkyl dithio. The term "sulfide" embraces mercapto, alkyl mercapto and alkylthio, while the term disulfide embraces alkylthio. Electron extraction and / or electron donation groups are halo and lower alkoxy, especially fluorine and methoxy. Such preferred substituents may be present on any one or more of the groups R, R 1, R 2, R 3, R 4, R 5, Re, Re, R 7 or R 8 as defined herein.

Representative Z-Y groups of R2 and / or R3 include hydroxy, alkoxy

(such as methoxy and ethoxy), aryloxy (such as phenoxy), thioalkoxy (such as thiomethoxy and thioethoxy), thioaryloxy (such as thiophenoxy), amino, alkylamino (such as methylamino and ethylamino), arylamino (such as anilino) , lower dialkylamino (such as dimethylamino), trialkylammonium, hydrazino, alkylhydrazino and arylhydrazino salt (such as N-methylhydrazino and N-phenylhydrazino), carbalkoxyhydrazino, aralkoxycarbonylhydrazino, aryloxycarbonylhydrazino, such as hydroxylaminox (such as NHOH)), lower alkoxyamino (NHOR18 wherein R18 is lower alkyl, e.g. methyl), N-lower alkylhydroxylamino (N (R18) OH where R18 is lower alkyl), N-lower alkyl-O hydroxylamino-lower alkyl (N (Rs) ORig where R18 and R3 are independently lower alkyl) and o-hydroxylamino (-O-NH2)), alkylamido (such as acetamido), trifluoroacetamide and heterocyclylamino ( such as pyrazoylamino).

Preferred representative heterocyclic groups of R2 and / or R3 are 5- or 6-membered monocyclic heterocyclic moieties of the formula:

<formula> formula see original document page 19 </formula>

including partially and fully saturated unsaturated forms thereof where η is O or 1; R50 is hydrogen or an electron extraction or electron donation group; A, E, L, J and G are independently CH or the hetero atom selected from the group consisting of Ν, O and S; but when η is O, G is CH or a heteroatom selected from the group consisting of N1 O and S; provided that at most two of A, E, L, J and G are heteroatoms.

If η is O, the above monocyclic heterocyclic ring has 5 elements while, if η is 1, the ring has 6 elements. If the ring depicted hereinabove contains a nitrogen atom in the ring, then N-oxide forms are also considered to be within the scope of the invention.

When R 2 or R 3 comprises a heterocyclic group of the above formula, it may be attached to the main chain through a ring carbon atom. When η is 0, R2 or R3 it may additionally be attached to the main chain through a nitrogen atom in the ring.

Other preferred portions of R 2 and R 3 are hydrogen, aryl (e.g. phenyl), arylalkyl (e.g. benzyl) and alkyl. Such portions may be unsubstituted or mono- or polysubstituted by electron extraction and / or electron donation groups. In various embodiments, R 2 and R 3 are independently hydrogen; lower alkyl, whether or not substituted or substituted by one or more electron extraction and / or electron donation groups, such as lower alkoxy (for example methoxy, ethoxy and the like); N-hydroxylamino; N-lower alkyl hydroxyamino; N-lower alkyl-O-lower alkyl; or alkyl hydroxylamino.

In some embodiments, one of R2 and R3 is hydrogen.

In one embodiment, η in Formula (I) is 1 and one of R2 and R3 is hydrogen. Illustratively, in this embodiment, R2 is hydrogen and R3 is lower alkyl or Z-Y where Z is O, NR4 or PR4 and Y is hydrogen or lower alkyl;

or Z-Y is NR4NR5R7, NR4OR5, ONR4R7,

NR4C-R5 OR NR4C-OR5.

<formula> formula see original document page 20 </formula> In another embodiment, η is 1, R2 is hydrogen and R3 is lower alkyl which is unsubstituted or substituted by an electron extraction group or group of electrons. electron donation, NR4OR5 or ONR4R7.

In yet another embodiment: η is 1; R is lower alkyl aryl, aryl group which is unsubstituted or substituted by an electron extraction group, for example, aryl may be phenyl which is unsubstituted or substituted by halo;

R1 is lower alkyl;

R2 is hydrogen; and

R3 is lower alkyl which is unsubstituted or substituted by hydroxy, lower alkoxy, NR4OR5 or ONR4R7 wherein R4, R5 and R7 are independently hydrogen or lower alkyl.

In yet another embodiment, R 2 is hydrogen and R 3 is hydrogen, an alkyl group which is unsubstituted or substituted by at least one electron extraction group or electron donation group or Z-Y. In this embodiment, R 3 is illustratively hydrogen, an alkyl group such as methyl which is unsubstituted or substituted by an electron donating group such as lower alkoxy, more especially methoxy or ethoxy or by NR4OR5 or ONR4R7 wherein R4 R5 and R7 are independently hydrogen or lower alkyl.

In yet another embodiment, R 2 and R 3 are independently hydrogen, lower alkyl or Z-Y; Z is O, NR4 or PR4; Y is hydrogen or lower alkyl; or Z-Y is NR4NR5R7, NR4OR5, ONR4R7,

NR4C-R5 or NR4C-OR5

THE

It is preferred that R is lower alkyl aryl. The most preferred arila

for R is phenyl. The most preferred group R is benzyl. The aryl group is unsubstituted or substituted by an electron extraction group or an electron donation group. If the aryl ring in R is replaced, it is more preferable that it be replaced by an electron extraction group. The most preferred electron extraction group for R is halo, especially fluorine.

Preferred R 1 is lower alkyl, especially methyl.

In one embodiment, R is lower alkyl aryl, for example benzyl and R 1 is lower alkyl, for example methyl. Other preferred compounds are compounds of Formula (I) in

what:

η is 1;

R is aryl or lower alkyl aryl, such as benzyl wherein the aryl group is unsubstituted or substituted by an electron donating or electron donating group;

R1 is lower alkyl; R2 is hydrogen; and R3 is hydrogen, a lower alkyl group, especially methyl, which is substituted by an electron extraction or electron donation group or Z-Y.

In this embodiment, it is more preferred that R3 is hydrogen, a lower alkyl group, especially methyl, which may be substituted by an electron extraction group such as lower alkoxy (e.g. methoxy, ethoxy or the like), NR4OR5 or ONR4R7 wherein these groups are as defined herein above.

In one aspect, the compound is represented by Formula (II):

<formula> formula see original document page 22 </formula>

or a pharmaceutically acceptable salt thereof wherein: Ar is aryl, especially phenyl, which is unsubstituted or substituted by at least one halo;

R1 is lower alkyl, especially C1-3 alkyl, for example,

methyl; and

R3 is hydrogen or lower alkyl which is unsubstituted or substituted by at least one electron extraction or electron donation group or Z-Y; for example, R3 is -CH2-Q wherein Q is lower alkoxy, especially C1-3 alkoxy, for example methoxy.

In another aspect, the compound has the formula (I) wherein: η is 1; R is unsubstituted or substituted benzyl, in particular halosubstituted benzyl;

R1 is lower alkyl, especially C1-3 alkyl, for example,

methyl;

R2 is hydrogen; and

R3 is as broadly defined herein.

In yet another aspect, the compound is represented by the

Mule (III):

<formula> formula see original document page 23 </formula>

or a pharmaceutically acceptable salt thereof wherein:

R4 is one or more substituents independently selected from the group consisting of hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, carboxy, formyl, carboxyamido, aryl, quaternary ammonium, haloalkyl, aryl alkanoyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryloxy, mercapto, alkylthio, alkylmercapto and disulfide;

R 3 is selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, N-alkoxy-N-alkylamino and N-alkoxyamino; and

Ri is alkyl.

Alkyl, alkoxy, alkenyl and alkynyl groups in a compound of Formula (III) are lower alkyl, alkoxy, alkenyl and alkynyl groups having no more than 6, more typically no more than 3 carbon atoms.

In a particular aspect, R 4 substituents on a compound of Formula (III) are independently selected from hydrogen and halo, more particularly fluorine substituents. In a particular aspect, R3 in a compound of Formula (III) is

alkoxyalkyl, phenyl, N-alkoxy-N-alkylamino or N-alkoxyamino.

In a particular aspect, R1 in a compound of Formula (III) is

C1-3 alkyl.

In a more particular aspect, no more than one FU substituent is fluorine and all others are hydrogen; R3 is selected from the group consisting of methoxymethyl, phenyl, N-methoxy-N-methylamino and N-methoxyamino; and Ri is methyl.

It should be understood that combinations and permutations of groups R1, R2, R3 and R and n values, even if such combinations and permutations are not explicitly described herein, are considered to be within the scope of the present invention. In addition, the present invention also encompasses therapeutic combinations comprising a compound having one or more elements of each of the Markush groupings described for R1, R2, R3 and R and the various combinations thereof. Thus, for example, the present invention considers that R 1 and R may independently be one or more of the substituents listed hereinabove in combination with any of the substituents R 2 and R 3, independently with respect to each of the subunits η of the compound. of Formula (I).

<formula> formula see original document page 24 </formula>

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. The configuration around a chiral carbon atom can also be described as R or S in the Cahn-Prelog-Ingold system. All of the various configurations around each asymmetric carbon, including the various enantiomers and diastereomers, as well as mixtures of enantiomers, diastereomers or both including, but not limited to racemic mixtures, are considered by the present invention.

More particularly, in a compound of Formula (I) where R2 and R3 are not identical, there is asymmetry in the carbon atom to which groups R2 and R3 are attached. As used herein, the term "configuration" generally refers to the configuration around the carbon atom to which R2 and R3 are attached, even though other chiral centers may be present in the molecule. Therefore, unless the context otherwise requires, when referring to a particular configuration, such as D or L, it should be understood to mean the stereoisomer D or L at the carbon atom to which R2 and R3 are attached. However, all possible enantiomers and diastereomers possible at other chiral centers, if any, present in the compound are encompassed herein.

The compounds useful herein may comprise the L or D stereoisomers as defined above or any mixture thereof including, without limitation, a racemic mixture. D stereoisomers are generally preferred. In lacosamide, the D-stereoisomer corresponds to the R-enantiomer according to the terminology R, S.

In one embodiment, the compound, for example lacosamide, is substantially enantiopuro. As used herein, the term "substantially enantiopuro" means having at least 88%, preferably at least 90%, more preferably at least 95%, 96%, 97%, 98% or 99% enantiomeric purity.

Illustrative compounds which may be used in the present combination include:

(R) -2-acetamido-N-benzyl-3-methoxypropionamide (lacosamide); (R) -2-acetamido-N-benzyl-3-ethoxypropionamide;

O-methyl-N-acetyl-D-serine-m-fluorobenzylamide;

O-methyl-N-acetyl-D-serine-p-fluorobenzylamide;

N-acetyl-D-phenyl glycine benzylamide;

D-1,2- (N, O-Dimethyl hydroxylamino) -2-acetamido acetic acid benzylamide; and

D-1,2- (O-Methyl hydroxylamino) -2-acetamido acetic acid benzylamide.

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

Pharmaceutically acceptable salts are those having therapeutic efficacy without unacceptable toxicity. Salts of inorganic acids such as hydrochloric, hydroiodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid as well as salts of organic acids such as tartaric, acetic, citric, malic, benzoic, perchloric, glycolic, gluconic, succinic, aryl sulfonic (e.g., p-toluene sulfonic, benzene sulfonic), phosphoric and malonic and the like may be used.

Compounds useful herein may be prepared by any synthetic procedure, for example, as described in the above-mentioned U.S. Patent Nos. 5,378,729 and No. 5,773,475, each of which is incorporated herein by reference.

