KR20090018863A - Therapeutic combination for painful medical conditions - Google Patents

Abstract

A therapeutic combination comprises a first agent comprising a compound as defined herein, illustratively lacosamide, or a pharmaceutically acceptable salt thereof, and a second agent effective in combination therewith to provide enhanced treatment of pain associated with or caused by a medical condition, by comparison with the first agent alone. The combination can be provided in a single dosage form or separate dosage forms and is illustratively useful for treatment of an arthritic condition and/or pain related thereto.

Description

Therapeutic combination for painful medical conditions

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

By 2020, it is estimated that more than 60 million Americans will have arthritis. Arthritis is the leading cause of physical disability (widely defined as a need for help when walking or climbing stairs) and limited daily activities in more than 7 million Americans, an increase of more than 11.6 million by 2020. It is expected to be. See http://www.arthritis.org/resources/ActionPlanlnterior.pdf.

Treating arthritis and its complications is quite expensive. In 1997, the total cost of arthritis and other rheumatic conditions in the United States was $ 86 billion. In 1997, direct medical costs for arthritis and other rheumatic conditions were $ 51.1 billion. Indirect costs (because of low wages) for arthritis and other rheumatic conditions were $ 33.5 billion. See http: //www.cdc.qov/mmwr/preview/mmwrhtml/mm5318a3.htm .

Rheumatoid arthritis is a chronic disease characterized by lining of the joints or inflammation of the synovial membrane. Rheumatoid arthritis can cause long-term joint damage, resulting in chronic pain, loss of function and disability. Rheumatoid arthritis affects about 1% of the US population or 21 million Americans.

Rheumatoid arthritis has three stages. The first step includes swelling of the lubricating membrane inner layer that causes pain, warmth, stiffness, redness and swelling around the joints. The second step involves rapid division and growth of cells or pannus, causing thickening of the lubricating membrane. In the third stage, inflammatory cells secrete enzymes capable of digesting bone and cartilage, often causing associated joints to lose their form and alignment and cause more pain and loss of movement.

Because rheumatoid arthritis is a systemic disease, it can also affect other organs in the body. Early diagnosis and treatment of rheumatoid arthritis is very important for the continued running of a productive lifestyle. Studies have shown that early aggressive treatment of rheumatoid arthritis can limit joint damage, which can lead to loss of exercise, decreased performance and higher medical costs and potential surgical procedures. See http: //www.arthritis.orq/conditions/DiseaseCenter/RA/ra overview.asp .

Osteoarthritis is an acquired musculoskeletal that is believed to be non-inflammatory in origin, which occurs when the rate of cartilage degradation exceeds the rate of cartilage regeneration, resulting in cartilage erosion, subchondral bone thickening, and joint damage. Acquired musculoskeletal disorder. As the cartilage becomes thinner, its surface integrity is lost, gaps are formed, and cartilage tends to erode more easily as the joint moves. When new cartilage is formed, the cartilage tends to be more fibrous and less capable of withstanding mechanical stress. Over time, the underlying bone, which has been weakened in its ability to withstand mechanical stress, may be exposed, resulting in microfracture. Localized osteonecrosis can occur at the bottom of the bone surface, resulting in cysts that can further weaken the cartilage support of the bone.

As osteoarthritis progresses, osteoarthritis can ultimately affect the structure surrounding the joint. For example, local inflammation, such as synovial inflammation, may occur in response to an inflammatory mediator secreted during the cartilage degeneration process. Articular capsules tend to thicken and nutrient inflow into the joints and outflow of metabolic waste from the joints may be limited. Ultimately, as osteoarthritis progresses, periarticular muscle wasting becomes apparent, and joints are used less frequently or inappropriately. Since the cartilage has no nerve (aneural), the pain of osteoarthritis is thought not to be due to cartilage degeneration itself, but to the effect on the surrounding tissues including the bone.

According to the Centers for Disease Control and Prevention (CDC), osteoarthritis is the most common form of joint disease affecting 21 million Americans. See http://www.cdc.gov/arthritis/data_statistics/arthritis_related_statistics.htm#2.

The prevalence of osteoarthritis increases with age and age is the greatest risk factor. Brandt (2001) Principles of Internal Medicine . 15th ed. (Braunwald et al., Eds.), New York: McGraw-Hill, pp. Investigations reported by 1987-1994 found that only 2% of women under 45 had radiographic evidence of osteoarthritis. However, in women aged 45-64 years, the prevalence was 30%, and in women 65 years and older, the prevalence was 68%. Other risk factors include overweight, genetic factors, estrogen deficiency, repeated joint use, and trauma.

Typical patients with osteoarthritis are middle-aged or mature and complain of pain in the knees, buttocks, hands or spine. The distal and proximal interphalangeal joints of the hand are the most common site of osteoarthritis, but also the least likely site of symptoms. The buttocks and knees are the most common joints observed to have been affected on X-ray at 2nd and 3rd place, and knee pain is more likely to be symptomatic.

Pain is a major symptom of osteoarthritis. Osteoarthritis pain may have one or both inflammatory and non-inflammatory components. Anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 inhibitors, can be useful for treating or managing inflammatory components, and opioid analgesics and other analgesics can be used to treat or manage non-inflammatory components. Can be useful. However, such drug treatment is not always effective and may have side effects that are not well acceptable in all patients.

Non-inflammatory pain is often characterized by the absence of edema or warmth, the absence of inflammatory or systemic manifestations, and the absence of minimal morning stiffness.

Non-inflammatory osteoarthritis pain, in particular, can contribute to static lifestry, depression and sleep problems in older adults. Pain is often characterized by deep, aching sensation that intensifies during operation. It is usually hepatic, often mild, but persistent and severe. In general, crepitus is noted in the affected joints.

Certain peptides that exhibit central nervous system (CNS) activity are known and are useful in the treatment of prehepatic and other CNS diseases. Such peptides are described, for example, in US Pat. No. 5,378,729.

Related peptides are disclosed in US Pat. No. 5,773,475 as useful for the treatment of CNS diseases.

International Publication No. WO 02/074784, which is hereby incorporated by reference in its entirety, discloses acute and chronic pain of different kinds and symptoms, in particular, non-neuropathic inflammatory pain, for example rheumatoid arthritis pain or secondary inflammatory. It relates to the use of such peptide compounds for the treatment of osteoarthritis pain.

International Patent Application Publication WO 02/074297 has the formula

In the formula,

Ar is an unsubstituted or phenyl group substituted with one or more halo; R ₃ is C _1-3 alkoxy and R ₁ is methyl for the treatment of allodynia associated with peripheral neuropathic pain.

Lacosamide (also referred to as SPM 927 or harcoseride) is a compound of the formula having a mode of action that is not fully characterized (Bialer et al., (2002) Epilepsy Res. 51: 31-71). The mode of action of lacosamide and other peptides disclosed in the aforementioned patents and documents differs from that of conventional antiepileptic drugs. Ion channels are not affected by these compounds in a manner similar to other known antiepileptic drugs. For example, gamma-aminobutyric acid (GABA) induced currents are enhanced, but no direct interaction with known GABA receptor subtypes was observed. Glutamate induced currents are attenuated, but these compounds do not interact directly with known glutamate receptor subtypes.

As a symptom, there is a need for improved therapies that can treat medical conditions with pain, especially non-inflammatory pain, such as arthritis.

Summary of the Invention

It has following formula (I),

In the formula,

R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl or lower cycloalkyl lower alkyl, R is Unsubstituted or substituted with one or more electron-withdrawing groups and / or one or more electron-donating groups;

R ₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, lower alkyl heterocyclic, heterocyclic, lower cycloalkyl, or lower cycloalkyl lower alkyl, May be unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups;

R ₂ and R ₃ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower Cycloalkyl lower alkyl, or R ₂ and R _3, are each independently ZY unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups;

Z is 0, S, S (O) _a , NR ₄ , NR ′ ₆ , PR ₄ or a chemical bond;

Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, or lower alkyl heterocyclic, unsubstituted or one or more electron withdrawing groups and May be substituted with one or more electron donating groups, Y is halo, Z is a chemical bond, or

ZY taken together is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ , OPR ₄ R ₅ , PR ₄ OR ₅ , SNR ₄ R ₇ , NR ₄ SR ₇ , SPR ₄ R ₅ , PR ₄ SR ₇ , NR ₄ PR ₅ R ₆ , PR ₄ NR ₅ R ₇ , N ⁺ R ₅ R ₆ R ₇ ,

인 조건을 만족하고;

Satisfies the condition of;

R ' ₆ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl, which may be unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups;

R ₄ , R ₅ and R ₆ are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, each independently unsubstituted or one or more electron withdrawing groups and / or one or more electron balls Substituted here;

R ₇ is R ₆ , COOR ₈ , or COR ₈ and may be unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups;

R ₈ is hydrogen, lower alkyl, or aryl lower alkyl and may be substituted with one or more electron withdrawing groups and / or one or more electron donating groups; And

n is 1-4; And

a is a first agent comprising a compound or a pharmaceutically acceptable salt thereof, and compared to the first agent alone, (a) a pain caused by or associated with a medical condition Providing an enhanced treatment, (b) comprising a second agent effective to combine with the first agent to treat another symptom or underlying cause of the medical condition, wherein the second agent is of formula (I) Therapeutic combinations are provided that include one or more drugs that are not compounds.

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

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

Also provided are methods of treating a painful medical condition and / or pain associated therewith in a subject comprising administering to the subject a combination of the foregoing therapeutic agents.

A method of treating arthritis condition and / or pain associated therewith is also provided, comprising administering to a subject a combination of the foregoing therapeutic agents, wherein the second agent comprises one or more anti-arthritis agents.

According to one of the foregoing embodiments, an exemplary compound of formula (I) is lacosamide, (R) -2-acetamido-N-benzyl-3-methoxypropionamide.

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

details

Therapeutic combinations, drug dosage forms and methods of using and combinations thereof are provided for treating arthritis conditions and / or pain associated therewith.

The term “therapeutic combination” refers to a plurality of agents that, when administered together or separately to an individual, co-active to provide a therapeutic effect to the individual. Such administration is referred to as "combination therapy", "cotherapy", "adjuctive therapy", or "add-on therapy". For example, one agent may enhance or enhance the therapeutic effect of another agent, reduce the deleterious side effects of another agent, or lower administration than when one or more agents are used alone. It may be administered in an effective amount, or may provide a greater therapeutic effect than when used alone, or complementarily resolve different aspects, symptoms, or etiological factors of a disease or condition. You can ..

A "medical condition" herein can be a disease, disorder or condition, typically clinically diagnosed. Medical conditions addressed by the present invention are painful or painful as symptoms thereof, and are referred to herein as " painful medical conditions. &Quot; Pain may be inflammatory or non-inflammatory in nature, or may have both inflammatory and non-inflammatory components. For example, many arthritic conditions have both non-inflammatory pain components and inflammatory pain components.

Non-limiting examples of conditions and / or types of pain in which the therapeutic combinations and methods of the invention may be useful include those listed below, and recognize that many of the listed conditions and types of pain overlap.

Acute inflammatory pain;

-Acute pain;

Alcoholism-associated or alcoholism-induced neuropathic pain;

Allodynia (independently or as a symptom of another condition);

-Arthritis state;

-Back pain;

Cancer-related neuropathic pain, eg painful compression by tumor growth of adjacent nerves, brain or spinal cord;

Central neuropathic pain;

-Chronic headache;

Chronic inflammatory pain;

-Chronic pain;

Chronic pain due to peripheral nerve damage;

Diabetes-associated or diabetes-induced neuropathic pain;

Diabetic pain;

Diabetic distal sensory neuropathy;

Diabetic distal sensory polyneuropathy;

Fibritis;

- headache;

Hyperalgesia (independently or as a symptom of another condition);

Hyperesthesia;

Hyperpathia;

Migraine headaches, including typical migraine and general migraine headaches;

- Muscle pain;

Myofascial pain syndrome;

Neuralgia;

Neuroma;

Non-inflammatory musculoskeletal pain;

Non-inflammatory osteoarthritis pain;

Non-neuropathic inflammatory pain;

Neuropathic pain;

Pain associated with or induced by chemotherapy or radiation therapy;

Pain associated with or induced by traumatic nerve injury or compression or traumatic injury to the brain or spinal cord;

Painful diabetic neuropathy;

Peripheral neuropathic pain;

Persistent clinical pain;

Phantom pain;

-Rheumatoid arthritis pain;

Secondary inflammatory osteoarthritis pain;

Trigeminal neuralgia; And

Vascular headache.

An "arthritic condition" as used herein is a musculoskeletal disorder of one or more joints of an individual, usually accompanied by pain, and includes arthritis associated with or concomitant with a condition that is not necessarily primarily arthritic. The most important arthritic conditions include osteoarthritis, which may be idiopathic or primary in origin, or incidental to other conditions, and rheumatoid arthritis including juvenile rheumatoid arthritis. Other diseases included herein as "arthritis states" include, without limitation, psoriatic arthritis, infectious arthritis, ankylosing spondylitis, neuroarthritis, and polyarthralgia. The conditions in which arthritis can be secondary are, without limitation, Sjogren's syndrome, Behcet's syndrome, Reiter syndrome. Systemic lupus erythematosus, rheumatic fever, gout, pseudogout, Lyme disease, sarcoidosis and ulcerative colitis.

For example, the pain associated with arthritis in osteoarthritis may be inflammatory, non-inflammatory, or both. Non-inflammatory osteoarthritis pain is a particular type of non-inflammatory musculoskeletal pain that typically results from the effects of osteoarthritis-related morphological changes such as cartilage degeneration, bone changes in sensory neurons, and vascularizaiton of bone remodeling. Non-inflammatory osteoarthritis is clearly distinguished from inflammatory osteoarthritis pain arising from synovial inflammation after pathological processes in cartilage and bone, which typically involve macrophage infiltration (causing edema) associated with tissue damage and classical immune system responses.

Stohr et al., Incorporated herein by reference in their entirety, but not recognized as prior art of the present invention. (2006) Eur. J. Pain 10 (3): 241-249 describes the results showing the effect of lacosamide for the treatment of inflammatory pain.

Unless the context otherwise requires, the term “treat, treating, or treatment” refers to a risk or prognosis of a prognosis, including a medical condition with non-inflammatory pain as its symptom, eg, an arthritis condition such as osteoarthritis. In an individual with a therapeutic or prophylactic use of a combination, eg, a combination of a first agent and a second agent as defined herein, and to reduce, alleviate the intensity of the condition or pain associated therewith, Therapies for reducing or eliminating the condition or pain associated with it or its root cause include the use of such a combination in an individual already experiencing such condition.

The term “subject” means a warm blooded animal, generally a mammal such as a primate, including, for example, cats, dogs, horses, cattle, pigs, mice, mice, and humans. In one embodiment, the subject is a human, eg, a patient with a clinically diagnosed arthritis condition.

The terms "synergism", "synergistic effect", "enhanced prevention", "enhanced alleviation" or "enhanced treatment" refer to compounds alone Means a more potent therapeutic effect of the combination of two or more compounds relative to the additive effect of. For example, a therapeutic combination described herein can have a synergistic effect in the prevention, alleviation and / or treatment of pain associated with or caused by a medical condition as described herein.

Therapeutic combinations as described herein are also adverse effects when administered in the prevention, alleviation and / or treatment of pain associated with or caused by a medical condition as described herein or a medical condition as described herein. And / or have a synergistic effect in reducing toxicity.

The therapeutic combination of the present invention comprises a first agent comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described above. One or more such compounds or salts may optionally be present in the first agent. Unless otherwise indicated herein, terms used in the description of the compound of formula (I) and the like are defined as follows.

The term "alkyl", alone or in combination with another term, refers to one to about 20 carbon atoms, more typically one to about eight carbon atoms, and more typically one to about six carbons. It refers to a straight or branched chain saturated hydrocarbon substituent containing an atom.

The term "lower alkyl" means an alkyl substituent comprising 1 to 6 carbon atoms, in particular 1 to 3 carbon atoms, which may be straight or branched. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and their equivalents and isomers thereof.

The term “alkenyl”, alone or in combination with another term, refers to one or more double bonds and typically from 2 to about 20 carbon atoms, more typically from 2 to about 8 carbon atoms, and much more. It usually refers to a straight or branched chain hydrocarbon substituent containing 2 to about 6 carbon atoms. If asymmetric, the alkenyl group may be cis structure or trans structure.

The term "lower alkenyl" refers to an alkenyl substituent containing 2 to 6 carbon atoms which may be straight or branched and may be Z or E. Examples are 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, such as 1,3 or 2,4-pentadienyl, and the like.

The term “alkynyl”, alone or in combination with another term, refers to one or more triple bonds and, typically, 2 to about 20 carbon atoms, more typically 2 to about 8 carbon atoms, and much more. More typically means straight-chain or branched hydrocarbon substituents containing from 2 to about 6 carbon atoms.

The term "lower alkynyl" refers to an alkynyl substituent containing 2 to 6 carbon atoms, which may be straight or branched. Lower alkynyl is ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-pentynyl, 3-pentynyl, 1-hexynyl, 2 Functional groups such as hexynyl, 3-hexynyl and the like.

The term "cycloalkyl", alone or in combination with another term, refers to a fully or partially saturated alicyclic hydrocarbon group containing from 3 to about 18 ring carbon atoms. Cycloalkyl groups can be monocyclic or polycyclic. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl, cyclopeptenyl, decalinyl, hydroindanyl, indanyl , Fenchyl, pineneyl, adamantyl, and the like. Cycloalkyls include cis or trans forms. Cycloalkyl groups can be unsubstituted or mono-substituted or multiple-substituted with electron withdrawing groups and / or electron donor groups as described below. Substituents may also be in endo or exo positions in a bridged bicyclic system. "Lower cycloalkyl" groups have 3 to 6 carbon atoms.

The term “alkoxy”, alone or in combination with another term, refers to an alkylether, ie an —O-alkyl substituent.

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

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

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

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

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

The term “carbalkoxy” means —CO—O-alkyl, wherein the alkyl may be lower alkyl as previously defined.

The prefix "halo" indicates that the substituents to which the prefix is added are substituted by one or more independently selected halogen radicals. For example, haloalkyl refers to an alkyl substituent wherein one or more hydrogen radicals are replaced by halogen radicals. Examples of haloalkyl substituents include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and equivalents thereof. To illustrate further, "haloalkoxy" means an alkoxy substituent wherein one or more hydrogen radicals are replaced by halogen radicals. Examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), 1,1,1-trifluoro Ethoxy, and equivalents thereof. When a substituent is substituted by one or more halogen radicals, it should be recognized that unless otherwise indicated, the halogen radicals may be the same or different.

The term "acyl" includes alkanoyl containing from 1 to about 20 carbon atoms, preferably from 1 to 6 carbon atoms, and may be straight or branched. Acyl groups include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, tertiary butyryl, pentanoyl and isomers thereof, and hexanoyl and isomers thereof.

The terms " electron-withdrawing " and " electron donating " refer to the ability of a substituent to attract or donate electrons relative to hydrogen, respectively, when the hydrogen atoms occupy the same position in the molecule. These terms are fully understood by those skilled in the art to which this invention pertains, and March (1985), Advanced Organic Chemistry . New York: John Wiley & Sons, at pp. It is reviewed in 16-18. Electron aspirators include halo, nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxamido, aryl, quaternary ammonium, (trifluoromethyl) (including fluoro, chloro, bromo, and iodo) Such as haloalkyl, aryl lower alkanoyl, carvalcocci and the like. Electron donor groups include hydroxy, lower alkoxy (including methoxy, ethoxy, etc.), lower alkyl (including methyl, ethyl, etc.), amino, lower alkylamino, di (lower alkyl) amino, (phenoxy and Such as) aryloxy, mercapto, lower alkylthio, lower alkyl mercapto, disulfide (lower alkyldithio) and the like. Those skilled in the art will appreciate that some of the substituents described above may be considered to donate electrons or attract electrons under different chemical conditions. In addition, the present invention contemplates any combination of substituents selected from the groups described above.

The term “heterocyclic” means a ring substituent comprising one or more sulfur, nitrogen and / or oxygen ring atoms. Heterocyclic groups include heteroaromatic and saturated heterocyclic groups 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 may include a total of about 25 carbon atoms, but preferably 5- or 6-membered rings (5- to 6 -membered ring). Heterocyclic groups also include so-called benzoheterocyclics. Representative heterocyclic groups are furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, pyrrole Ferrazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, furinyl, indolinyl, pyrazolindinyl , Imidazolinyl, imadazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxeta N-oxides such as nil, and azetidinyl, and nitrogen-containing heterocycles such as pyridyl, pyrazinyl, and pyrimidinyl groups. Heterocyclic groups may be unsubstituted or monosubstituted or polysubstituted with electron withdrawing groups and / or electron donors.