A compound as described herein is used in a therapeutically effective amount. A physician may determine an appropriate dosage of a compound, which may vary with the particular compound chosen, the route and method of administration and the age and other characteristics of the individual patient. The physician may initiate treatment with small doses, for example substantially less than an optimal dose of the compound and increase the dose in small increments until an optimal effect under the circumstances is obtained. When the composition is administered orally, larger amounts of the compound may be required to produce the same therapeutic benefit as a smaller amount supplied parenterally.

In a particular aspect, the compound, for example, Iacosamide, is administered in an amount ranging from about 1 mg to about 10 mg per kilogram body weight per day. Typically, a patient may be treated with the compound, for example lacosamide, at a dose of at least about 50 mg / day, for example at least about 100 mg / day, at least about 200 mg / day, at least about 300 mg / day or at least about 400 mg / day. Generally, a suitable dose is not greater than about 6 g / day, for example not greater than about 1 g / day or not greater than about 600 mg / day. In some cases, however, larger or smaller doses may be required. In another aspect, the daily dose is increased until a predetermined daily dose is reached which is maintained during further treatment.

In yet another aspect, several divided doses are administered

daily. For example, no more than three doses per day or no more than two doses per day may be administered. However, it is often more convenient to administer no more than a single dose per day.

Doses expressed here on a daily basis, for example, in

mg / day should not be interpreted as requiring once-daily dosing. For example, a dose of 300 mg / day may be given as 100 mg three times daily or 600 mg every other day.

In yet another aspect, an amount of the compound, e.g.

For example, lacosamide is administered which results in a plasma concentration of the compound from about 0.1 to about 15 μg / ml (serum) and about 5 to about 18.5 μg / ml (peak) calculated as an average over a plurality of treated individuals.

The compound of Formulas (I), (II) or (III), for example lacosamide

It may be administered in any convenient and effective manner, such as via the oral, intravenous, intraperitoneal, intramuscular, intrathecal, subcutaneous or transmucosal (e.g. buccal) routes. Oral or intravenous administration is generally preferred.

For oral administration, the compound is typically administered

as a component of an orally distributable pharmaceutical composition which further comprises an inert diluent or an assimilable ingestible carrier or may be incorporated into the subject's food. In an orally distributable pharmaceutical composition, the compound may be incorporated

together with one or more excipients and administered in the form of tablets, exchanges, pills, capsules, elixirs, suspensions, syrups, wafers or the like. Such compositions typically contain at least about 1%, more typically about 5% to about 80% by weight of the compound, for example lacosamide. The amount of the compound in the composition is such that upon administration of the composition a suitable dosage as set forth above may conveniently be provided. Illustratively, a pharmaceutical composition useful for oral delivery of a compound of Formulas (I), (II) or (III), for example lacosamide, contains from about 10mg to about 6g, for example about 50 to about 1000 mg or about 100 to about 600 mg of the compound.

In particular embodiments, the composition is enclosed in hard or soft shell capsules (e.g. gelatin) or in a tablet or molded tablet form. The composition illustratively comprises as excipients one or more of a diluent, such as lactose or dicalcium phosphate (in the case of capsules, a liquid carrier may be present); a binding agent, such as gum tragacanth, Acacia, cornstarch or gelatin; a disintegrating agent such as cornstarch, potato starch, alginic acid or the like; a lubricant, such as magnesium stearate; and a sweetening agent such as sucrose or saccharin and / or a flavoring agent such as peppermint, menthol oil or cherry flavoring may be added if desired. Several other excipients may be present as coatings.

otherwise modify the physical form of the composition. For example, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, extracted as a sweetening agent, methyl- and propyl-parabens as preservatives, a coloring and flavoring such as cherry or orange flavoring. The active compound can be incorporated into a sustained release formulation. For example, sustained release dosage forms are considered wherein the compound is bonded to an ion exchange resin which optionally may be coated with a diffusion barrier coating to modify the release properties. of the resin.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where the compound is water soluble), sterile dispersions and powders for extemporaneous preparation of sterile injectable solutions or dispersions. In such cases, the injectable composition should be sterile and must be sufficiently fluid to allow easy flowability in a syringe. The composition should be stable under the conditions of manufacture and storage and should typically be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol, liquid or similar polyethylene glycol), suitable mixtures thereof and vegetable oils. Proper flowability may be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions and by the use of surfactants. Microbial action may be inhibited by various antifungal and antibacterial agents, eg parabens, chlorobutanol, phenol, sorbic acid, thimerosal or the like. In many cases, it will be preferable to include tonicity agents, for example sugars or sodium chloride, to provide a substantially isotonic injection liquid. Prolonged absorption of injectable compositions may be maintained by the use of absorption delaying agents in the compositions, for example aluminum monostearate or gelatin.

Sterile injectable solutions may be prepared by incorporating the active compound in a required amount into an appropriate solvent with several of the other ingredients mentioned above as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the sterilized active compound into a sterile vehicle which contains the dispersing medium and other excipient ingredients such as those mentioned above. Sterile powders for the preparation of sterile injectable solutions may be prepared by vacuum drying or lyophilizing a sterile previously filtered solution or dispersion.

The therapeutic combination of the invention comprises, in addition to the first agent as described above, a second agent effective in combination therewith to (a) provide intensified treatment of pain associated with or caused by a medical condition as compared to the first agent alone; and / or (b) treat another symptom or underlying cause of a medical condition; the second agent comprising one or more other drugs than a compound of Formula (I).

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

An "anti-arthritis drug" is a drug having efficacy in treating (including preventing) any aspect, symptom (e.g., pain or inflammation) and / or an underlying cause of an arthritic condition as defined herein. For example, an anti-arthritis drug included with or as the second agent may be effective for the treatment of pain, ie analgesia. Suitable analgesics include opioid and non-opioid analgesics, as well as certain anti-inflammatory drugs (see immediately below). A combination comprising a compound of Formulas (I), (II) or (III), for example lacosamide, and an opioid or non-opioid analgesic may be useful in any arthritic condition accompanied by pain, in particular where Such pain has a noninflammatory component, such as osteoarthritis.

Alternatively or in addition, an anti-arthritis drug included in or as the second agent may be effective for treating inflammation and / or pain related thereto. Suitable antiinflammatory drugs include steroidal and non-steroidal antiinflammatory drugs. Non-steroidal anti-inflammatory drugs (NSAIDs) include traditional NSAIDs and selective cyclooxygenase-2 (COX-2) inhibitors. A combination comprising a compound of Formulas (I), (II) or (III), for example lacosamide, and an anti-inflammatory may be useful in any condition accompanied by inflammatory pain or where inflammatory and non-inflammatory types of pain. are present. Non-limiting examples of opioid and non-opioid analgesics that may be useful in the second agent include acetaminophen, alfentanil, allylprodin, alphaprodin, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, deomorphine, dextromorphine, dextromorphine, dextromorphine, dextromide , diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimethoxadol, dimethyltiambutene, dioxapetyl butyrate, dipipanone, dipyrone (metamizole), eptazocine, ethoheptazine, ethylmethylthymbine, ethanmorphine, hydronaphthyrone, ethanitone, hydronaphenone hydroxypetidine, isomethadone, ketobemidone, levallorphan, ievorfanol, levofenacil-morphan, lofentanil, meperidine, meptazinol, methazocine, methadone, morphine, myrophin, nalbuphine, nalorphine, narorin, norporphine, norphorone, norphorone opium, oxycodone, oxymorphone, papaveretum, pentazocine, fenadoxone, phenazocine, fenomorphan, f enoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, NO-naproxen, NCX-701, ALGRX-4975, pharmaceutically acceptable salts thereof and combinations thereof.

Non-limiting examples of steroidal antiinflammatories which may be useful in the second agent include alclometasone, amcinonide, betamethasone, betamethasone 17-valerate, clobetasol, iobasol propionate, clocortolone, cortisone, dehydrotestosterone, deoxycorticosterone, desonone, deoxide dexamethasone, dexamethasone 21-isonicotinate, diflorasone, fluocinonide, fluocinolone, fluorometolone, flurandrenolide, fluticaronone, halcinonide, halobetasol, hydrocortisone acetate, hydrocortisone hydrochloride, hydrocortisone succinate hydrocortisone hydrochloride hydrocortisone sodium, isoflupredone, isoflupredone acetate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisolone suleptnate, mometasone, prednicarbate, prednisolone, prednisolone acetate, prednisone hemisuccinate phosphate, predisolone sodium succinate, valerate prednisolone acetate, prednisone, triamcinolone, triamcinolone acetate, pharmaceutically acceptable salts thereof and combinations thereof.

Non-limiting examples of NSAIDs that may be useful in the second agent include salicylic acid derivatives (such as salicylic acid, acetyl salicylic acid, methyl salicylate, diflunisal, olsalazine, salsalate and sulfasalazine), indole and indene acetic acids. (such as indomethacin, etodolac and sulindac), fenomes (such as etophenamic, meclophenamic, mefenamic, flufenamic, niflumic, tolfenamic), heteroaryl acetic acid (such as acemetacin, alclofenac, clidanac, diclofenac, diclofenac, diclofenac furofenac, ibufenac, isoxepac, ketorolac, oxipinac, thiopinac, tolmetin, zidometacin and zomepirac), aryl acetic acid and propionic acid derivatives (such as alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, fluprofen , ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, thiaprofenic acid and thioxaprofen), enolic acids (such as such as ampiroxicam, cinnoxicam, droxicam, lornoxicam, meloxicam, piroxicam, sudoxicam and tenoxicam derivatives and pyrazolone derivatives aminopyrine, antipyrine, apazone, dipyrone, oxiphenbutazone and phenylbutazone (nalanumide) , proquazone, MX-1094, lycofelone and pharmaceutically acceptable salts thereof and combinations thereof. Non-limiting examples of selective COX-2 inhibitors that

may be useful in the second agent include celecoxib, deracoxib, valdecoxib, parecoxib, rofecoxib, etoricoxib, lumiracoxib, PAC-10549, cimicoxib, GW-406381, LAS-34475, CS-502, pharmaceutically acceptable salts thereof and combinations of the same. Alternatively or in addition, the second agent may comprise

illustratively illustrate a disease modifying osteoarthritis drug (DMOAD). Non-limiting examples of DMOADs that may be useful in the second agent include methotrexate, diacerein, glycosamine, chondroitin sulphate, anakinra, MMP inhibitors, doxycycline, minocycline, misoprostol, proton pump inhibitors, unacetylated salicylates, salicylates unacetylated, tamoxifen, prednisone, methylprednisolone, polysulfated glycosaminoglycans, calcitonin, alendronate, risedronate, zoledronic acid, teriparatide, VX-765, pralnacasan, SB-462795, CPA-926, ON-.4817, S-3536, PG-530742, CP-544439 and pharmaceutically acceptable salts thereof and combinations thereof.

Alternatively or in addition, the second agent may illustratively comprise a disease modifying antirheumatic drug (DMARD). Non-limiting examples of DMARDs that may be useful in the second agent include etanercept, adalimumab, infliximab, IL-1 receptor antagonists, prednisone, methylprednisolone, penicillamine, hydroxychloroquine sulfate, chlorambucil cyclosphosphamide, leflunomide, cyclosporine, aurotioglose, gold azathioprine, sodium thiomalate, methotrexate, cyclophosphamide, minocycline, sulfasalazine, abatacept, rituximab, buccinamine, chloroquine, hydroxychloroquine, lobenzarit, misoprostol and pharmaceutically acceptable salts thereof and combinations thereof.

Alternatively or in addition, the second agent may illustratively comprise a symptom modifying anti-arthritis drug not mentioned above. Non-limiting examples of such drugs which may be useful in the second agent include ADL-100116, AD-827, HOE-140, DA-5018, pharmaceutically acceptable salts thereof and combinations thereof.