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

In another embodiment, the heterocyclic group is furyl, pyrrolyl, already substituted with furyl, optionally one or more lower alkyl groups (preferably lower alkyl groups having 1 to 3 carbon atoms, eg methyl) Is selected from dazolyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl and thiazolyl, in particular from furyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl and thiazolyl, more particularly furyl , Pyridyl, pyrimidinyl, and oxazolyl.

By way of example, in compounds of formula (I), n is 1, but di- (n = 2), tri- (n = 3) and tetrapeptide (n = 4) are also contemplated as being useful in the present invention.

R in the compound of formula (I) is illustratively aryl lower alkyl, in particular benzyl, in which the phenyl ring is unsubstituted or substituted with an electron donor group and / or an electron withdrawing group such as halo (eg fluoro).

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

Particularly suitable electron-withdrawing substituents and / or electron-donating substituents are halo, nitro, alkanoyl, formyl, arylalkanoyl, alyloyl, carboxyl, carvalcoxyl, carboxamido, cyano, sulfonyl, sulfoxide Seed, heterocyclic, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salt, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di (lower alkyl) amino, amino lower alkyl, Mercapto, mercaptoalkyl, alkylthio, and alkyldithio. The term "sulfide" includes mercapto, mercapto alkyl and alkylthio, and the term disulfide includes alkyldithio. Preferred electron-withdrawing and / or electron-donating groups are halo and lower alkoxy, in particular fluoro and methoxy. Such preferred substituents may be present in one or more of R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ' ₆ , R ₇ , or R ₈ as defined herein.

Representative ZY groups of R ₂ and / or R ₃ include hydroxy, alkoxy (such as methoxy and ethoxy), aryloxy (such as phenoxy), thioalkoxy (such as thiomethoxy and thioethoxy), ( Thioaryloxy, such as thiophenoxy, amino, alkylamino (such as methylamino and ethylamino), arylamino (such as anilino), lower dialkylamino (such as dimethylamino), trialkyl ammonium salts, Hydrazino, alkylhydrazino and arylhydrazino (such as N-methylhydrazino and N-phenylhydrazino), carvalcoxyl hydrazino, aralcoxicarbonyl hydrazino, aryloxycarbonyl hydrazino, (N- Hydroxylamino, such as hydroxylamino (-NHOH), lower alkoxy amino (R ₁₈ is lower alkyl, eg, methyl (NHOR ₁₈ )), N-lower alkylhydroxyamino (R ₁₈ is lower alkyl) (N (R ₁₈ ) OH), N-lower alkyl-O-lower alkylhydroxyamino (R ₁₈ And R ₁₉ is independently lower alkyl N (R ₁₈ ) OR ₁₉ ), and o-hydroxyamino (-0-NH ₂ ), alkylamido (such as acetamido), trifluoroacetamido and ( Heterocyclic amino, such as pyrazoylamino.

Preferred heterocyclic groups representing R ₂ and / or R ₃ have the formula and include 5- or 6-membered monocyclic heterocyclic groups, including unsubstituted, partially saturated and fully saturated forms thereof. It is a moiety (monocyclic 5- or 6-membered heterocyclic moiety):

N is 0 or 1 in the formula; R ₅₀ is H or an electron withdrawing group or an electron donating group; A, E, L, J and G are independently CH or heteroatoms selected from the group consisting of N, O, S; However, when up to two of A, E, L, J and G satisfy heteroatoms, and when n is 0, G is CH or a heteroatom selected from the group consisting of NH, O and S.

When n is 0, the aforementioned monocyclic heterocyclic ring is a ring of 5 atoms, and when n is 1, the ring is a ring of 6 atoms.

If the aforementioned ring contains nitrogen ring atoms, it is contemplated that the N-oxide form is also within the scope of the present invention.

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

Other preferred moieties of R ₂ and R ₃ are hydrogen, aryl (eg phenyl), aryl alkyl (eg benzyl) and alkyl. Such moieties may be unsubstituted or monosubstituted or multisubstituted with an electron donor or / and electron withdrawing. In various embodiments, lower alkyl wherein R ₂ and R ₃ are independently substituted or unsubstituted with an electron withdrawing group and / or an electron donor, such as hydrogen, lower alkoxy (eg, methoxy, ethoxy, etc.), N-hydroxyamino, N-lower alkylhydroxyamino, N-lower alkyl-O-lower alkyl or alkylhydroxyamino.

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

In one embodiment, n is 1 in formula (I) and one of R ₂ and R ₃ is Hydrogen. By way of example, in this embodiment, R ₂ is hydrogen and R ₃ is lower alkyl or ZY

이다.Z is 0, NR ₄ or PR ₄ ; Y is hydrogen or lower alkyl; ZY is NR ₄ NR ₅ R ₇ , NR ₄ 0R ₅ , ONR ₄ R ₇ ,

to be.

In another embodiment, n = 1, R ₂ is hydrogen and R ₃ is lower alkyl, NR ₄ OR ₅ or ONR ₄ R _{7 which} is unsubstituted or substituted with an electron donor or electron withdrawing group.

In another embodiment, n is 1;

R is aryl lower alkyl wherein the aryl group is unsubstituted or substituted by an electron-withdrawing group, for example aryl may be unsubstituted or phenyl substituted by halo,

R ₁ is lower alkyl,

R ₂ is hydrogen, and

R ₃ is lower alkyl, NR ₄ OR ₅ or ONR ₄ R ₇ which is unsubstituted or substituted by hydroxy or lower alkoxy, wherein R ₄ , R ₅ and R ₇ are independently hydrogen or lower alkyl.

In another embodiment, R ₂ is hydrogen and R ₃ is hydrogen, an unsubstituted alkyl group substituted with one or more electron donor groups or electron withdrawing groups or ZY. In this embodiment, R ₃ is illustratively hydrogen, unsubstituted or an electron donating group such as lower alkoxy, in particular methoxy or ethoxy or or R ₄ , R ₅ and R ₇ are independently hydrogen or lower alkyl Alkyl group, such as methyl, substituted with phosphorus NR ₄ OR ₅ or ONR ₄ R ₇ .

In another embodiment, R ₂ and R ₃ are independently hydrogen, lower alkyl, or ZY;

Z is 0, NR ₄ or PR ₄ ; Y is hydrogen or lower alkyl or

이다.ZY is NR ₄ NR ₅ R ₇ , NR ₄ 0R ₅ , ONR ₄ R ₇ ,

to be.

R is preferably aryl lower alkyl. Most preferred aryl for R is phenyl. Most preferred R group is benzyl. The aryl group is unsubstituted or substituted with an electron donating group or an electron withdrawing group. When the aryl ring of R is substituted, it is most preferable to substitute with an electron withdrawing group. The most preferred electron withdrawing group for R is halo, in particular fluoro.

Preferred R ₁ is lower alkyl, in particular methyl.

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

Another preferred compound is:

n is 1;

R is aryl or aryl lower alkyl, eg benzyl, wherein the aryl group is unsubstituted or substituted with an electron-withdrawing group or an electron-donating group;

R ₁ is lower alkyl;

R ₂ is hydrogen; And

R ₃ is a compound of formula (I) which is a lower alkyl group substituted with hydrogen, an electron-withdrawing group or an electron-donating group, in particular methyl, or ZY.

In this embodiment, R ₃ is a lower alkyl group, in particular methyl, NR ₄ OR ₅ as defined above, which may be substituted with an electron donor such as hydrogen, lower alkoxy (eg methoxy, ethoxy, etc.) Or ON ₄ R ₇ is more preferable.

In one embodiment, the compound of the present invention is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

Wherein Ar is aryl, in particular phenyl, unsubstituted or substituted with one or more halo,

R ₁ is lower alkyl, in particular C _1-3 alkyl, eg methyl; And

R ₃ is hydrogen or lower alkyl or ZY unsubstituted or substituted with one or more electron donor groups or electron substituents, for example, R ₃ is Q is lower alkoxy, especially C _1-3 alkoxy, for example And CH ₂ -Q which is methoxy.

In another embodiment, the compound of the present invention

n is 1,

R is unsubstituted or substituted benzyl, in particular halo-substituted benzyl,

R ₁ is lower alkyl, in particular C _1-3 alkyl, for example methyl,

R ₂ is hydrogen, and

R ₃ has formula (I) as broadly defined herein.

In another embodiment, the compound of the present invention is represented by the following formula (III),

Wherein R ₄ is hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, carboxy, formyl, carboxamido, aryl, quaternary ammonium, haloalkyl, aryl alkanoyl, hydroxy, alkoxy, amino, alkyl One or more substituents independently selected from the group consisting of amino, 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

R ₁ is alkyl or a pharmaceutically acceptable salt thereof.

In the compounds of formula (III), alkyl, alkoxy, alkenyl and alkynyl groups are lower alkyl, alkoxy, alkenyl and alkynyl groups having up to 6 carbon atoms, more typically up to 3 carbon atoms.

In certain embodiments, the R ₄ substituents in the compound of formula (III) are independently selected from hydrogen and halo, more specifically fluoro substituents.

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

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

In a more particular embodiment, up to one R ₄ substituent is fluoro, the remainder is hydrogen, and R ₃ is selected from the group consisting of methoxymethyl, phenyl, N-methoxy-N-methylamino and N-methoxyamino Become; And R ₁ is methyl.

Combinations and permutations of the R ₁ , R ₂ , R _3, and R groups with n values are contemplated to be within the scope of the present invention, even if such combinations and variations are not expressly described herein. The present invention also encompasses therapeutic combinations comprising compounds having various combinations of one or more elements of each of the Markush groups described for R ₁ , R ₂ , R ₃ and R. Thus, for example, the present invention R ₁ and R is formula independently of the sub-unit, each of the n to a compound of (I), R ₂ and R ₃ substituents in combination with, one or more previously independent listed Consider that it may be a substituent:

.

.

Compounds useful in the present invention may include one or more asymmetric carbons and may exist in optically active forms. The arrangement around each asymmetric carbon may be a D arrangement or an L arrangement. The arrangement around the chiral carbon atom can be described as R or S in the Cahn-Prelog-lngold system. All various arrangements around each asymmetric carbon are contemplated by the present invention, including various enantiomers and diastereomers and enantiomeric mixtures, diastereomeric mixtures, or mixtures of both.