More than one anti-arthritis drug may be administered in combination or adjunctive therapy with a compound of Formulas (I), (II) or (III), for example lacosamide. In one embodiment, two or more of such agents are included in the combination or adjunctive therapy selected from two or more of the following classes:

(i) opioid and non-opioid analgesics;

(ii) steroidal anti-inflammatory drugs;

(iii) NSAIDs and selective COX-2 inhibitors;

(iv) DMOARDs; and

(v) DMARDs.

In a particular embodiment, the two or more agents administered in combination or adjunctive therapy with a compound of Formula (I), (II) or (III), for example lacosamide, are selected from the agents listed above, in that at least one of the agents is a DMOARD or a DMARD.

In one embodiment, administration of the therapeutic combination is useful for treating an arthritic condition and pain related thereto.

Illustratively, a compound of Formulas (I), (II) or (III), for example Ia-cosamide, may be used to treat pain, more particularly non-inflammatory pain, associated with an arthritic condition and at least one drug. Anti-arthritis, such as those listed above, may be used in combination with the compounds of Formulas (I), (II) or (III) to treat an underlying process that causes or contributes to an arthritic condition or to treat another symptom. , for example, inflammatory pain, from an arthritic condition.

In another embodiment, the second agent is present in an amount effective in combination with the first agent to provide enhanced pain treatment, more particularly noninflammatory pain, as compared to the first agent alone. Any drug which, in combination with the first agent, provides such enhanced treatment may be used as or included in the second agent, for example an opioid or non-opioid analgesic, an anticonvulsant, an antidepressant and / or a NMDA receptor antagonist. "Intensified pain management" in the present context means that the combination is superior to the first agent alone in at least one of the following:

(a) greater reduction in pain intensity and / or duration;

(b) permits dose reduction of the first agent or second agent or both compared to a typical effective dose when used alone.

(c) reduction in adverse side effects; and / or

(d) improved therapeutic ratio.

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 greater than would be expected based on the efficacy of the agent alone at the same dose. . According to the present embodiment, the second agent may comprise one or more analgesics, for example selected from those listed above. In an illustrative example, the second agent comprises morphine or a pharmaceutically acceptable salt thereof.

Alternatively or in addition, the second agent may comprise one or more anticonvulsants, for example selected from acetyl pheneturide, albutoin, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atractactamide, beclamide, buramate, carbamazepine , cinromide, clometiazole, clonazepam, decimemide, dietadione, dimetadione, doxenitoin, eterobarb, etadione, etosuximide, ettoin, felbamate, fluoresone, tosphenytoin, gabapentin, ganaxolone, lamotrigine, Ievetiracetam, lorazital methambital methambital, methirbital , midazolam, narcobarbital, nitrazepam, oxcarbazepine, paramethadione, phenacemide, fenetarbital, pheneturide, phenobarbital, fensuximide, phenylmethylbarbituric acid, phenytoin, phenethylate, pregabalin, primidone, progabide, remacemide, rufinetrin, tufmetrelampanel, tuphamelamide, rufinamine, thiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrin, zonisamide, pharmaceutically acceptable salts of same and combinations thereof.

In a more particular embodiment, the second agent comprises one or more anticonvulsants selected from carbamazepine, phenytoin, gabapentin, pregabalin, lamotrigine, Ievetiracetam and pharmaceutically acceptable salts thereof. In an illustrative example, the second group comprises gabapentin.

Alternatively or in addition, the second agent may comprise one or more antidepressants including, without limitation, bicyclic, tricyclic and tetracyclic antidepressants, hydrazides, hydrazines, phenoxyazolidinones and pyrrolidones. An antidepressant may be, for example, selected from adinazolam, adrafinil, amineptine, amitriptyline, amitriptylinoxide, amoxapine, befloxatone, bupropion, butacetin, butriptyline, caroxazone, citalopram, clomipramine, cotinine, demexiptyline, desepamine, dimethylamine, desipramine, dimetazan, dioxadrol, dotiepine, doxepine, duloxetine, etoperidone, femoxetine, phenamine, fenpentadiol, fluacizine, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, imipramine, imipramine N-oxide, indalpine, indelprine, indelprine, indolazine iproniazid, isocarboxazid, ievofacetoperan, lofepramine, maprotiline, medifoxamine, melitracen, metapramine, metralindole, mianserin, milnacipran, minaprine, mirtazapine, moclobemide, nefazodone, nefopam, nialamiphosphamine, oxypropylamine, mephaline oxitriptan, oxipertine, paroxetine, phenelzine, piberalin, pizotiline, prolintane, propizepine, protriptyline, pyrisuccideanol, quinupramine, re boxetine, ritanserine, roxindola, rubidium chloride, sertraline, sulpiride, tandospirone, thiazesim, tozalinone, thianeptine, tofenacin, toloxatone, tranylcypromine, trazodone, trimipramine, tryptophan, venlafaxine, villoxadine pharmaceutically acceptable salts same and combinations thereof. In an illustrative example, the second agent comprises duloxetine.

Alternatively or in addition, the second agent may comprise one or more NMDA receptor antagonists, for example, selected from amantadine, D-AP5, aptiganel, CPP, dexanabinol, dextromethorphan, dextropropoxyphene, acid 5,7 dichloroquinurenic, gavestinel, ifendopril, ketamine, ketobemidone, licostinel, LY-235959, memantine, methadone, MK-801, phencyclidine, remacemide, selfotel, tiletamine, pharmaceutically acceptable salts thereof and combinations thereof. In an illustrative example, the second agent comprises memantine.

In another embodiment, the second agent comprises one or more drugs independently selected from the group consisting of GABA analogs, thiophene propane derivatives, morphine and opioid analogs, the family of 2-arylpropionic acid (profen), amantadine derivatives ( 1-aminoadamantane). An example of a GABA analog is gabapentin. An example of a triophene propane derivative is duloxetine. An example of opioids is morphine. One member of the 2-arylpropionic acid family is naproxen. A derivative of amantadine is memantine. In another embodiment, the second agent comprises one or more

more drugs independently selected from the group consisting of gabapentin, duloxetine, morphine, naproxen and memantine. In yet another embodiment, the second agent comprises one or more drugs independently selected from the group consisting of duloxetine, morphine, naproxen 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 present invention, the first agent comprises lacosamide and the second agent comprises duloxetine.

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

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

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

In one embodiment of the present invention, the combination of the present invention provides enhanced treatment of pain associated with or caused by a medical condition wherein the medical condition is accompanied by or has, as a symptom thereof, noninflammatory pain. In one embodiment of the present invention, the combination of the present invention provides intensified treatment of pain, wherein medical condition-related pain comprises noninflammatory pain.

In one embodiment of the present invention, the combination of the present invention provides intensified treatment of pain associated with or caused by a medical condition wherein the medical condition is an arthritic condition and / or pain related thereto. The arthritic condition may comprise osteoarthritis. In this embodiment, in combination, the first agent and the second agent may be present in absolute and relative amounts effective to treat an arthritic condition and / or pain related thereto. In combination, the first agent and the second agent may be present in absolute and relative amounts effective to treat components of noninflammatory and inflammatory pain associated with or caused by an arthritic condition.

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

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

Osteoarthritic pain may be associated with cartilage degradation, structural bone changes and / or vascularization of osteoarthritic remodeling areas.

The arthritic condition may comprise one or more disorders selected from the group consisting of idiopathic osteoarthritis, secondary osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, neurogenic arthropathy, polyarthralgia syndrome, and associated arthritis syndrome Behçet's syndrome, Reiter's syndrome, systemic Iupus erythematosus, rheumatic fever, gout, pseudologist, Lyme disease, sarcoidosis and ulcerative colitis.

The arthritic condition may comprise rheumatoid arthritis or juvenile rheumatoid arthritis.

In another embodiment of the present invention, the combination of the present invention provides enhanced treatment of pain associated with or caused by a medical condition wherein the medical condition is pain in painful diabetic neuropathy. Painful diabetic neuropathy may be diabetic distal sensory neuropathy. In combination, the first and second agents may be effective for treating a selected pain aspect of the group consisting of mean daily pain, overall pain, intensity of pain present, interference of pain with sleep, individual's perception of interference. of pain with general activity, the patient's overall impression of pain change, overall clinical impression of pain change, the individual's perception of different neuropathic pain qualities, quality of life, and proportion of days without pain.

In the present invention, painful diabetic neuropathy may be associated with Type II and Type I Diabetes mellitus. Painful diabetic neuropathy may also be associated with Type II Diabetes mellitus.

In another embodiment of the present invention, the combination of the present invention provides intensified treatment of pain associated with or caused by a medical condition wherein the medical condition or pain related thereto is selected from the group consisting of acute inflammatory pain; acute pain; neuropathic pain associated with alcoholism or induced by alcoholism; allodynia; arthritic conditions; back pain; cancer-related neuropathic pain; central neuropathic pain; chronic headache; chronic inflammatory pain; chronic pain; chronic pain due to peripheral nerve injury; diabetes-associated or diabetes-induced neuropathic pain; diabetic distal sensory neuropathy; di-diabetic distal sensory polyneuropathy; diabetic pain; fibromyalgia; Headache; hyperalgesia; hyperesthesia; hyperpathy; migraine; myalgia; myofascial pain syndrome; neuralgia; neuroma; noninflammatory osteoarthritic pain; non-neuropathic inflammatory pain; neuropathic pain; pain associated with or induced by chemotherapy or radiation therapy; pain associated with or induced by traumatic nerve injury or compression or traumatic injury to the brain or spinal column; painful diabetic neuropathy; peripheral neuropathic pain; persistent clinical pain; phantom pain; rheumatoid arthritis pain; secondary osteoarthritic inflammatory pain; trigeminal neuralgia; vascular headache; and combinations thereof.

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

Still another aspect of the present invention is a method for treating a painful medical condition and / or related pain in an individual, the method comprising administering to the individual the therapeutic combination of the present invention. In the method of the present invention, the painful medical condition and / or pain related thereto is selected from the conditions as described herein.

In one embodiment of the method, the medical condition or pain related thereto is selected from the group consisting of acute inflammatory pain; acute pain; neuropathic pain associated with alcoholism or induced by alcoholism; allodynia; arthritic conditions; back pain;; cancer-related neuropathic pain; central neuropathic pain; chronic headache; chronic inflammatory pain; chronic pain; chronic pain due to peripheral nerve injury; diabetes-associated or diabetes-induced neuropathic pain; diabetic distal sensory neuropathy; diabetic distal sensory polyneuropathy; diabetic pain; fibromyalgia; Headache; hyperalgesia; hyperesthesia; hyperpathy; migraine; myalgia; myofascial pain syndrome; neuralgia; neuroma; noninflammatory osteoarthritic pain; non-neuropathic inflammatory pain; neuropathic pain; pain associated with or induced by chemotherapy or radiation therapy; pain associated with or induced by traumatic nerve attachment or compression or traumatic injury to the brain or spinal column; painful diabetic neuropathy; peripheral neuropathic pain; persistent clinical pain; phantasma pain; rheumatoid arthritis pain; secondary osteoarthritic inflammatory pain; trigeminal neuralgia; vascular headache; and combinations thereof.

In yet another embodiment, the method of the present invention employs, in said combination, a first agent comprising laconamide.

Still another aspect of the present invention is the use of a combination as defined herein for the preparation of a medicament for the prevention, alleviation and / or intensified treatment of pain associated with or caused by a medical condition as compared to compound of Formula (I) alone; said second agent comprising one or more other drugs than a compound of Formula (I).

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

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

Suitable regimens including doses and routes of administration for particular drugs in or how the second agent may be determined from readily available reference sources for such drugs, for example, Phvsicians' 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 adjunctive therapy with a compound of Formulas (I), (II) or (III), for example lacosamide, a drug useful in or as the second agent may be used in a complete dose, but the physician may choose to administer less than a total dose of such drug, at least initially.

The first agent and the second agent may be provided in a pharmaceutical preparation (single dosage form) for administration to the individual at the same time or in two or more separate preparations (distinct dosage forms) for administration to the individual at the same time or at different times, for example sequentially and / or at the same time or at different frequencies. The two distinct preparations may be provided in forms adapted for administration via the same or different routes.

Various dosage forms may optionally be packaged, for example, in a single container or in a plurality of containers within a single outer packaging or presented in separate packages ("common presentation"). As an example of a common packaging or presentation, a kit is considered to comprise, in a first container, a compound of Formulas (I), (II) or (III), for example lacosamide and, in a second container, a second agent as described herein. In another example, a compound of Formulas (I), (II) or (III), for example lacosamide, and a second agent are separately packaged and available for sale independently of each other, but are co-marketed or co-moved to use according to the invention. Distinct dosage forms may also be presented to a separate and independently subject for use in accordance with the invention.

Depending on the dosage forms, which may be identical or different, for example, quick release dosage forms, controlled release dosage forms or depot forms, the compound of Formulas (I), (II) or (III), for example, lacosamide and the second member may be administered on the same or different schedules, for example on a daily, weekly or monthly basis.

In one embodiment, administration of the therapeutic combination is useful for treating noninflammatory osteoarthritic pain. In particular, such administration is useful when noninflammatory osteoarthritic pain is associated with cartilage degradation, bone structural changes and / or vascularization of bone remodeling areas. The bone undergoes continuous remodeling. Remodeling is a process by which an old bone is replaced by a new bone to maintain peak bone density. Vascularization occurs through the proliferation of capillaries during the remodeling process and may be increased under conditions such as osteoarthritis.

In one embodiment, administration of the therapeutic combination inhibits pain transmission. Inhibition of pain transmission, typically a contributing effect of the compound of Formulas (I), (II) or (III), for example lacosamide, may be accompanied by preventing spinal neurons from responding to neurotransmitters such as glutamate released by nociceptors. Examples Example 1

This example describes a study demonstrating the efficacy of

lacosamide thio-nociceptive inhibition of mechanical hyperalgesia, as measured by paw withdrawal threshold for muscle pressure and mechanical allodynia, as measured by biceps muscle holding resistance, occurring in TNF-induced musculoskeletal pain in rats. The model used in this example is applicable to musculoskeletal pain which occurs in fibromyalgia, myofascial pain syndrome, back pain or osteoarthritis.

For comparative purposes, the non-opioid dipyrone analgesic (metamizole) and pregabalin and gabapentin anticonvulsants were included in the study. Animals, muscle pain induction

Adult male Sprague Dawley rats with a molecular weight of 250 g to 300 g were used (supplier: Charles River, Sulzfeld, Germany). The animals were housed in groups (3 animals per cage) and kept in a temperature controlled room (21-22 ° C) and an inverted chiaroscuro cycle (12 h / 12 h) with food and water available ad Libitum All experiments were approved by the Bavarian State Animal Experimentation Committee and performed in accordance with its regulations.

Recombinant rat tumor necrosis alpha factor (referred to herein as THF) was obtained from R&D Systems, Minneapolis, MN, U.S. TNF was diluted in 0.9% NaCI and used at a concentration of 1 μg by 50 μΙ. Injections were made into halothane short narcosis with a 30 g needle bilaterally in the gastrocnemius or biceps brachii muscle. All rats were used for behavioral testing prior to injections and baseline values were recorded during three days of testing. Behavioral Reading: Muscle Pressure (RandaII-SeIitto)

Mechanical withdrawal thresholds for muscle pressure were measured with an analgesometer (Ugo Basile, Comerio, Italy). The mouse has been allowed to roam in a sock, which helps the mouse to relax. The hind limbs were positioned so that increasing pressure could be applied to the gastrocnemius muscle (250 g maximum). The pressure required to stimulate withdrawal was recorded. The means of 3 experiments for each hind limb were calculated (interstimulus interval> 30 sec). Only animals with a significant TNF effect were included for further analysis.

Rats were injected with TNF into the gastrocnemius muscle at .2 pm. Eighteen hours later, rats were tested for pre- and post-administration hyperalgesia of the test drug. Rats were tested for pressure hyperalgesia 30 to 60 minutes after drug administration.

Behavioral reading: holding resistance

Holding strength of the front limbs was tested with a digital grip strength gauge (DFIS series, Chatillon, Greensboro, NC, USA). The mouse was positioned to hold the grille with the front limbs and was gently pushed so that the holding resistance could be recorded. The means of three experiments were calculated. The effect of TNF treatment was calculated for each animal separately. Only animals with a significant TNF effect were included for further analysis.

The rats were injected with TNF into the biceps brachii muscle at .8 in the morning. Six hours later, the holding strength of the front limbs was tested with a digital grip strength measurement. Test drug was administered and holding resistance was retested after .30 to 60 minutes.

Administration Protocol

The mice, initially 10 per group, were treated with 3, 10 or .30 mg / kg lacosamide, 2 mg / kg metamizole, 30 or 100 mg / kg pregabalin, 100 mg / kg gabapentin or the vehicle. NaCI, ip (intraperitoneally). The volume of injections i.p. was 0.5 ml. A pilot study was performed to conform that i.m. (intramuscular) of 1 μg TNF in the gastrocnemius muscle was sufficient to induce pressure hyperalgesia.

Groups and treatments are summarized for injections of TNF into the gastrocnemius and biceps brachii muscle, respectively, in Tables 1 <table> table see original document page 45 </column> </row> <table>

Table 2: TNF Injection into Biceps Brachii

<table> table see original document page 45 </column> </row> <table>

Data Presentation and Statistics

Data are shown in graphs showing means and standard errors of means (SEM). Pre- and post-treatment data were compared using ANOVA (analysis of variance) and a Dunnett post hoc test. The maximum possible effects (MPE) were calculated for all treatment types.

Results: muscle pressure hyperalgesia Only rats in which withdrawal thresholds were significantly reduced after TNF injection were included. In about 13% of rats, the effect of TNF was absent. Figure 1 shows the absolute values of the pressure withdrawal thresholds.

A complete reversal of mechanical muscle hyperalgesia was observed with 30 mg / kg Iacosamide and 2 mg / kg Metamizole.

A significant reversal of mechanical muscle hyperalgesia was also observed for pregabalin at 30 and 100 mg / kg and gabapentin at .100 mg / kg.

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

Results: Biceps muscle holding resistance

Only rats in which the holding resistance was significantly reduced after TNF injection were included. In about 13% of rats, the effect of TNF was absent. Figure 3 shows absolute values of holding strength.

A significant reversal of reduced TNF-induced holding resistance was observed with Iacosamide at 10 and 30 mg / kg. Significant reversal was also observed for 100 mg / kg pregabalin, 100 mg / kg gabapentin and 2 mg / kg metamizole.

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

Discussion

Iacosamide dose-dependently improved TNF injection-induced muscle hyperalgesia in the paw pressure test, achieving complete reversal to 30 mg / kg. Compared to pregabalin and gabapentin anticonvulsants, Iacosamide had a stronger effect on muscle pain. Neither pregabalin nor gabapentin led to a complete reversal of muscle hyperalgesia. In the holding resistance test indicative of mechanical allodynia, Iacosamide reversed the effect of TNF on muscle at 10 mg / kg. Again, Iacosamide was more potent than pregabalin and gabapentin, which improved holding strength at 100 mg / kg.

In conclusion, Iacosamide was effective in reducing muscle injected TNF-induced muscle hyperalgesia and mechanical allodynia. Thus, it is concluded that lacosamide, illustrative of the compounds of Formulas (I), (II) or (III), has therapeutic efficacy in the treatment, in particular systemic treatment, of specific manifestations of noninflammatory musculoskeletal pain. such as muscle hyperalgesia and allodynia, which occur, for example, in fibromyalgia, myofascial pain syndrome, back pain or osteoarthritis. Example 2

This example describes a study demonstrating the anti-nociceptive efficacy of lacosamide in a rat model of iodoacetate. The model used in this example is applicable to noninflammatory osteoarthritic pain. For comparative purposes, morphine analgesic opioid and diclofenac NSAID were included in the study.

One of the rat models best characterized for osteoarthritis is injection of the metabolic inhibitor monosodium iodoacetate into a joint, for example, a knee joint, which inhibits glyceraldehyde-3-phosphate dehydrogenase activity in chondrocytes, resulting in in glycolysis disruption and eventually cell death (Guzman et al. (2003) Toxicol. Pathol. 31 (6): 619-624; Kalbhen (1987) J. Rheumatol. 14 (Spec. Ne): 130-131) . Progressive loss of chondrocytes results in histological and morphological changes in articular cartilage, closely resembling those observed in human patients with osteoarthritis. Animals

Male Wistar rats (Janview, France) weighing 170-200 g at baseline were used. The animals were housed in groups (3 animals per cage) in a temperature-controlled room (21-22eC) and an inverted chiaroscuro cycle (12 h / 12 h) and had free access to food and water. Osteoarthritis Induction

Osteoarthritis was induced by intra-articular injection in 50 μ 3 of 3 mg monosodium iodoacetate (MIA) (Sigma) through intrapatellar ligament of the right knee. Control rats were injected with an equivalent volume of saline. Up to five days after iodoacetate injection, substantial inflammation of the synovial joints was observed in this model. The overall health of the animals was monitored. No signs of suffering were observed. Histology

On each of days 3, 7 and 14 after iodacetate treatment, four animals were sacrificed for histology study. The knees were collected and fixed overnight in 10% formalin and subsequently decalcified with 10% formic acid for 72 h before being embedded in paraffin. Sections 10 μιτι in thickness were prepared every 250 μιτι.

Hematoxylin / eosin staining was performed to assess the extent of inflammatory infiltrates in the joints and surrounding tissues and Seflanin-O Fast green staining was performed to measure cartilage degeneration.

Evaluation of the effect of compounds on nociception

In the first round of experiments, the iodoacetate-treated rats were randomly assigned to six experimental groups (12 animals per group), which received the following treatments (po = per; sc = subcutaneous) on the evaluation days. pain (days 3, 7 and 14 after iodoacetate treatment):

p.o. saline (vehicle); p.o. 3 mg / kg lacosamide; p.o. 10 mg / kg lacosamide;

p.o. 30 mg / kg lacosamide; s.c. injection of 3 mg / kg morphine.

Diclofenac (30 mg / kg, s.c.) was tested in a separate experiment by the same researchers under the same conditions around the same time. Control group not treated with iodoacetate (control) received p.o. of saline 45 minutes before pain assessment. Lacosamide, diclofenac and morphine were injected 60 minutes prior to the implementation of behavioral tests. Each group was blindly examined. Evaluation of tactile allodynia and mechanical hyperalgesia

For tactile allodynia testing, rats were placed on a metal grid floor. Nociceptive testing was done by inserting a von Frey filament (Bioseb, France) through the grid floor and applying it to the plantar surface of the hind foot. One experiment consisted of several applications of different von Frey filaments (at a frequency of about 1 Hz). The von Frey filaments were applied from filament 10 g to .100 g. As soon as the animal removed its paw, the test was stopped and the filament number was recorded to represent the paw withdrawal threshold.

For mechanical hyperalgesia testing, nociceptive flexion reflexes were quantified using the Randall-Selitto paw pressure device (Bioserb, France), which applied a linearly increasing mechanical force to the rat hind paw. Paw withdrawal threshold was defined as the force at which the rat withdrew its paw. The shear pressure was adjusted to 250 g.