More specifically, in compounds of formula (I) wherein R ₂ and R ₃ are not identical, there is an asymmetry in the carbon atom to which R ₂ and R ₃ are bonded. As used herein, the term "configuration" generally refers to the arrangement around the carbon atom to which R ₂ and R ₃ are bonded, even if there are other chiral centers in the molecule. Thus, unless the context otherwise requires, when referring to a specific arrangement such as D or L, it is understood that R ₂ and R ₃ are meant to mean D-stereoisomers or L-stereoisomers at the bonded carbon atoms. However, when present, all possible enantiomers and diastereomers at all other chiral centers in the compound are included in the present invention.

Compounds useful in the present invention may include L-type stereoisomers or D-type stereoisomers or mixtures thereof, including racemic mixtures, without limitation, as described above. D-type stereoisomers are generally preferred. In lacosamide, the D-type stereoisomer corresponds to the R-type enantiomer according to the R, S terminology.

In one embodiment, the compound, eg lacosamide, is a substantially pure enantiopure. The term "substantially pure enantiomer" as used herein refers to an enantiomeric purity of at least 88%, preferably at least 90%, more preferably at 95, 96, 97, 98, or 99%. It means to have.

Exemplary compounds that can be used in this combination are:

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

(R) -2-acetamido-N-benzyl-3-ethoxypropionamide

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

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

N-acetyl-D-phenylglycinebenzylamide;

D-1,2- (N, O-dimethylhydroxyamino) -2-acetamido acetate benzylamide; And

D-1,2- (O-methylhydroxyamino) -2-acetamido acetate benzylamide; and the like.

Depending on the substituent, certain compounds of the present invention may form salts. For example, the compounds of formulas (I), (II) and (III) can form salts with various inorganic and organic acids, including pharmaceutically acceptable acids. Such salts have increased water solubility and can be particularly useful for preparing pharmaceutical compositions for use in situations where increased water solubility is advantageous.

Pharmaceutically acceptable salts are salts that have a therapeutic effect without unacceptable toxicity. Salts of inorganic acids such as hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid and tartaric acid, acetic acid, citric acid, malic acid, benzoic acid, perchloric acid, glycolic acid, gluconic acid, succinic acid, arylsulfonic acid (e.g. For example, salts of organic acids such as p-toluene sulfonic acid, benzenesulfonic acid), phosphoric acid, malonic acid and the like may be used.

Compounds useful in the present invention may be prepared by known synthetic methods, such as, for example, incorporated herein by reference, respectively, and described in previously referenced US Pat. Nos. 5,378,729 and 5,773.475.

The compounds disclosed herein are used in therapeutically effective amounts. The physician may determine the appropriate dosage of the compound, which may vary depending on the particular compound selected, the route and method of administration, and the age and other characteristics of the individual patient. The physician may begin treatment at a lower dose, eg, a dose substantially less than the optimal dose of the compound, and may increase the dose in small amounts until the optimum effect is achieved in a given situation. When the composition is administered orally, higher amounts of the compound may be required to produce the same effect as the smaller amount administered parenterally.

In certain embodiments, the compound, eg, lacosamide, is administered in an amount in the range of about 1 mg to about 10 mg / kg body weight / day. Typically, the patient is 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 about the drug, for example, lacosamide. It can be treated at a dosage of 400 mg / day or more. In general, suitable dosages are about 6 g / day or less, for example about 1 g / day or less or about 600 mg / day or less. In some cases, however, higher or lower dosages may be needed.

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

In another embodiment, several divided doses may be administered daily. For example, up to three doses per day, or up to two doses per day, may be administered. However, once daily administration is often the most convenient.

Dosages expressed on a daily basis, eg mg / day, herein are not to be construed as requiring a frequency of once daily. For example, a dose of 300 mg / day may be given at 100 mg three times a day or at 600 mg at two day intervals.

In another embodiment, the present invention results in a plasma concentration of about 0.1 to about 15 μg / ml (lowest) and about 5 to about 18.5 μg / ml (highest), calculated as an average for the plurality of treated subjects. The amount of the compound, for example lacosamide, may be administered.

Compounds of formula (I), (II) or (III), such as lacosamide, can be administered orally, intravenously, intraperitoneally, intramuscularly, intradural, subcutaneous or transmucosal (eg, oral Can be administered in a convenient and effective manner such as Oral or intravenous administration is generally preferred.

For oral administration, the compounds of the present invention may be administered as components of an orally deliverable pharmaceutical composition, which typically further comprises an inert diluent or an assimilable edible carrier, or may be incorporated into the subject's food. In orally deliverable pharmaceutical compositions, the compound may be contained with one or more excipients and may be contained in tablets, troches, pills, capsules, elixirs, suspensions, syrups, wafers or It may be administered in the form of its equivalent. Such compositions typically comprise at least about 1%, more typically from about 5% to about 80%, by weight of the compounds of the present invention, for example lacosamide. The amount of the compound in the composition is such that after administration of the composition, a suitable dosage as indicated above can be conveniently provided. By way of example, a pharmaceutical composition useful for oral delivery of a compound of formula (I), (II) or (III), eg, lacosamide, may be from about 10 mg to about 6 g, such as about 50 To about 1000 mg, or about 100 to about 600 mg of the compound.

In certain embodiments, the composition may be enclosed in hard or soft (eg gelatin) capsules or may be compressed or molded tablets. The composition may be excipient, for example, by diluents such as lactose, dicalcium phosphate (in the case of capsules, liquid carriers may be present); Binders such as tragacan gum, acacia, corn starch or gelatin; Disintegrants such as corn starch, potato starch, alginic acid and the like; Lubricants such as magnesium stearate; And one or more sweetening agents, such as sucrose or saccharin, and / or if desired, flavoring agents such as peppermint, methyl salicylate (oil of wintergreen), or cherry flavor can be added.

Various other excipients may be present in the coating or modify the physical form of the composition. For example, tablets, pills, or capsules may be coated with shellac, sugar or both. Syrups or elixirs may include active compounds, sucrose as sweetener, methylparaben and propylparaben as preservatives, dyes and flavoring agents such as cherry or orange flavors. The active compound may be incorporated into sustained release formulations. For example, sustained release dosage forms are contemplated in which the compound is bound to an ion exchange resin that can be optionally coated with a diffusion barrier coating to modify the release properties of the resin.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (if the compound is water soluble) or dispersants and sterile powders for the instant preparation of sterile injectable solutions or dispersants. In such cases, the injectable composition must be sterile and must be fluid to the extent that easy syringability in the syringe is possible. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium comprising water, ethanol, polyols (eg glycerol, propylene glycol, liquid polyethylene glycols, etc.), suitable mixtures thereof, and vegetable oils. Suitable fluidity should be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the desired particle size in the case of dispersants and by the use of surfactants. Microbial action should be inhibited by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be desirable to include a tonicity agent, for example, sugars or sodium chloride, to provide a solution that is substantially isotonic for injection. Prolonged absorption of the injectable composition can be achieved by the use of agents that delay absorption in the composition, such as aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by mixing the required amount of the active compound in a suitable solvent containing the various ingredients described above as needed and subject to filtered sterilization. Generally, dispersants are prepared by mixing a sterile active compound into a sterile vehicle that contains a dispersion medium and other excipient components, such as those described above. Sterile powders for the preparation of sterile injectable solutions may be prepared by vacuum drying or lyophilizing a previously sterile-filtered solution or dispersion.

The therapeutic combination of the present invention, in addition to the first agent as described above, provides (a) an increased improvement in pain associated with or caused by a medical condition, in comparison to the first agent alone, and / or (b) ) To treat another symptom or root cause of the medical condition, comprising a second agent effective for combining with the first agent, the second agent comprising one or more drugs that are not a compound of formula (I) do.

In one embodiment, the second agent comprises an anti-arthritis agent that is not a compound of formula (I) and the combination of the present invention is useful for the treatment of arthritic conditions and / or pain associated therewith. . One or more anti-arthritis agents may optionally be present in the second agent.

"Anti-arthritis drug" is effective for treating (including preventing) the aspects, symptoms (eg, pain or inflammation) and / or root cause of arthritis conditions as defined herein. It is a drug.

For example, anti-arthritis agents that are included in or are second agents may be effective for the treatment of pain, i.e., analgesic. Suitable analgesics include certain anti-inflammatory drugs and opioid analgesics and non-opioid analgesics (see immediately below). Arthritis conditions involving pain, in particular combinations comprising compounds of formula (I), (II) or (III), for example lacosamide and opiate or non-opioid analgesics, It may be useful in arthritic conditions that are non-inflammatory components, such as in osteoarthritis.

Alternatively, or in addition, anti-arthritis agents included in, or as a second agent, may be effective in the treatment of inflammation and / or pain associated therewith. Suitable anti-inflammatory agents include steroidal anti-inflammatory agents and non-steroidal anti-inflammatory agents. Nonsterodial anti-inflammatory drugs (NSAIDs) include traditional NSAIDs and cyclooxygenase-2 (COX-2) selective inhibitors. Compounds of formula (I), (II) or (III), for example, combinations comprising lacosamide and anti-inflammatory agents may be used for arthritis conditions with inflammatory pain or arthritis conditions with both inflammatory and non-inflammatory pain. May be useful in

Non-limiting examples of opiate and non-opioid analgesics that may be useful in the second agent include acetaminophen, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, benzitramide, Buprenorphine, Butorpanol, Clonitogen, Codeine, Cyclazosin, Desomorphine, Dextromoramide, Dextropropoxyphene, Dezosin, Diampramide, Diamorphone, Dihydrocodeine, Dehydro Morphine, Dimenoxadol, Dimefetanol, Dimethylthibutene, Dioxaptyl Butyrate, Dipipanone, Dipyrone (methamizole), Ephthazosin, Etoheptazine, Ethylmethylthiambutene, Ethylmorphine, Etonita Zen, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypetidine, isometadon, ketomidone, levalorphan, levorpanol, levofenacylmorphan, lofentanil, meperidine, meftazinol, Metazosin, methadone, methopone, morphine, miropin, nal Buffin, nallopine, narcein, nicomorphine, norreborpanol, normethadon, normorphine, norfipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocin, phenadoxin, phenazoscin, phenomor Pan, Phenoferidine, Piminodine, Pyramidamide, Propheptazine, Promethol, Properidine, Propyram, Propoxyphene, Sufentanil, Tilidine, Tramadol, NO-naproxen, NCX-701, ALGRX- 4975, pharmaceutically acceptable salts thereof, and combinations thereof.