Pharmaceuticals and Reagents

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

Data analysis and statistics

Comparisons of behavioral data groups at each individual time point were conducted using ANOVA, followed by post-hoc analysis (Dunnett's test).

Results

Joint pathology was assessed on days 3, 7, and 14 after intra-articular iodoacetate injection. On day 3, there was a substantial initial inflammatory response. This inflammation was characterized by an expansion of the synovial membrane, most likely caused by proteinaceous edema fluid and fibrin, with macrophages, neutrophils, plasma cells, and infiltrating lymphocytes. The cartilage was still intact. On Day 7, inflammation within the synovium and surrounding tissue was greatly resolved. On day 14, loss of proteoglycan was observed through cartilage depth. The synovial membrane appeared normal and contained no inflammatory cells.

Tactile allodynia, tested with von Frey filaments, was evaluated on days 3, 7, and 14 in rats treated with iodoacetate compared with control rats. Iacosamide (30 mg / kg) and morphine (3 mg / kg) treatment improved tactile allodynia in iodoacetate-treated rats on day 3 (figure 5A) and .7 (figure 5B), but not on day 14 (figure 5C) and lower doses of Iacosamide showed a tendency for such improvement. Diclofenac (30 mg / kg) had no effect on tactile allodynia on day 3 (Figure 6A), day 7 (Figure 6B) or day 14 (Figure 6C).

There was a marked mechanical hyperalgesia, as evidenced by a reduction in paw pressure withdrawal thresholds in animals treated with iodoacetate / vehicle compared with animals treated with control / vehicle. Treatment of iodoacetate-treated rats with 3 mg / kg lacosamide, 3 mg / kg morphine and 30 mg / kg diclofenac induced in each case an increase in the paw pressure withdrawal threshold compared to treated animals. with iodoacetate / vehicle on day 3 (Figures 7A, 8A). On day 7, lacosamide at all doses tested (3, 10 and 30 mg / kg), morphine and diclofenac each reduced mechanical hyperalgesia (Figures .7B, 8B). Similar results were observed on day 14 after iodoacetate treatment, except that the group treated with 10 mg / kg lacosamide did not show a statistically significant effect (Figures 7C, 8C). Interestingly, in animals treated with iodoacetate, mechanical hyperalgesia developed from day 3 and lasted at least 14 days, compared with tactile allodynia, which was more pronounced during the early stage of arthritis development, reflecting continued development. No pain sensitization based on different molecular mechanisms during 14 days post-iodoacetate treatment.

Example 3

This example describes a study demonstrating the efficacy of lacosamide alone and in combination with gabapentin in the rat formalin paw test (late phase) as described by Wheeler-Aceto & Cowan (1991) Psychopharmacoloqv 104: 35-44, which detects analgesic activity. Materials and methods

The rats were given an intraplantar formalin injection at

5% (50 μΙ) in the posterior left paw. This treatment induces a response to demonstrate fear and recognizable licking of the affected paw in control animals. The number of demonstrations of fear was counted for 15 minutes, starting 20 minutes after formalin injection. The time spent licking the affected paw was also recorded.

Male Rj: Wistar (Han) 1 10 mice per group, weighing 100-130 g at the beginning of the experiments were studied by group. The test was performed blindly.

Lacosamide (20 mg / kg), gabapentin (50 and 100 mg / kg), combinations of Iacosamide (20 mg / kg) with gabapentin (50 and 100 mg / kg) and vehicle were administered i.p. 10 minutes before formalin injection. Results

The test results are presented in Tables 3 (number of fear demonstrations) and 4 (number of licks). Table 3. Effect of Lacosamide, Gabapentin and Combinations on Number <table> table see original document page 51 </column> </row> <table> Table 4. Effect of Lacosamide, Gabapentin and Combinations on Licking Time__

<table> table see original document page 52 </column> </row> <table> NS = not significant; * = ρ <0.05; ** = ρ <0.01; *** = ρ <0.001 (a): compared to vehicle control

(b): compared with lacosamide alone at the appropriate dose (c): compared with gabapentin alone at the appropriate dose #: missing value (1/10)

Lacosamide alone at 20 mg / kg tended to decrease the number of fear demonstrations by 33% when compared to vehicle controls. It also tended to decrease licking time by 34% compared to vehicle controls (p = 0.0962).

Gabapentin alone at 50 and 100 mg / kg globally, but did not significantly decrease the number of fear demonstrations by 24% and 31%, respectively, when compared to vehicle controls. Gapapentin dose-dependently decreased licking time by 28% (50 mg / kg) and 60% (100 mg / kg), significantly at 100 mg / kg (p <0.05).

Lacosamide at 20 mg / kg combined with gabapentin at 50 and 100 mg / kg clearly and dose-dependently decreased the number of demonstrations of fear by 64% and 76%, respectively (p <0.01) when compared with vehicle controls. The combination clearly and dose-dependently decreased the time spent licking by 74% (p <0.01) and 82% (p <0.001), respectively. The effects of Iacosamide combined with gabapentin on the number of fear demonstrations and time spent licking were significantly more pronounced than the effects of Iacosamide alone (p <0.05 or ρ <0.01). Example 4

This example describes a study demonstrating the efficacy of Iacosamide alone and in combination with morphine in the rat paw formalin test (late phase), as described by Wheeler-Aceto & Cowan (1991), supra. Materials and methods

Test methods were similar to those of Example 3. Lacosamide (10 and 20 mg / kg), morphine (2 and 4 mg / kg), combinations of Iacosamide (10 and 20 mg / kg) with morphine (2 and 4 mg / kg) and vehicle were administered ip10 minutes before formalin injection. Results

The test results are presented in Tables 5 (number of fear demonstrations) and 6 (time spent licking). Table 5. Effect of Lacosamide, Morphine, and Combinations on the Number of Fear Demonstrations

<table> table see original document page 54 </column> </row> <table> Table 6. Effect of lacosamide, morphine and combinations on time spent

licking

<table> table see original document page 55 </column> </row> <table> NS = not significant; * = ρ <0.05; ** = ρ <0.01; *** = ρ <0.001

(a): compared with vehicle control

(b): compared with lacosamide alone at the appropriate dose.

(c): compared with morphine alone at the appropriate dose.

Lacosamide alone at 10 and 20 mg / kg did not strongly affect the number of fear statements when compared to vehicle controls (22% increase and 35% decrease, respectively) although the tendency to decrease to 20 mg / kg was approaching a statistical significance (p = 0.0961). Lacosamide dose-dependently decreased licking time by 28% (p <0.05) at 10 mg / kg and 56% (p <.001) at 20 mg / kg.

Morphine at only 2 and 4 mg / kg dose-dependently decreases the number of fear demonstrations and the time spent licking when compared to vehicle controls. However, these effects do not reach statistical significance.

Lacosamide 10 mg / kg combined with 4 mg / kg morphine but not 2 mg / kg morphine clearly decreased the number of fear demonstrations by 86% (p <0.001) and the time spent licking in 48% (p <0.01) when compared to vehicle controls. The effects of 10 mg / kg lactosamide combined with 4 mg / kg morphine on the number of demonstrations of fear but not on the time spent licking were more pronounced than the effects of Iacosamide alone on the same. dose (p <0.001).

Lacosamide at 20 mg / kg combined with morphine at 2 and 4 mg / kg clearly and dose-dependently decreased the number of fear demonstrations by 70% (p <0.01) and 87% (p <0.001) respectively, when compared to vehicle controls. The combination clearly and dose-dependently decreased the time spent licking by 69% and 94%, respectively (p <0.001). The effects of 20 mg / kg Iacosamide combined with morphine on the number of fear demonstrations and time spent licking were significantly more pronounced than the effects of Iacosamide alone at the same dose (p <0.05 or ρ <0 , 01), except for the time spent licking at a dose of 2 mg / kg morphine.

Example 5

This example describes a study demonstrating the efficacy of Iacosamide alone and in combination with the duloxetine antidepressant in the formalin rat paw test (late phase), as described by Wheeler-Aceto & Cowan (1991), supra. Materials and methods

The test methods were similar to those of Example 3. Lacosamide (10 mg / kg), duloxetine (8 mg / kg), a combination of Iacosamide (10 mg / kg) and duloxetine (8 mg / kg) and vehicle were administered ip 10 minutes before formalin injection. Results

The test results are presented in Tables 7 (number of fear statements) and 8 (time spent licking). Table 7. Effect of lacosamide, duloxetine and combination on the number of

fear statements

<table> table see original document page 57 </column> </row> <table> Table 8. Effect of lacosamide, duloxetine and combination on licking time _

<table> table see original document page 57 </column> </row> <table>

NS = not significant; * = ρ <0.05; ** = ρ <0.01; *** = ρ <0.001 (a): compared to vehicle control

(b): compared with lacosamide alone at the appropriate dose (c): compared with duloxetine alone at the appropriate dose Lacosamide at 10 mg / kg alone had no significant effects, although it tended to decrease licking time (decrease of .30% , ρ = 0.0538).

Duloxetine at 8 mg / kg alone had no clear effects.

Lacosamide at 10 mg / kg combined with duloxetine at 8 mg / kg significantly decreased the number of demonstrations of fear when compared to vehicle controls by 31% (p <0.05). The combination decreased licking time by 63% (p <0.001). The effects of iacosamide combined with duloxetine on the number of fear demonstrations and the time spent licking were more pronounced than the effects of iacosamide alone (p <0.05 to ρ <0.01).

Example 6

This example describes a study demonstrating the efficacy of Iacosamide alone and in combination with the NMDA receptor antagonist memantine the formalin rat paw test (late phase) as described by Wheeler-Aceto & Cowan (1991), supra. . Materials and methods

The test methods were similar to those of Example 3. Lacosamide (10 and 20 mg / kg), memantine (4 and 8 mg / kg), combinations of Iacoamide (10 and 20 mg / kg) with memantine (4 and 8 mg / kg) and vehicle were administered ip 10 minutes before formalin injection.

Results

Test results are presented in Tables 9 (number of fear statements) and 10 (time spent licking). Table 9. Effect of Lacosamide, Memantine, and Combinations on the Number of Fear Demonstrations__

<table> table see original document page 59 </column> </row> <table> Table 10. Effect of lacosamide, memantine, and combinations on licking time

<table> table see original document page 60 </column> </row> <table>

NS = not significant; * = ρ <0.05; ** = ρ <0.01; *** = ρ <0.001 (a): compared with control vehicle (b): compared with lacosamide alone at the appropriate dose (c): compared with memantine alone at the appropriate dose

#: missing value (1/10)

Lacosamide alone at 10 and 20 mg / kg dose-dependently decreased the number of demonstrations of fear when compared with vehicle controls by 31% and 48% respectively, very significantly at 20 mg / kg (p <0.05). Lacosamide clearly decreased licking time to 20 mg / kg (52% decrease, ρ <0.01) but had no clear effect at 10 mg / kg. Memantine alone at 4 and 8 mg / kg did not clearly affect the number of demonstrations of fear when compared to vehicle controls. Memantine dose-dependently increased the time spent licking (25% increase, ρ = 0.0537 and 35% increase, ρ <0.05).

Lacosamide at 10 mg / kg combined with memantine at 4 and 8 mg / kg dose-dependently decreased the number of demonstrations when compared to vehicle controls by 36% and 50% respectively (p <0.05). . The combination significantly decreased licking time at 8 but not 4 mg / kg memantine (35% decrease, ρ <10 0.05). The effects of Iacosamide combined with Memantine on the number of demonstrations of fear and the time spent licking were not different from the effects of Iacosamide alone.