Steroidal anti-inflammatory agents that may be useful in the second agent are alclomethasone, amcinolone, betamethasone, betamethasone 17-valerate, clobetasol, clobetasol propionate, clocortolone, cortisone , Dehydrotestosterone, deoxycorticosterone, desonide, desoximetasone, dexamethasone, dexamethasone 21-isonicotinate, diflorason, fluorinide, Fluorcinolone, Fluorometholone, Fluandrenolide, Fluticasone, Halcinolone, Halobetasol, Hydrocortisone, Hydrocortisone acetate, Hydrocortisone cypionate, Hydrocortisone hemisuccinate, Hydro Cortisone 21-lysinate, hydrocortisone sodium succinate, isoflupredone, isoflupredone acetate, methylpredni Solon, Methylprednisolone Acetate, Methylprednisolone Sodium Succinate, Methylprednisolone Suleftanate, Mometasone, Prednicabate, Prednisolone, Prednisolone Acetate, Prednisolone Hemisuccinate, Prednisolone Sodium Phosphate, Prednisolone Sodium Succinate, -Acetate, prednisone, triamcinolone, triamcinolone acetonide, pharmaceutically acceptable salts thereof and combinations thereof.

Non-limiting examples of NSAIDs that may be useful in the second agent include salicylic acid derivatives (e.g. salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, olsalazine, salsalate and sulfasalazine) , Indole and indene acetic acid (e.g. indomethacin, etodolak and sulindac), phenamate (e.g. etofenamic acid, meclofenamic acid, mefenamic acid, flufenamic acid, niflumic acid And tolfenacic acid), heteroaryl acetic acid (e.g. acemethacin, alclofenac, clidanac, diclofenac, fenclofenac, pentiazac, furofenac, ibufenac, isoxepac, ketorolac ), Oxipinac, thiopinac, tolmetin, dozimethacin and zomepirac), aryl acetic acid and propionic acid derivatives (e.g., aminopropene, venoxapropene, bucloxane (bucloxic acid), carpropene, fenbufen, phenopropene, flupro Pens, fluviprofen, ibuprofen, indoprofen, ketoprofen, myroprofen, naproxen, oxaprozin, pirprofen, pranopropene, suprofen, thiapropenic acid and thiaxapropene) Nolanic acid (e.g., ampyoxycamps, cynoxycamps, doxycamps, lormoxicams, meloxycamps, pyroxicams, sudoxicams and tenoxycams, which are oxycam derivatives, and aminopyrins which are pyrazolone derivatives, Antipyrine, apazone, dipyrone, oxyphenbutazone and phenylbutazone), alkanones (eg, nabumethone), nimesulide, proquazone, MX-1094, lycopene, and their Pharmaceutically acceptable salts and combinations thereof.

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

Alternatively, or in addition, the second agent may illustratively include a disease-modifying Osteoarthritis Drug (DMOAD). Non-limiting examples of DMOADs that may be useful in the second agent include methotrexate, diacerane, glucosamine, chondroitin sulfate, anakinra, MMP inhibitors, doxycycline, minocycline, misprostole, proton pump inhibitors, non Acetylated salicylate, tamoxifen, prednisone, methylprednisolone, polysulfated glycosaminoglycan, calcitonin, alledronate, risedronate, zoledronic acid, teriparatide, VX-765, Pranacaic acid, SB-462795, CPA-926, ONO-4817, S-3536, PG-530742, CP-544439, pharmaceutically acceptable salts thereof and combinations thereof.

Alternatively, or in addition, the second agent may illustratively include a disease-modifying anti-rheumatic drug (DMARD). Non-limiting examples of DMARDs that may be useful in the second agent include etanercept, adalibumab, infliximab, IL-1 receptor antagonists, prednisone and methylprednisolone Glucocorticoids, penicillamine, hydroxychloroquine sulfate, chlorambucil, cyclophosphamide, leflunomide, cyclosporin, auranopine, aurothioglucose, azathioprine, gold sodium thiomaleate (gold sodium thiomalate), methotrexate, cyclophosphamide, minocycline, sulfasalazine, abatacept, rituximab, busilamine, chloroquine, hydroxychloroquine, robbenzat, misoprostol, Pharmaceutically acceptable salts thereof, and combinations thereof.

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

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

(i) opiate and non-opioid analgesics;

(ii) steroidal anti-inflammatory agents;

(iii) NSAID and COX-2 selective inhibitors;

(iv) DMOAD; And

(v) DMARD.

In certain embodiments, two or more agents administered in combination or adjuvant therapy with a compound of formula (I), (II) or (III), eg, lacosamide, are selected from the aforementioned agents, At least one of is DMOAD or DMARD.

In one embodiment, administration of the therapeutic combinations of the invention is useful for the treatment of arthritis conditions and pain associated therewith. By way of example, a compound of formula (I), (II) or (III), eg, lacosamide, may be used to treat pain associated with arthritis conditions, more specifically non-inflammatory pain, As described above, one or more anti-arthritis agents may be used to treat intrinsic processes that cause or contribute to arthritis conditions, or to treat another symptom of arthritis conditions, such as inflammatory pain, It can be used together with the compound of (II) or (III).

In another embodiment, the second agent is present in an amount effective to provide an increased treatment of pain, more specifically non-inflammatory pain, in combination with the first agent alone. Drugs that provide such increased treatment in combination with the first agent are used as or are used as second agents, such as opioid or non-opioid analgesics, anticonvulsants, antidepressants and / or NMDA receptor antagonists. It can be included in two agents.

"Enhanced treatment of pain" in the present invention means that the combination is superior to the first agent in one or more of the following aspects:

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

(b) a dose reduction of either the first agent or the second agent, or both, relative to the conventional effective amount used in monotherapy;

(c) the reduction of adverse side effects; And / or

(d) improved therapeutic ratio.

It is not required for the first agent and the second agent to interact beyond the additive effect, but in some cases, the reduction in the intensity and / or duration of pain provided by the combination may result in a single dose of each agent alone at the same dose. It may be larger than expected based on the effectiveness.

According to an embodiment of the invention, the second agent may comprise one or more analgesics, for example one or more analgesics selected from those described above. In an exemplary embodiment, the second agent comprises morphine or a pharmaceutically acceptable salt thereof.

Alternatively or additionally, the second agent may be one or more anticonvulsants, such as acetylpheneturide, albutoin, aminoglutetimide, 4-amino-3-hydroxybutyric acid, atrolactamide , Beclamide, briamate, carbamazepine, pyrromid, clomeththiazole, clonazepam, decimemid, dietadione, dimethadione, doxenitoin, etherovar, etadione, etosucci Mead, ethotoin, felbamate, fluoresone, phosphphenytoin, gabapentin, ganoxolone, lamotrigine, levetiracetam, lorazepam, mefenitoin, mepobarbital, metabital, methe Toyne, metsuximide, midazolam, narcobarbital, nitrazepam, oxcarbazepine, paramethadione, phenacemid, phentarbital, peneturide, phenobarbital, pensuccimid, phenylmethylbarbitur Mountains, phenytoin, penetile , Pregabalin, primidone, progabide, remasemide, lufinamide, suclofenide, sulthiame, talampanel, tetratoin, tiagabine, topiramate, trimetadione, valpro And one or more anticonvulsants selected from acids, valpromide, bivathrin, zonamidamide, pharmaceutically acceptable salts thereof, and combinations thereof.

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

Alternatively, or in addition, the second agent includes bicyclic, tricyclic and tetracyclic antidepressants, hydrazides, hydrazines, phenyloxazolidinones and pyrrolidones, And, but not limited to, one or more antidepressants. Antidepressants are, for example, adinazolam, adrafinil, aminephthine, amitriptyline, amitriptylinoxide, amoxapine, befloxatone, bupropion, butetacetin, butliprifrin, caroxazone, citatal Tropram, clomipramine, cotinine, demexiptiline, decipramine, dibenzepine, dimethacrine, dimethazane, dioxadol, dotipine, doxepin, duloxetine, etoferidone, Phenoxetine, Fencamine, Fenpentadiol, Fluasizin, Fluoxetine, Fluvoxamine, Hematoporphyrin, Hypericin, Imipramine, Imipramine N-oxide, Indalpine, Phosphorus Deloxazine, ifrindol, ifroclosidide, ifroniazide, isocarboxazide, levopacetoferran, lofepramine, mapproline, medipoxamine, melitracene, metapramine, metalolin, Mianserine, Milnacifran, Minaphrine, Mirtazapine, Moclobemid, Nefazodone, Nepofam, Aramid, nomifensin, nortriptyline, oxycipillin, octamoxin, opipramol, oxaprozane, oxytriphtan, oxyfertin, paroxetine, phenelzin, fiberalline, pizotillin, Prolinetans, propizepine, protriphthyllines, pyrisuccideanol, quinupramine, reboxetine, ritanserine, roxindole, rubidium chloride, sertraline, sulfides, ballistic spirons, thiazimes , Tozalinone, thianephthine, tophenasin, toloxatone, tranilcipromin, trazodone, trimipramine, tryptophan, venlafaxazine, viloxazine, gemeldine, pharmaceutically acceptable Salts and combinations thereof. In an exemplary embodiment, the second agent comprises duloxetine.

Alternatively or additionally, the second agent may comprise one or more NMDA receptor antagonists, such as amantadine, D-AP5, aftiganel, CPP, dexanabinol, dextromethorphan, dextrosepropoxyphen, 5 (5,7-dichlorokynurenic acid), gavestinel, fendocril, ketamine, ketobemidone, lycostinel, LY-235959, memantine, methadone, MK-801, penciclidine, NMDA receptor antagonists selected from remasemide, selpotel, tiletamine, pharmaceutically acceptable salts thereof, and combinations thereof. In an exemplary embodiment, the second agent comprises methine.

In another embodiment, the second agent consists of GABA analogs, thiophene propane derivatives, morphine analogs and opioids, the 2-arylpropionic acid (propene) family of NSAIDs, and amantadine (1-aminoadamantane) derivatives One or more drugs independently selected from the group.

One example of a GABA analog is gabapentin. One example of a thiophene propane derivative is duloxetine. One example of an opioid is morphine. The composition of the 2-arylpropionic acid family of NSAIDs is naproxen. An analog of amantadine is memantine.

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

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

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

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

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

In another embodiment, in a 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 for increased treatment of pain associated with or caused by a medical condition, wherein the medical condition is accompanied by, or is a symptom of, non-inflammatory pain. Have inflammatory pain.

In one embodiment of the present invention, the combination of the present invention provides for an increased treatment of pain and the pain associated with the medical condition comprises non-inflammatory pain.

In one embodiment of the invention, the combination of the invention provides an increased treatment of pain associated with or caused by a medical condition, the medical condition comprising an arthritis condition and / or pain associated therewith. Arthritis conditions include osteoarthritis. In this embodiment, in the combination, the first agent and the second agent may be present in absolute and relative amounts effective to treat arthritis conditions and / or pain associated therewith. In combination, the first agent and the second agent may be present in absolute and relative amounts effective to treat both non-inflammatory and inflammatory components of pain associated with or caused by arthritis conditions.

In combination, the first agent and the second agent may be present in absolute and relative amounts effective to treat non-inflammatory pain associated with arthritis conditions. The first agent and the second agent may be present in absolute and relative amounts effective to treat non-inflammatory osteoarthritis pain.

In combination, the first agent and the second agent may be present in absolute and relative amounts effective to treat inflammatory pain associated with a bone joint condition. The first agent and the second agent may be present in absolute and relative amounts effective to treat inflammatory osteoarthritis pain.

Osteoarthritis pain may be associated with cartilage degeneration, structural bone changes, and vascularization of osteoarthritis remodeling.

Arthritic conditions include idiopathic osteoarthritis, secondary osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, infectious arthritis, ankylosing spondylitis, neuroarthritis, polyarthralgia, and Sjogren's syndrome, Behcet's syndrome, Reiter syndrome. One or more diseases selected from systemic lupus erythematosus, rheumatic fever, gout, pseudogout, Lyme disease, sarcoidosis and arthritis associated with ulcerative colitis.

The arthritic condition may include rheumatoid arthritis or combustible rheumatoid arthritis.

In another embodiment of the present invention, the combination of the present invention provides an increased treatment of pain associated with or caused by a medical condition, said medical condition being in painful diabetic neuropathy. Pain. Painful diabetic neuropathy is painful diabetic neuropathy is diabetic distal sensory polyneuropathy. In combination, the first agent and the second agent are associated with average daily pain, overall pain, present pain intensity, pain interference with sleep, pain. From the group consisting of the individual's perception of disturbance of general activity by the subject, the patient's overall impression of pain changes, the individual's perception of the quality of different neuropathic pain, the individual's perception of the quality of life and the percentage of painless days It may be effective in the treatment of the aspect of pain selected.

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

In another embodiment of the present invention, the combination of the present invention provides an increased treatment of pain associated with or caused by a medical condition, wherein the medical condition or pain associated therewith is acute inflammatory pain, acute pain, alcohol Addiction-associated or alcoholism-induced neuropathic pain, allodynia, arthritis condition, back pain, cancer-related neuropathic pain, central neuropathic pain, chronic headache, chronic inflammatory pain, chronic pain, chronic pain due to peripheral nerve damage, diabetes Associated or diabetes-induced neuropathic pain, diabetic distal sensory neuropathy, diabetic distal sensory polyneuropathy, diabetic pain, fibromyalgia, headache, hyperalgesia, hyperesthesia, hyperalgesia (hyperpathia), migraine, myofascial pain syndrome, neuralgia, neuroma, non-inflammatory osteoarthritis pain, non-neuroinflammatory inflammatory pain , Pain associated with or induced by neuropathic pain, chemotherapy or radiation therapy, pain associated with or induced by traumatic nerve injury or compression or traumatic injury to the brain or spinal cord, painful diabetic neuropathy, Peripheral neuropathic pain, persistent clinical pain, phantom pain, rheumatoid arthritis pain, secondary inflammatory osteoarthritic pain, trigeminal neuralgia, vascular headache, and Selected from the group consisting of combinations thereof.

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

Another aspect of the invention is a method of treating a painful medical condition and / or pain associated therewith in an individual, the method comprising administering to the individual a combination of the therapeutic agents of the invention. In the methods of the invention, the painful medical condition and / or pain associated therewith is selected from conditions such as those described herein.

In one embodiment of the invention, the medical condition or pain associated therewith is acute inflammatory pain, acute pain, alcoholism-associated or alcoholism-induced neuropathic pain, allodynia, arthritis state, back pain, cancer-related neuropathic pain , Central neuropathic pain, chronic headache, chronic inflammatory pain, chronic pain, chronic pain caused by peripheral nerve injury, diabetes-associated or diabetes-induced neuropathic pain, diabetic distal sensory neuropathy, diabetic distal sensory polyneuropathy, diabetes Sexual pain, fibritis, headache, hypersensitivity, tactile hypersensitivity, hyperalgesia, migraine, myalgia, myofascial pain syndrome, neuralgia, neuroma, non-inflammatory osteoarthritis pain, non-neuropathic inflammatory pain, neuropathic pain, chemotherapy or radiation Pain associated with or induced by therapy, traumatic nerve injury or compression, or trauma to the brain or spinal cord Selected from the group consisting of pain associated with or induced by, painful diabetic neuropathy, peripheral neuropathic pain, persistent clinical pain, annular pain, rheumatoid arthritis pain, secondary inflammatory osteoarthritis pain, trigeminal neuralgia, vascular headache and combinations thereof do.

In another embodiment, the methods of this invention make use of a first agent comprising lacosamide in the combination above.

Another aspect of the invention is defined herein for the manufacture of a medicament for increased prevention, alleviation and / or treatment of pain associated with or caused by a medical condition, relative to a compound of formula (I) alone And the second agent comprises at least one drug which is not a compound of formula (I).

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

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

Suitable regimens, including dosages and routes of administration of particular drugs useful in or as the second agent, are readily available references, such as Physicians' Desk Reference (PDR), associated with such drugs. , 60th edition, Montvale, NJ: Thomson (2006) and various Internet sources known to those skilled in the art to which this invention pertains. When administered in combination or adjuvant therapy with a compound of formula (I), (II) or (III), eg, lacosamide, a drug useful in a second agent or as a second agent may be dose, but the physician may at least initially choose to administer less than the full dose of such a drug.

The first agent and the second agent are provided in one pharmaceutical formulation (single dosage form) for simultaneous administration to an individual, or simultaneously or at different times, for example, sequentially and / or the same frequency and And / or two or more separate agents (separate dosage forms) for administration at different frequencies. Two separate agents may be provided in a form adapted for administration by the same route or by different routes.

Individual dosage forms may optionally be packaged together, for example in one container or in a plurality of containers contained in one outer package, or presented together in separate packages (“common presentation”). As an example of co-packaging or common presentation, a compound of formula (I), (II), or (III) in a first container, such as lacosamide, and a second container as described herein Kits containing the same second agent are contemplated. In another embodiment, the compounds of formula (I), (II) or (III), such as lacosamide and the second agent, may be packaged separately and sold independently of each other, but according to the invention It may be co-sold or co-promote for use. Separate dosage forms can also be presented separately and independently to the subject for use according to the invention.

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

In one embodiment, administration of the therapeutic combination is useful for the treatment of non-inflammatory osteoarthritis pain. In particular, such administration is useful when non-inflammatory osteoarthritis pain is associated with cartilage degeneration, structural bone changes, and vascularization of the bone remodeling area. Goals continue to be remodeled. Remodeling is the process by which old bone is continuously replaced with new bone to maintain peak bone density. Angiogenesis may be caused by proliferation of capillaries during the remodeling process and angiogenesis may be increased in conditions such as osteoarthritis.

In one embodiment, administration of the therapeutic combination inhibits delivery of pain. Typically, inhibition of pain delivery, a contributing effect of a compound of formula (I), (II) or (III), for example lacosamide, is a glutamate such that spinal cord neurons are secreted by nociceptors. It can be achieved by preventing the response to neurotransmitters.

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

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

FIG. 2 shows the maximum possible effects of lacosamide 3, 10 and 30 mg / kg, compared to pregabalin, gabapentin and metamizol (dipyrone) for muscle pressure hyperalgesia induced by TNF. Is a graphical representation of the results of the study of Example 1.

FIG. 3 is a graphical representation of the results of the study of Example 1 showing the effect of lacosamide 3, 10 and 30 mg / kg on biceps muscle grip strength after TNF-induced myalgia. FIG.

4 shows the maximum possible effects (MPE) of lacosamide 3, 10 and 30 mg / kg, compared to pregabalin, gabapentin and metamizol (dipyrone) on bicep grip strength after TNF-induced myalgia 1 is a graphical representation of the results of the study.

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

6A-C are graphical representations of the results of the study of Example 2 demonstrating the effects of diclofenac on monosodium iodoacetate-induced tactile allodynia at Days 3, 7, and 14 of the study, respectively.

7A-C are graphical representations of the results of the study of Example 2 demonstrating the effects of lacosamide and morphine on monosodium iodoacetate-induced mechanical hyperalgesia at Days 3, 7, and 14 of the study, respectively. .

8A-C are graphical representations of the results of the study of Example 2 demonstrating the effects of diclofenac on monosodium iodoacetate-induced mechanical hyperalgesia at Days 3, 7, and 14 of the study, respectively.

Example 1

Mechanical pain measured by mechanical allodynia measured by biceps muscle grip strength and by paw withdrawal threshold for muscle pressure, which occurs in TNF-induced musculoskeletal pain in rats A study demonstrating the antinociceptive effect of lacosamide on the inhibition of mechanical hyperalgesia. The model used in this embodiment can be applied to musculoskeletal pain arising from fibromyalgia, myofascial pain syndrome, back pain or osteoarthritis. For comparison, non-opioid analgesics dipyrone (methamizol) and anticonvulsants pregabalin and gabapentin were included in this study.

Animals, Induction of Muscle Pain

Mature male Sprague Dawley rats weighing 250 g to 300 g were used (School River, Sulzfeld, Germany). Animals are housed in groups (3 per cage) and under conditions that make food and food available as desired in rooms of controlled temperature (21-22 ° C.) and inverted light-dark cycles (12 hours / 12 hours). Maintained. All experiments were approved by the Bavarian Animal Experimentation Committee and performed according to the regulations.

Recombinant rat tumor necrosis factor alpha (hereinafter referred to as TNF) was obtained from R & D Systems, Minneapolis, MN, U.S.A. TNF was diluted in 0.9% NaCl and used at a concentration of 1 μg / 50 μl. Injections were performed on both sides of the gastrocnemius or biceps brachii muscle with a 30 g needle under short halotan anesthesia. All rats were used for behavioral tests prior to injection and baseline values were recorded over three days of test days.

Behavioral readout: muscle pressure (Randall-Selitto)

Mechanical withdrawal thresholds for muscle pressure were measured with an analgesimeter (Ugo Basile, Comerio, Italy). The rat was crawled into a sock to help relax. The hind paw was positioned so that increased pressure could be applied to the gastrocnemius muscle (up to 250 g). The pressure required to cause withdrawal was recorded. The average of three measurements for each hind paw was calculated (interstimulus interval longer than 30 seconds). Only animals showing significant TNF effects were included in further analysis.