Lacosamide at 20 mg / kg combined with 4 and 8 mg / kg memantine clearly decreased the number of demonstrations of fear when compared to vehicle controls by 74% and 64% respectively (p <0.001). The combination clearly decreased the time spent licking, although inversely related to the memantine dose (decrease of 69%, ρ <0.001 and decrease of 49%, ρ <0.05, respectively). The effects of Iacosamide combined with 4 mg / kg memantine on the number of demonstrations of fear but not on the time spent licking were significantly more pronounced than the effects of Iacosamide alone (p <0.05). . Example 7

This example describes a study demonstrating the efficacy of Iacosamide alone and in combination with naproxen in the formalin rat paw test (late phase), as described by Wheeler-Aceto & Cowan (1991), supra. Materials and methods

The test methods were similar to those of Example 3. Lacosamide (10 and 20 mg / kg), naproxen (8 and 16 mg / kg), combinations of Iacoamide (10 and 20 mg / kg) with memantine (8 and 16 mg / kg) and vehicle was administered ip 10 minutes before formalin injection. Morphine (8 mg / kg) was included as a comparative treatment. Results

Test results are presented in Tables 11 (number

demonstrations of fear) and 12 (time spent licking).

Table 11. Effect of Iacosamide1 naproxen and combinations on the number of fear statements

<table> table see original document page 62 </column> </row> <table> Table 12. Effect of lacosamide, naproxen and combinations over time

asto licking <formula> formula see original document page 63 </formula>

NS = not significant; * = ρ <0.05; ** = ρ <0.01; *** = ρ <0,001 (a): compared to control vehicle

(b): compared with lacosamide alone at the appropriate dose (c): compared with naproxen alone at the appropriate dose #: missing value (1/10)

Lacosamide alone at 10 and 20 mg / kg does not clearly affect the number of demonstrations of fear when compared to vehicle controls. It clearly decreases the time spent licking at 20 mg / kg by 59% (p <0.001), but had no clear effect at 10 mg / kg.

Naproxen alone at 8 and 16 mg / kg did not clearly affect the number of fear demonstrations or the time spent licking when compared to vehicle controls.

Lacosamide at 10 mg / kg combined with naproxen 8 and 16 mg / kg does not clearly affect the number of displays of fear compared to vehicle controls. Lacosamide at 10 mg / kg combined with na-proxen at 16 but not at 8 mg / kg significantly decreased licking time by 38% (p <0.05). The effects of 10 mg / kg Iacosamide combined with naproxen on the number of demonstrations of fear and the time spent licking were not different from the effects of Iacosamide alone.

Lacosamide at 20 mg / kg combined with naproxen at 8 and 16 mg / kg does not clearly affect the number of demonstrations of fear when compared to vehicle controls. Lacosamide at 20 mg / kg combined with naproxen at 16 but not at 8 mg / kg significantly decreased licking time by 53% (p <0.01). The effects of 20 mg / kg Iacosamide combined with naproxen on the number of demonstrations of fear and time spent licking were not different from the effects of Iacosamide alone.

Morphine alone at 8 mg / kg administered under the same experimental conditions eliminated fear and time spent licking when compared to vehicle controls (p <0.001).

In summary, Examples 3 to 7 demonstrate the synergistic effects between Iacosamide and a compound selected from gabapentin, dodoxetine, morphine, naproxen and memantine. All patents and publications cited herein are incorporated by

by reference to this application in its entirety. The words "understand", "understand" and "understanding" must be interpreted even rather than exclusively.

Subjects of the present invention are the following embodiments: Item 1. A therapeutic combination comprising a first

The agent comprising a compound of Formula (I): <formula> formula see original document page 65 </formula>

on what:

R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, lower alkyl aryl, heterocyclic, lower heterocyclic alkyl, lower heterocyclic alkyl, lower cycloalkyl or lower cycloalkyl, and R is unsubstituted or substituted by at least one group electron extraction and / or at least one electron donation group;

R1 is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, lower aryl lower alkyl, aryl, lower heterocyclic alkyl, lower heterocyclic, heterocyclic lower alkyl or lower cycloalkyl and is unsubstituted or substituted by at least one. electron extraction group and / or at least one electron donation group;

R2 and R3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl lower alkyl, aryl, halo, heterocyclic, lower heterocyclic alkyl, lower cycloalkyl, lower cycloalkyl lower alkyl or ZY where R2 and R3 are each independently unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group;

Z is O, S, S (O) a, NR 4, NR 16, PR 4 or a chemical bond;

Y is hydrogen, lower alkyl, aryl, lower alkyl aryl, lower alkenyl, lower alkynyl, halo, heterocyclic, lower heterocyclic alkyl or lower heterocyclic alkyl and is unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group provided that when Y is halo, Z is a chemical bond or

Z-Y taken together is NR4NR5R7, NR4OR5, ONR4R7, OPR4R5, PR4OR5, SNR4R7, NR4SR7, SPR4R5, PR4SR7, NR4PR5R6, PR4NR5R7, N + R5R6R7, <formula>

R'6 is hydrogen, lower alkyl, lower alkenyl or lower alkynyl and is unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group;

R 4, R 5 and R c are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl and are each independently unsubstituted or substituted by at least one electron extraction group and / or at least an electron donation group;

R7 is R6, COOR8 or COR8 and is unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group;

R8 is hydrogen, lower alkyl or lower alkyl aryl and is unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group;

n is 1-4; and air 1-3;

or a pharmaceutically acceptable salt thereof; and a second effective agent in combination with it to (a) provide intensified treatment of pain associated with or caused by a medical condition as compared to the compound of Formula (I) alone; and / or (b) treat another symptom or underlying cause of a medical condition; said second agent comprising one or more other drugs than a compound of Formula (I).

Item 2. The combination of Item 1, wherein in the compound of Formula (I) present in the first agent, one or both of R2 and R3 are heterocycles independently selected from the group consisting of furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrophilyl, tetraazoleyl indolinyl, pyrazolindinyl, imidazolinyl, imidazolidinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridine, oxetanyl, azetidinyl and, when N is present on the same heterocycle; said heterocycles being independently unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group.

Item 3. The combination of Item 1, wherein the first agent comprises

comprises a compound of Formula (III):

<formula> formula see original document page 67 </formula>

wherein: R4 is one or more substituents independently selected from the group consisting of hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, carboxy, formyl, carboxyamido, aryl, quaternary ammonium, haloalkyl, aryl alkanoyl, hydroxy, alkoxy, amino alkylamino, dialkylamino, aryloxy, mercapto, alkylthio, alkylmercapto and disulfide;

R 3 is selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, N-alkoxy-N-alkylamino and N-alkoxyamino; and

R1 is alkyl;

or a pharmaceutically acceptable salt thereof. Item 4. The combination of Item 3, wherein in the compound of

la (III) or salt thereof:

R4 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; and

R1 is lower alkyl.

Item 5. The combination of Item 4, wherein in the compound of Formula (III) or salt thereof, R3 is lower alkoxy-lower alkyl. Item 6. The combination of Item 3, wherein in the compound of Formula (III) or salt thereof:

R4 is hydrogen;

R3 is methoxymethyl; and R1 is methyl.

Item 7. The combination of Item 3, wherein the first agent comprises a compound selected from the group consisting of

(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-phenyl glycine benzylamide;

D-1,2- (N, O-Dimethyl hydroxylamino) -2-acetamide acetic acid benzylamide; and

D-1,2- (N, 0-methylhydroxylamino) acetic acid benzylamide

no) -2-acetamide.

Item 8. The combination of Item 3, wherein the compound of Formula (III) is substantially enantiopure.

Item 9. The combination of Item 3, wherein the first agent comprises

holds lacosamide.

Item 10. The combination of Item 9, comprising lacosamide in an amount providing a dose of from about 100 to about 6000 mg / day.

Item 11. The combination of Item 9, comprising lacosamide

in an amount providing a dose of from about 200 to about 1000 mg / day.

Item 12. The combination of Item 9, comprising lacosamide in an amount providing a dose of from about 300 to about 600 mg / day.

Item 13. The combination of Item 1, wherein the medical condition is accompanied by or has, as a symptom thereof, noninflammatory pain.

Item 14. The combination of Item 1 wherein the medical condition is an arthritic condition.

Item 15. The combination of Item 14, wherein the second agent comprises one or more anti-arthritic drugs.

Item 16. The combination of Item 15, wherein 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, DMOADs, and DMARDs. .

Item 17. The combination of Item 15, wherein the second agent comprises one or more analgesics selected from the group consisting of acetaminophen, alfentanil, allyprodin, alphaprodin, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, somorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphine, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethyltobutene, dioxafetyl butyrate, dipipanone, eptazocine, ethoenylthiene, heroin, ethanamine hydromorphone, hydroxypetidine, isomethadone, ketobemidone, levallorphan, levevanol, levofenacil-morphan, lofentanyl, meperidine, meptazinol, metazocin, methadone, metopon, morphine, myrophin, nalbuphine, nalorphorine, noralorhin, nalorphine, noralphorine normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, fenadoxone, phenazocine, fenomorfan, fenoperid piminodine, piritramide, proheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, NO-naproxen, NCX-701, ALGRX-4975 and pharmaceutically acceptable salts thereof.

Item 18. The combination of Item 15, wherein the second agent comprises one or more steroidal anti-inflammatory drugs selected from the group consisting of alclometasone, amcinonide, betamethasone, betamethasone valerate, clobetasol, lobetasol propionate, clocort - tarpaulin, cortisone, dehydrotestosterone, deoxycorticosterone, desonide, deoxymethasone, dexamethasone, dexamethasone 21-isonicotinate, diflorasone, fluocinonide, fluocinolone, fluorometolone, flurandrenolide, fluticasone, halcisone hydrocortisone, hydrobisone, , hydrocortisone hemisuccinate, hydrocortisone 21-lysinate, hydrocortisone sodium succinate, isoflupredone, isofluprone acetate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisone suleptnate, mompretasone , prednisolone, prednisolone acetate, prednisone hemisuccinate, sodium phosphate prednisolone, prednisolone sodium succinate, prednisolone valerate acetate, prednisone, triamcinolone, triamcinolone acetonide and pharmaceutically acceptable salts thereof.

Item 19. The combination of Item 15, wherein the second agent comprises one or more non-steroidal anti-inflammatory drugs selected from the group consisting of salicylic acid, acetyl salicylic acid, methyl salicylate, diflunisal, olsalazine, salsalate, sulfasalazine. , indomethacin, etodolac, sulindac, etophenamic acid, meclofenamic acid, mefenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, acemetaine, alclofenac, diclofenac, fenclofenac, fentiazac, furofenac, furofenac, furofenac, furofenac , ketorolac, oxipinac, thiopinac, tolmetine, zidometacin, zomepiper, alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, miroprofen, miroprofen, suprofen, thiaprofenic acid, thioxaprofen, ampiroxicam, cinnoxicam, droxicam, lornoxicam, meloxicam, piroxicam, sudoxicam, tenoxicam, aminopyrine, antipyrine, apazone, dipyr one, oxyphenbutazone, phenylbutazone, nabumetone, nimesulide, proquazone, MX-1094, lycofelone and pharmaceutically acceptable salts thereof.

Item 20. The combination of Item 15, wherein the second agent comprises one or more selective COX-2 inhibitors selected from the group consisting of celecoxib, deracoxib, valdecoxib, parecoxib, rofecoxib, etoricoxib, lumiracoxib, PAC-10549, cimicoxib , GW-406381, LAS-34475, CS-502 and pharmaceutically acceptable salts thereof.

Item 21. The combination of Item 15, wherein the second agent comprises one or more DMOADs selected from the group consisting of methotrexate, diacerein, glycosamine, chondroitin sulfate, anakinra, MMP inhibitors, doxycycline, minocycline, misoprostol, proton pump, unacetylated salicylates, unacetylated salicylates, tamoxifen, prednisone, methylprednisolone, polysulfated glycosaminoglycan, calcitonin, alendronate, risedronate, zoledronic acid, teriparatide, VX-765, pralna-casan, SB-462795, ONO-4817, S-3536, PG-530742, CP-544439 and pharmaceutically acceptable salts thereof.

Item 22. The combination of Item 15, wherein the second agent

comprises one or more DMARDs selected from the group consisting of e-tanercept, adalimumab, infliximab, IL-I receptor antagonists, prednisone, methylprednisolone, penicillamine, hydroxychloroquine sulfate, chlorambucil cyclosphosphamide, leflunomide, cyclosporine, auranophycin, aurothioglose, aurotropin - gold oprina, sodium thiomalate, methotrexate, cyclophosphamide, minocycline, sulfasalazine, abatacept, rituximab, buccylamine, chloroquine, hydroxychloroquine, lobenzarit, misoprostol and pharmaceutically acceptable salts thereof.

Item 23. The combination of Item 14, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat an arthritic condition and / or pain related thereto.

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

Item 25. The combination of Item 14, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat components of noninflammatory and inflammatory pain associated with or caused by an arthritic condition.

Item 26. The combination of Item 1, wherein the second agent is present in an effective amount, in combination with the first agent, to provide enhanced pain treatment compared to the first agent alone.

Item 27. The combination of Item 26, wherein said intensified treatment is 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 NMDA receptor analgesics, anticonvulsants, antidepressants and antagonists. Item 29. The combination of Item 26, wherein the second agent comprises one or more analgesics selected from the group consisting of acetaminophen, alfentanil, allyprodin, alphaprodin, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, somorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphine, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethyltobutene, dioxafetyl butyrate, dipipanone, eptazocine, ethoenylthiene, heroin, ethanamine hydromorphone, hydroxypetidine, isomethadone, ketobemidone, levallorphan, levevanol, levofenacil-morphan, lofentanyl, meperidine, meptazinol, metazocin, methadone, metopon, morphine, myrophin, nalbuphine, nalorphorine, noralorhin, nalorphine, noralphorine normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, fenadoxone, phenazocine, fenomorfan, fenoperi dine, piminodine, piritramide, proheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, NO-naproxen, NCX-701, ALGRX-4975 and pharmaceutically acceptable salts thereof.

Item 30. The combination of Item 26, wherein the second agent comprises one or more anticonvulsants selected from the group consisting of acetylpheneturide, albutoin, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, carbamazepine, cinro - mida, clometiazole, clonazepam, decimemide, dietadione, dimetadione, doxenitoine, eterobarb, etadione, etosuximide, ettoinine, felbamate, fluoresone, phosphfenitoin, gabapentin, ganaxolone, lamotrigine, levetiracetam, iorazeital metarbital, metamorphite, meorazital metarbital , methsuximide, midazolam, narcobarbital, nitrazepam, oxcarbazepine, paramethadione, phenacemide, fenetarbital, feneturide, phenobarbital, fensuximide, phenylmethylbarbituric acid, phenytoin, phenethylate, pregabalin, primidone, progabide, sumacamide, remacamide thalampanel, tetrantoin, tiagabine, topiramate, trimethadione, valproic acid, valpromide, vigabatrin, zonisamide and pharmaceutically acceptable salts. and acceptable thereof.

Item 31. The combination of Item 26, wherein the second agent comprises one or more antidepressants selected from the group consisting of adinazolam, adrafinil, amineptine, amitriptyline, amitriptyline oxide, amoxapine, befloxatone, bupropion, butacetin, butriptyline, caroxazone, citalopram, clomipramine, cotinine, demexiptyline, desipramine, dibenzepine, dimethacrine, dimetazan, dioxadrol, dotiepine, doxepine, duloxetine, etoperidone, fenoxetine, phencamine, phenpentadiol, fluacizine, fluoxetine, fluvamine, imoxamine, tophoxine, fluvorine, Imipramine N-oxide, indalpine, indeloxazine, iprindola, iproclozide, iproniazid, isocarboxazid, levofacetoperane, lofepramine, maprotiline, medifoxamine, melitracen, metapramine, metralindole, mianserine, milnacin, mnapazirtazone nefopam, nialamide, nomifensin, nortriptyline, noxiptyline, octamoxin, opipramol, oxaflozana, oxitriptan, oxipertine, paroxetine, phenelzine, pandaline , pizotillin, prolintane, propizepine, protriptyline, pirisuccideanol, quinutamine, reboxetine, ritanserine, roxindola, rubidium chloride, sertraline, sulpyride, tandospirone, thiazesim, tozalinone, thianeptin, tofenacin, toloxatone trimodiazole, trimoxatone venlafaxine, viloxazine, zymeldine and pharmaceutically acceptable salts thereof.

Item 32. The combination of Item 26, wherein the second agent comprises one or more NMDA receptor antagonists selected from the group consisting of amantadine, D-AP5, aptiganel, CPP1 dexanabinol, dextromethorphan, dextropropoxyphene, 5,7- dichloroquinurenic, gavestinel, i-fendopril, ketamine, ketobemidone, lycostinel, LY-235959, memantine, methadone, MK-801, phencyclidine, remacemide, selfotel, tiletamine and pharmaceutically acceptable salts thereof.

Item 33. The combination of Item 1, wherein the first agent and the second agent are provided in separate dosage forms for administration through the same or different routes at the same time or at different times.

Item 34. The combination of Item 1, wherein at least the first agent is provided in a dosage form adapted for oral or parenteral administration.

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

Item 36. The combination of Item 34, wherein the second agent is orally bioavailable and is provided in a dosage form adapted for oral administration.

Item 37. A pharmaceutical dosage form comprising the combination of Item 1 and at least one pharmaceutically acceptable excipient.

Item 38. The dosage form of Item 37, wherein the first member comprises lacosamide.

Item 39. The dosage form of Item 37, which is adapted for oral or parenteral administration.

Item 40. A method for treating a painful medical condition and / or related pain in an individual, the method comprising administering to the individual the therapeutic combination of Item 1.

Item 41. The method of Item 40, wherein the medical condition or pain related thereto is selected from the group consisting of acute inflammatory pain; acute pain; neuropathic pain associated with alcoholism or induced by alcoholism; allodynia; arthritic conditions; back pain;; cancer-related neuropathic pain; central neuropathic pain; chronic headache; chronic inflammatory pain; chronic pain; chronic pain due to peripheral nerve injury; diabetes-associated or diabetes-induced neuropathic pain; diabetic distal sensory neuropathy; diabetic distal sensory polyneuropathy; diabetic pain; fibromyalgia; Headache; hyperalgesia; hyperesthesia; hyperpathy; migraine; myalgia; myofascial pain syndrome; neuralgia; neuroma; noninflammatory musculoskeletal pain; noninflammatory osteoarthritic pain; non-neuropathic inflammatory pain; neuropathic pain; pain associated with or induced by chemotherapy or radiation therapy; pain associated with or induced by traumatic nerve injury or compression or traumatic injury to the brain or spinal column; painful diabetic neuropathy; peripheral neuropathic pain; persistent clinical pain; phantom pain; rheumatoid arthritis pain; secondary osteoarthritic inflammatory pain; trigeminal neuralgia; vascular headache; and combinations thereof.

Item 42. The method of Item 40, wherein medical-related pain comprises noninflammatory pain.

Item 43. A method of treating an arthritic condition and / or pain related thereto in an individual, the method comprising administering to the individual the therapeutic composition of Item 15.

Item 44. The method of Item 43, wherein the arthritic condition and pain related thereto are treated.

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

Item 46. The method of Item 45, wherein lacosamide is administered according to a regimen wherein daily doses are increased until a predetermined daily dose is reached, which is maintained during further treatment.

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

Item 48. The method of Item 47, wherein lacosamide is administered in an amount that provides an effective daily dose to provide a plasma lacosamide concentration of from about 0.1 to about 15 pg / ml ( about 5 to about 18.5 pg / ml (peak), calculated as an average over a plurality of treated subjects.

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

Item 50. The method of Item 43, wherein the arthritic condition comprises osteoarthritis.

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

Claims (55)