TNF was injected into the gastrocnemius of rats at 2 pm. After 18 hours, the hyperalgesia of the rats was tested before and after application of the test drug. Rats were tested for pressure hyperalgesia 30 to 60 minutes after drug administration.

Behavioral readings: grip strength

Forefoot grip strength was tested with a digital pressure gauge (DFIS series, Chatillon, Greensboro, NC, USA). Rats were placed to grab the grid with their paws and pulled lightly so that grip strength could be recorded. The average of three measurements was calculated. The effects of TNF treatment were calculated separately for each animal and only animals with significant TNF effects were included in further analysis.

TNF was injected into the biceps of the rat at 8 am. After 6 hours, the grip strength of the forefoot was tested with a digital grip meter. Test drug was applied and grip strength was tested again after 30-60 minutes.

Application protocol

10 rats per group intraperitoneally (ip) with 3, 10 or 30 mg / kg lacosamide, 2 mg / kg metamizol, 30 or 100 mg / kg pregabalin, 100 mg / kg gabapentin, or NaCl vehicle It was. The injection dose of intraperitoneal injection was 0.5 ml. A pilot study was performed to demonstrate that intramuscular injection of 1 μg TNF into gastrocnemius muscle was sufficient to induce pressure hyperalgesia.

For gastrocnemius muscle and biceps brachii muscle injections of TNF, groups and treatments are summarized in Tables 1 and 2, respectively.

Table 1: gastrocnemius injection of TNF

Table 2: Brachial Biceps Injection of TNF

Data presentation and statistics

Data is plotted on a graph representing the mean and standard error of the mean (SEM). Pre- and post-treatment data were compared using Analysis of Variance (ANOVA) and Turkey post hot test. Means of treatment groups were compared using one-way ANOVA and Dunnett's post hoc test. Maximum possible effect (MPE) was calculated for all kinds of treatments.

result

Muscle pressure hyperalgesia

Only rats with significantly decreased retraction thresholds after TNF injection were included. In about 13% of rats, there was no TNF effect. 1 shows the absolute value of the withdrawal threshold for pressure.

Full reversal of muscle mechanical hyperalgesia of the muscle was observed at 30 mg / kg of lacosamide and 2 mg / kg of metamizol.

Significant reversal of muscle hyperalgesia in the muscle was also observed at pregabalin 30 and 100 mg / kg, and gabapentin 100 mg / kg.

For lacosamide 10 mg / kg and 30 mg / kg, pregabalin 30 and 100 mg / kg, gabapentin 100 mg / kg, and metamizol 2 mg / kg, the maximum possible effect (FIG. 2) was significant with vehicle. It was different. Vehicle did not work.

Result: bicep grip strength

Only rats with significantly decreased retraction thresholds after TNF injection were included. In about 13% of rats, there was no TNF effect. 3 shows the absolute value of the grip strength.

Significant reversal of TNF-induced grip strength reduction was observed at 10 mg / kg and 30 mg / kg of lacosamide. In addition, significant reversal was observed for 100 mg / kg of pregabalin, 100 mg / kg of gabapentin and 2 mg / kg of metamizol. .

For lacosamide 10 mg / kg and 30 mg / kg, pregabalin 100 mg / kg, gabapentin 100 mg / kg, and metamizol 2 mg / kg, MPE (FIG. 4) differed significantly from vehicle. Vehicle did not work.

Review

Lacosamide improved dose-dependent muscle hyperalgesia induced by TNF injection in the paw pressure test, reaching full reversal at 30 mg / kg. Compared to the anticonvulsants pregabalin and gabapentin, lacosamide had a stronger effect on myalgia. Neither pregabalin nor gabapentin induced a complete reversal of muscle hyperalgesia. In grip strength tests indicating mechanical allodynia, lacosamide reversed the effect of TNF on muscle already at 10 mg / kg. Lacosamide was also more potent than pregabalin and gabapentin, which improved grip strength only at 100 mg / kg.

In conclusion, lacosamide was effective in relieving muscle hyperalgesia and mechanical allodynia induced by TNF injected into muscle. Thus, lacosamide, which exemplifies the compounds of formulas (I), (II) and (III), is a particular symptom of non-inflammatory musculoskeletal pain such as muscular hyperalgesia and allodynia that occurs in fibromyalgia, fascia pain syndrome, back pain or osteoarthritis. It is concluded to have therapeutic efficacy in the treatment of, especially systemic treatment.

Example 2

This example describes a study demonstrating the antinociceptive effect of lacosamide in an iodoacetate rat model. The model used in this example can be applied to non-inflammatory osteoarthritis pain. For comparison purposes, opiate analgesics morphine and NSAID diclofenac were included in this study.

One of the greatest features of the rat model for osteoarthritis is a metabolic inhibitor that inhibits the activity of glyceraldehyde-2-phosphate dehydrogenase in chondrocytes, leading to destruction of glycolysis and ultimately cell death. Monosodium iodoacetate is injected into a joint, eg, a knee joint (Guzman et al. (2003) Toxicol. Pathol. 31 (6): 619-624; Kalbhen (1987) J, Rheumatol. 14 (Spec No.): 130-131). Progressive loss of chondrocytes results in histological and morphological changes of articular cartilage, very similar to that observed in human osteoarthritis patients.

animal

Male Wistar rats (Janview, France) weighing 170-200 g were used at the start of the study. Animals were housed in groups (3 per cage) in rooms of controlled temperature (21-22 ° C.) and inverted light-dark cycles (12 hours / 12 hours) and made available to feed and food as desired.

Induction of Osteoarthritis

Osteoarthritis was induced by intraarticular injection with 50 μl of 3 mg monosodium iodoacetate (MIA) (Sigma) via intrapatellar ligament of the right knee. Control rats were injected with the same amount of saline. In this model, significant inflammation of the lubricating joint was observed up to 5 days after iodoacetate injection. The overall health of the animals was monitored. No signs of pain were observed.

histology

At day 3, 7 and 14, respectively, after iodoacetate treatment, 4 animals were sacrificed for histological studies. Knees were collected and fixed overnight with 10% formalin followed by decalcification with 10% formic acid for 72 hours and embedded in paraffin. 10 μm thick sections were prepared every 250 μm. Hematoxylin / eosin staining was performed to assess the degree of inflammatory infiltrae in joints and surrounding tissues, and safranin-O tests were performed to measure cartilage degeneration.

Assessing the Effect of Compounds on Nociception

In the first experiment, the iodoacetate-treated rats were randomly grouped into six experimental groups (12 per group) and the following treatments were performed on the day of pain assessment (day 3, day 7 and day 14 after iodoacetate treatment): (Po = per os , sc = subcutaneous):

Brine (vehicle) p.o. injection;

P.o. of 3 mg / kg lacosamide. injection;

P.o. of 10 mg / kg lacosamide. injection;

P.o. of 30 mg / kg lacosamide. injection;

S. Of 3 mg / kg morphine. c. injection.

Diclofenac (30 mg / kg, s.c.) was tested in separate experiments almost simultaneously under the same conditions by the same researchers. 45 minutes prior to pain assessment in the control group (control) not treated with iodoacetate, p.o. Injection was performed. Lacosamide, diclofenac and morphine were injected 60 minutes before conducting the behavioral test. Each group was examined blindly.

Assessment of tactile allodynia and mechanical hyperalgesia

To test tactile allodynia, rats were placed on a metallic grid floor. A nociceptive test was performed by inserting von Frey filament (Bioseb, France) through the grid bottom and applying it to the flat surface of the hind paw. The test consisted of several applications of different Von Frey fibers (frequency of about 1 Hz). The von Frey fibers were applied from 10 g to 100 g of filaments. When the animal removed the hind paw, the test was stopped immediately and the filament number indicating the paw withdrawal threshold was recorded.

To test mechanical hyperalgesia, nociceptive flexion using a Randall-Selitto paw pressure device (Bioseb, France), which applies a linearly increasing mechanical force on the dorsal back of the rat reflexe) was quantified. The foot retraction threshold was defined as the force with which the rat withdrew his foot. Cutoff pressure was set at 250 g.

Drugs 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 performed at a dose of 1 ml / kg.

Data analysis and statistics

ANOVA and subsequent post-hoc analysis (Dunnett's test) were used to compare the behavioral data of the groups at each individual time point.

result

The pathological condition of the knee was assessed on Days 3, 7 and 14 after intra-knee injection of iodoacetate. On day 3 there was a significant initial inflammatory response. This inflammation is characterized by proteinaceous edema fluid with infiltrating macrophages, neutrophils, plasma cells and lymphocytes and swelling of the lubricating membrane which is likely to be caused by fibrin. Cartilage was still intact. On day 7, most of the inflammation in the synovial membrane and surrounding tissues disintegrated. On day 14, proteoglycan loss was observed throughout the thickness of the cartilage. The synovial membrane appeared normal and did not contain inflammatory cells.

Tactile allodynia, tested with Von Frey fibers, was assessed on Days 3, 7, and 14 in iodoacetate-treated rats compared to control rats. Treatment with lacosamide (30 mg / kg) and morphine (3 mg / kg) improved tactile allodynia in iodoacetate-treated rats on days 3 (FIG. 5A) and 7 (FIG. 5B), At day 14 (FIG. 5C) it was not, and lower doses of lacosamide showed a trend for such improvement. Diclofenac (30 mg / kg) had no effect on tactile allodynia on Day 3 (FIG. 6A), Day 7 (FIG. 6B) or Day 14 (FIG. 6C).

There was significant mechanical hyperalgesia, as evidenced by the reduction in paw pressure withdrawal threshold in iodoacetate / vehicle treated animals compared to control / vehicle treated animals. Treatment of iodoacetate-treated rats with 3 mg / kg of lacosamide, 3 mg / kg of morphine and 30 mg / kg of diclofenac in each case compared to iodoacetate / vehicle treated animals on Day 3 (FIGS. 7A, 8A). An increase in foot pressure withdrawal threshold was induced. On day 7, all doses tested (3, 10 and 30 mg / kg) of lacosamide, morphine and diclofenac alleviated mechanical hyperalgesia, respectively (FIGS. 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 (FIGS. 7C, 8C). Interestingly, in iodoacetate-treated animals, mechanical hyperalgesia developed on day 3, lasting more than 14 days, in contrast to the more prominent tactile allodynia during the early stages of osteoarthritis onset, which was 14 days after iodoacetate-treated animals. It reflects the ongoing progression of pain sensitization based on different molecular mechanisms over days.