A therapeutic combination comprising a first agent comprising a compound of Formula (I): wherein: R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl , lower alkyl aryl, heterocyclic, lower heterocyclic alkyl, heterocyclic lower alkyl, lower cycloalkyl or lower cycloalkyl lower alkyl and R is unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group; R1 is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, lower heterocyclic alkyl, heterocyclic lower heterocyclic, lower cycloalkyl or lower alkyl lower cycloalkyl and is unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group; R 2 and R 3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkyl aryl, aryl, halo, heterocyclic, lower heterocyclic alkyl, heterocyclic lower alkyl, lower cycloalkyl, lower alkyl lower cycloalkyl or ZY, wherein R2 and R3 are each independently unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group; Z is O, S, S (O) a, NR 4, NR 16, PR 4 or a chemical bond; Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, lower heterocyclic alkyl or heterocyclic lower alkyl and is unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group provided that when Y is halo, Z is a chemical bond or ZY taken together is NR4NR5R7, NR4OR5, ONR4R7l OPR4R5, PR4OR5, SNR4R7, NR4SR7, SPR4R5, PR4SR7, NR4PR5, <formula> formula see original document page 77 </formula> R16 is hydrogen, lower alkyl, lower alkenyl or lower alkynyl and is unsubstituted or substituted by at least one electron extraction group and / or at least one group of electron donation; R 4, R 5 and R 6 are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl or lower alkynyl and are each independently unsubstituted or substituted by at least one electron extraction group and / or at least an electron donation group; R7 is R6, COOR8 or COR8 and is unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group; R8 is hydrogen, lower alkyl or lower alkyl aryl and is unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group; n is 1-4; and air 1-3; or a pharmaceutically acceptable salt thereof; and a second agent effective in combination therewith to provide intensified treatment of pain associated with or caused by a medical condition as compared to the compound of Formula (I) alone; said second agent comprising one or more other drugs than a compound of Formula (I). A combination according to claim 1 wherein, in the compound of Formula (I) present in the first agent, one or both of R2 and R3 are heterocycles independently selected from the group consisting of furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrophilazole, pyrethylidazole imidazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl-pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridine, oxetanyl, oliveidinyl and, when N is present in the heterocycle, N-oxides thereof; said heterocycles being independently unsubstituted or substituted by at least one electron extraction group and / or at least one electron donation group. The combination according to claim 1, wherein the first agent comprises a compound of Formula (III): wherein: R4 is one or more independently selected substituents. of the group consisting of hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, carboxy, formyl, carboxyamido, aryl, quaternary ammonium, haloalkyl, aryl alkanoyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryloxy, mercapto, alkylthio, alkylmercapto and disulfide; R 3 is selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, N-alkoxy-N-alkylamino and N-alkoxyamino; and R1 is alkyl; or a pharmaceutically acceptable salt thereof. A combination according to claim 3 wherein, in the compound of Formula (III) or salt thereof: R 4 is one or more substituents independently selected from the group consisting of hydrogen and halo; R 3 is selected from the group consisting of lower alkoxy-lower alkyl, aryl, N-lower alkoxy-N-lower alkylamino and N-lower alkoxyamino; and R1 is lower alkyl. A combination according to claim 4 wherein, in the compound of Formula (III) or salt thereof, R 3 is lower alkoxy-lower alkyl. A combination according to claim 3, wherein in the compound of Formula (III) or salt thereof: R 4 is hydrogen; R3 is methoxymethyl; and Ri is methyl. The combination of claim 3, wherein the first agent comprises a compound selected from the group consisting of: (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-phenylglycinabenzylamide; D-1,2- (N, O-Dimethylhydroxy-amino) -2-acetamide acidic acid benzylamide; and D-1,2- (N, 0-methylhydroxylamino) -2-acetamide acidic acid benzylamide. A combination according to any one of claims 3 to 7, wherein the compound of Formula (III) is substantially enantiopuro. A combination according to claim 3, wherein the first agent comprises lacosamide. A combination according to claim 9, comprising lacosamide in an amount providing a dose of from about 100 to about 6000 mg / day. A combination according to claim 9, comprising lacosamide in an amount providing a dose of from about 200 to about 1000 mg / day. A combination according to claim 9, comprising lacosamide in an amount providing a dose of from about 300 to about 600 mg / day. A combination according to any preceding claim, wherein the second agent comprises one or more drugs independently selected from the group consisting of analgesics, anticonvulsants, antidepressants and NMDA receptor antagonists. The combination according to claim 13, wherein the second agent comprises one or more analgesics selected from the group consisting of acetaminophen, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codei - na, cyclazocine, deomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorfone, dihydrocodeine, dihydromorphine, dimenoxadol, dimephaptanol, dimethyltiambutene, dioxaphietathene, ethoenathiazepine, ethoenathiazine, ethoenathiazine hydrocodone, hydromorphone, hydroxypetidine, isomethadone, ketobomone, levallorphan, levorphanol, levofenacil-morphan, lofentanyl, meperidine, meteptocin, methadone, metopon, morphine, myrophin, nalbuphine, nororphine, nalorphine, nalorphine, , normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, fenoxoxone, phenazocin a, fenomorphine, fenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propoxyphene, sufentanyl, tilidine, tramadol, naproxen, NO-naproxen, NCX-701, ALGRX-4975 and pharmaceutically acceptable salts thereof. A combination according to claim 13 or 14, wherein the second agent comprises one or more anticonvulsants selected from the group consisting of acetylpheneturide, albutoin, aminoglutethimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate, carbamazepine, cinromide, clometiazola, clonazepam, decimemide, dietadione, dimethadione, doxenitoin, eterobarb, etadione, ethosuximide, ethotoin, felbamate, fluoresphon, phosphenytoin, gabapentin, ganaxolone, lamotrigetin, meeve- tyrazine, meeve- mefobarbital, metarbital, metetoin, methuxuxide, midazolam, narcobarbital, nitrazepam, oxcarbazepine, paramethadione, phenacemide, phenetharbide, pheneturide, phenobarbital, fensuximide, phenylmethylbarbituric acid, phenytoin, progenamide, progenamide, pregemide , sultiame, talampanel, tetrantoin, thiapanin, topiramate, trimethadione, valproic acid, valpromide, vigabatrin, zonisamide and pharmaceutically acceptable salts thereof. A combination according to any one of claims 13 to 15, wherein the second agent comprises one or more antidepressants selected from the group consisting of adinazolam, adrafinil, amineptine, amitriptyline, amitriptyline oxide, amoxapine, befloxatone, bupropion. , butacetin, butriptyline, caroxazone, citalopram, clomipramine, cotinine, demexiptyline, desipramine, dibenzepine, dimethacrin, dimetazan, dioxadrol, dotiepine, doxepine, duloxetine, etoperidone, femoxetine, phenthazoxin, fluentropine, phenenathine, , impramine, imipramine N-oxide, indalpine, indeloxazine, iprindole, iproclozid, iproniazid, isocarboxazid, levofacetoperane, lofepramine, maprotiline, medifoxamine, melitracen, metapramine, metralindole, mianserin, mianserin, mianserin, mianserin , nefazodone, nefopam, nialamide, nomifensin, nortriptyline, noxiptyline, octamoxin, opipramol, oxaflozana, oxitriptan, oxipertine, pair oxetine, phenelzine, piberalin, pizotillin, prolintane, propizepine, protriptyline, pyrisuccideanol, quinupramine, reboxetine, ritanerine, roxindole, rubidium chloride, sertraline, sulpiride, tandospirone, thiaze- simin, tozalinone, thienatin, thiazone, Trazodone, trimipramine, tryptophan, venlafaxine, viloxazine, zymeldine and pharmaceutically acceptable salts thereof. A combination according to any one of claims 13 to 16, wherein the second agent comprises one or more NMDA receptor antagonists selected from the group consisting of amantadine, D-AP5, aptiganel, CPP, dexanabinol. , dextromethorphan, dextropropoxyphene, 5,7-dichloroquinurenic acid, gavestinel, ifendopril, ketamine, ketobemidone, lycostinel, LY-235959, memantine, methadone, MK-801, phencyclidine, remamid, selfotel, tiletamine and the same pharmaceutically acceptable salts. A combination according to any one of the preceding claims, wherein the second agent comprises one or more drugs independently selected from the group consisting of gabapentin, duloxetine, morphine, naxproxen and memantine. 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 methamine. A combination according to any one of the preceding claims, wherein the medical condition is accompanied by or has, as a symptom thereof, noninflammatory pain. A combination according to any preceding claim, wherein the pain related to the medical condition comprises non-inflammatory. A combination according to any preceding claim, wherein the medical condition is an arthritic condition and / or related pain. A combination according to claim 22, wherein the arthritic condition comprises osteoarthritis. 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 an arthritic condition and / or pain related thereto. A combination according to any one of claims 22 to 24, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat components of noninflammatory and inflammatory pain associated with or caused by a condition. arthritic A combination according to any one of claims 22 to 25, wherein the first and second agents are present in absolute and relative amounts effective to treat noninflammatory pain related to an arthritic condition. A combination according to any one of claims 22 to 26, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat noninflammatory osteoarthritic pain. A combination according to any one of claims 22 to 25, wherein the first and second agents are present in absolute and relative amounts effective to treat inflammatory pain related to an arthritic condition. A combination according to any one 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 osteoarthritic inflammatory pain. A combination according to claim 27 or 29, wherein osteoarthritic pain is associated with cartilage degradation, structural bone changes and / or vascularization of osteoarthritic remodeling areas. The combination according to any one of claims 22 to 30, wherein the arthritic condition comprises one or more disorders selected from the group consisting of idiopathic osteoarthritis, secondary osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, infectious arthritis, ankylosing spondylitis, neurogenic arthropathy, polyarthralgia and Sjogren's syndrome-associated arthritis, Behcet's syndrome, Reiter's syndrome, systemic lupus erythematosus, gout, pseudologist, Lyme disease, sarcoidosis and ulcerative colitis. A combination according to any one of claims 22 to 31, wherein the arthritic condition comprises rheumatoid arthritis or juvenile rheumatoid arthritis. A combination according to any one of claims 1 to 19, wherein the medical condition is pain in pain diabetic neuropathy. The combination of claim 33, wherein the painful diabetic neuropathy is diabetic distal sensory polyneuropathy. A combination according to claim 33 or 34, wherein the first and second agents are, in combination, effective for treating an aspect of pain selected from the group consisting of average daily pain, overall pain, present pain intensity, pain interference with sleep, the individual's perception of pain interference with general activity, the patient's overall impression of pain change, global clinical impression of pain change, the individual's perception of different neuropathic pain qualities , quality of life and proportion of days without pain. A combination according to any one of claims 33 to 35, wherein the painful diabetic neuropathy is associated with Type I or Type II Diabetes mellitus. A combination according to any one of the preceding claims, wherein the second agent is present in an amount effective in combination with the first agent to provide enhanced pain treatment compared to the first agent alone. . A combination according to any one of claims 1 to 19, wherein the medical condition or pain related thereto is selected from the group consisting of acute inflammatory pain; acute pain; neuropathic pain associated with alcoholism or induced by alcoholism; allodynia; arthritic conditions; back pain;; cancer-related neuropathic pain; central neuropathic pain; chronic headache; chronic inflammatory pain; chronic pain; chronic pain due to peripheral nerve injury; diabetes-associated or diabetes-induced neuropathic pain; diabetic distal sensory neuropathy; diabetic distal sensory polyneuropathy; diabetic pain; fibromyalgia; Headache; hyperalgesia; hyperesthesia; hyperpathy; migraine; myalgia; myofascial pain syndrome; neuralgia; neuroma; noninflammatory osteoarthritic pain; non-neuropathic inflammatory pain; neuropathic pain; pain associated with or induced by chemotherapy or radiation therapy; pain associated with or induced by traumatic nerve injury or compression or traumatic injury to the brain or spinal column; painful diabetic neuropathy; peripheral neuropathic pain; persistent clinical pain; phantom pain; rheumatoid arthritis pain; secondary osteoarthritic inflammatory pain; trigeminal neuralgia; vascular headache; and combinations thereof. A combination according to any one of the preceding claims, wherein the first agent and the second agent are provided in different dosage forms for administration through the same or different routes at the same time or at different times. . A combination according to any preceding claim, wherein at least the first agent is provided in a dosage form adapted for oral or parenteral administration. A combination according to any one of the preceding claims, wherein the first agent is provided in a dosage form adapted for oral administration of one to three doses per day. A combination according to any one of the preceding claims, wherein the second agent is orally bioavailable and is provided in a dosage form adapted for oral administration. A pharmaceutical dosage form comprising the combination as defined in claims 1 to 19, and at least one pharmaceutically acceptable excipient. The dosage form of claim 43, wherein the first agent comprises lacosamide. The dosage form of claim 43 or 44 which is adapted for oral or parenteral administration. A method for treating a painful medical condition and / or pain related thereto in an individual, the method comprising administering to the individual a therapeutic combination as defined in any one of claims 1 to 19. A method according to claim 46, wherein the painful medical condition and / or pain related thereto is selected from the conditions as defined in any one of claims 20 to 38. A method according to claim 46, wherein the medical condition or pain related thereto is selected from the group consisting of acute inflammatory pain; acute pain; neuropathic pain associated with alcoholism or induced by alcoholism; 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; neuropathic pain associated with diabetes or induced by diabetes; diabetic distal sensory neuropathy; diabetic distal sensory polyneuropathy; diabetic pain; fibromyalgia; Headache; hyperalgesia; hyperesthesia; hyperpathy; migraine; myalgia; myofascial pain syndrome; neuralgia; neuroma; noninflammatory osteoarthritic pain; non-neuropathic inflammatory pain; neuropathic pain; pain associated with or induced by chemotherapy or radiation therapy; pain associated with or induced by traumatic nerve injury or compression or traumatic injury to the brain or spinal column; painful diabetic neuropathy; peripheral neuropathic pain; persistent clinical pain; phantom pain; rheumatoid arthritis pain; secondary osteoarthritic inflammatory pain; trigeminal neuralgia; vascular headache; and combinations thereof. A method according to any one of claims 46 to 48, wherein in said combination the first agent comprises laconamide. A method according to any one of claims 46 to 49, wherein lacosamide is administered according to a regimen wherein daily doses are increased until a predetermined daily dose is reached which is maintained during further treatment. A method according to any one of claims 46 to 50, wherein lacosamide is administered orally. A method according to any one of claims 46 to 51, wherein lacosamide is administered in an amount that provides an effective daily dose to provide a plasma concentration of lacosamide from about 0.1 to about 15 pg. / ml (serum) and about 5 to about 18.5 pg / ml (peak), averaged over a plurality of treated subjects. Use of a combination as defined in any one of claims 1 to 19 for the preparation of a medicament for the intensified prevention, relief and / or treatment of pain associated with or caused by a medical condition as compared to compound of Formula (I) only; said second agent comprising one or more other drugs than a compound of Formula (I). Use according to claim 53, wherein the medical condition is selected from a condition as defined in any one of claims 20 to 38. Use according to claims 53 and 54, wherein, in said combination, the first agent comprises lacosamide.