The results show that lacosamide inhibits mechanical hyperalgesia during the post-inflammatory period, indicating the efficacy of lacosamide in treating non-inflammatory osteoarthritis pain.

Example 3

This example describes the use of lacosamide in combination with gabapentin and lacosamide alone in the rat formalin foot test (late), which detects analgesic activity, as described in Wheeler-Aceto & Cowan (1991) Psychopharmacology 104: 35-44. Explain the research that shows the effect.

Materials and methods

Rats were injected intraplantar with 5% formalin (50 μl) in the posterior left foot. This treatment induces a recognizable flinching and licking response of the treated paws in control animals. The number of withdrawals was counted for 15 minutes, beginning 20 minutes after injection of formalin. The time taken to lick the affected foot was also recorded.

Male Rj: Wistar (Han) rats with 100-130 g body weight at the start of the experiment were studied in groups of 10 rats per group. The test was performed blindly.

Lacosamide (20 mg / kg), Gabapentin (50 and 100 mg / kg), a combination of Lacosamide (20 mg / kg) and Gabapentin (50 and 100 mg / kg), and vehicle 10 minutes injection of formalin Prior to intraperitoneal (ip) administration.

result

The test results are shown in Table 3 (number of withdrawal) and Table 4 (licking time).

Table 3. Effect on the number of withdrawal of lacosamide, gabapentin and combination

Table 4. Effect on Licking Time of Lacosamide, Gabapentin, and Combinations

NS = not significant; * = p <0.05; ** = p <0.01; *** = p <0.001

(a): compared to vehicle control

(b): relative to appropriate dose of lacosamide alone

(c): gabapentin alone at a suitable dosage

#: Missing value (1/10)

Lacosamide alone at 20 mg / kg tended to reduce the number of flinch by 33% compared to the vehicle control. In addition, this tended to reduce the time spent licking by 34% compared to vehicle control (p = 0.0962).

Gabapentin alone at 50 and 100 mg / kg reduced the number of withdrawals to 24% and 31%, respectively, but not significantly, compared to the vehicle control. Gabapentin reduced dose-dependent time spent licking by 28% (50 mg / kg) and 60% (100 mg / kg) and significantly reduced even at 100 mg / kg (p <0.05).

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

Example 4

This example describes a study showing the effect of lacosamide alone and in combination with morphine in the rat formalin foot test (late), described in Wheeler-Aceto & Cowan (1991) described above.

Materials and methods

The test method was similar to Example 3. Lacosamide (10 and 20 mg / kg), morphine (2 and 4 mg / kg), a combination of lacosamide (10 and 20 mg / kg) and morphine (2 and 4 mg / kg), and vehicle Administration was intraperitoneally 10 minutes before injection of formalin.

result

Test results are shown in Table 5 (number of withdrawal) and Table 6 (Lick time).

Table 5. Effect on the number of withdrawals of lacosamide, morphine and combination

Table 6. Effect on lick time of lacosamide, morphine and combination

NS = no significance; * = p <0.05; ** = p <0.01; *** = p <0.001

(a): compared to vehicle control

(b): relative to appropriate dose of lacosamide alone

(c): morphine alone at a suitable dosage

Lacosamide alone at 10 and 20 mg / kg did not significantly affect the number of withdrawals compared to vehicle control (22% increase and 35% decrease, respectively), but the decreasing trend at 20 mg / kg approached statistical significance ( p = 0.0961). Lacosamide reduced dose-dependent time spent licking by 28% (p <0.05) at 10 mg / kg and 56% (p <0.001) at 20 mg / kg.

Morphine alone at 2 and 4 mg / kg dose-dependently reduced the number of withdrawals and the time spent licking compared to the vehicle control. However, this effect did not reach statistical significance.

10 mg / kg lacosamide in combination with 4 mg / kg morphine clearly reduced 86% withdrawal compared to vehicle control (p <0.001) and reduced lick time by 48% (p <0.01) But not reduced when combined with 2 mg / kg morphine. The effect on the number of withdrawals of 10 mg / kg lacosamide in combination with 4 mg / kg morphine was significantly more pronounced than the effect of lacosamide alone at the same dose (p <0.001), but the time spent on licking Not so.

20 mg / kg of lacosamide in combination with morphine 2 and 4 mg / kg clearly showed dose-dependent number of withdrawals 70% (p <0.01) and 87% (p <0.001), respectively, compared to vehicle control. Reduced. The combination reduced 69 and 94% of the time spent licking clearly and dose-dependently, respectively (p <0.001). The effect on the number of times withdrawal and the time spent on lickin of 20 mg / kg lacosamide in combination with morphine was the same except for the time spent on lick in the 2 mg / kg dose of morphine. It was much more pronounced than the effect of the amount of lacosamide alone (p <0.05 or p <0.01).

Example 5

This example describes a study showing the effect of lacosamide alone and in combination with the antidepressant duloxetine in the rat formalin foot test (late), described in Wheeler-Aceto & Cowan (1991) described above.

Materials and methods

The test method was similar to Example 3. Lacosamide (10 and 20 mg / kg), duloxetine (8 mg / kg), a combination of lacosamide (10 mg / kg) and duloxetine (8 mg / kg), and vehicle 10 minutes injection of formalin Prior to intraperitoneal administration.

result

The test results are shown in Table 7 (number of withdrawal) and Table 8 (lick time).

Table 7. Effect on the number of withdrawals of lacosamide, duloxetine and combinations

Table 8. Effects on Lick Time of Lacosamide, Duloxetine, and Combinations

NS = no significance; * = p <0.05; ** = p <0.01; *** = p <0.001

(a): compared to vehicle control

(b): relative to appropriate dose of lacosamide alone

(c): duloxetine alone at a suitable dosage

10 mg / kg of lacosamide alone tended to decrease the time spent licking, but did not have a significant effect (30% reduction, p = 0.00538).

Duloxetine 8 mg / kg alone did not have a definite effect.

10 mg / kg of lacosamide in combination with 8 mg / kg of duloxetine significantly reduced the number of withdrawals by 31% compared to the vehicle control (p <0.05). The combination reduced the time spent licking by 63% (p <0.001). The effect on the number of withdrawals and the time spent licking of lacosamide in combination with duloxetine was much more pronounced than the effect of lacosamide alone (p <0.05 to p <0.01).

Example 6

This example describes a study demonstrating the effects of lacosamide alone and in combination with memantine, an NMDA receptor antagonist, in the rat formalin foot test (late), described in Wheeler-Aceto & Cowan (1991), described above. .

Materials and methods

The test method was similar to Example 3. Lacosamide (10 and 20 mg / kg), memantine (4 and 8 mg / kg), a combination of lacosamide (10 and 20 mg / kg) and memantine (4 and 8 mg / kg), and vehicle Was administered intraperitoneally 10 minutes before injection of formalin.

result

Test results are shown in Table 9 (number of withdrawal) and Table 10 (Lick time).

Table 9. Effect on the number of withdrawals of lacosamide, memantine and combination

Table 10. Effect on lick time of lacosamide, memantine and combination

NS = no significance; * = p <0.05; ** = p <0.01; *** = p <0.001

(a): compared to vehicle control

(b): relative to appropriate dose of lacosamide alone

(c): memantine alone at a suitable dosage

#: Missing value (1/10)

Lacosamide alone at 10 mg / kg and 20 mg / kg reduced the number of withdrawals by 31% and 48%, respectively, in a dose-dependent manner compared to vehicle control, and significantly decreased at 20 mg / kg (p <0.05). . Lacosamide clearly reduced the time spent licking at 20 mg / kg (52% reduction, p <0.01) but did not have a clear effect at 10 mg / kg.

Memantine alone at 4 and 8 mg / kg did not significantly affect the number of withdrawals compared to the vehicle control. Memantine increased the time spent on dose-dependent licking (25% increase, p = 0.0537 and 35% increase, p <0.05).

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

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

Example 7

This example describes a study showing the effect of lacosamide alone and in combination with naproxen in the rat formalin foot test (late), described in Wheeler-Aceto & Cowan (1991) described above.

Materials and methods

The test method was similar to Example 3. Lacosamide (10 and 20 mg / kg), naproxen (8 and 16 mg / kg), a combination of lacosamide (10 and 20 mg / kg) and naproxen (8 and 16 mg / kg), and the vehicle is formalin Administration was intraperitoneally 10 minutes before injection. Morphine (8 mg / kg) was included in the comparative treatment.

result

Test results are shown in Table 11 (number of withdrawal) and Table 12 (licking time).

Table 11.Effect on Number of Withdrawals of Lacosamide, Naproxen and Combinations

Table 12. Effect on lick time of lacosamide, naproxen and combinations

NS = no significance; * = p <0.05; ** = p <0.01; *** = p <0.001

(a): compared to vehicle control

(b): relative to appropriate dose of lacosamide alone

(c): naproxen alone at a suitable dosage

#: Missing value (1/10)

Lacosamide alone at 10 mg / kg and 20 mg / kg did not significantly affect the number of withdrawals compared to the vehicle control. Lacosamide alone reduced the time spent licking at 20 mg / kg by 59% (p <0.001), but did not have a clear effect at 10 mg / kg.

Naproxen alone at 8 and 16 mg / kg did not significantly affect the number of withdrawals and the time spent licking compared to the vehicle control.

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

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

8 mg / kg of morphine alone administered under the same experimental conditions eliminated the time spent withering and licking compared to vehicle control (p <0.001).

In summary, Examples 3 to 7 show synergistic effects between lacosamide and compounds selected from gabapentin, duloxetine, morphine, naproxen and memantine.

All patents and documents cited herein are hereby incorporated by reference in their entirety.

The words "comprise", "comprising", and "comprising" are interpreted inclusively, not exclusively.

Subjects of the invention are the following embodiments:

Item 1 has the following formula (I):

In the above,

R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl or lower cycloalkyl lower alkyl, R is Unsubstituted or substituted with one or more electron-withdrawing groups and / or one or more electron-donating groups;

R ₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, lower alkyl heterocyclic, heterocyclic, lower cycloalkyl, or lower cycloalkyl lower alkyl, Unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups;

R ₂ and R ₃ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower Cycloalkyl lower alkyl, or R ₂ and R _3, are each independently ZY unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups;

Z is 0, S, S (O) _a , NR ₄ , NR ′ ₆ , PR ₄ or a chemical bond;

Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, or lower alkyl heterocyclic, unsubstituted or one or more electron withdrawing groups and May be substituted with one or more electron donating groups, Y is halo, Z is a chemical bond, or

ZY taken together is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ , OPR ₄ R ₅ , PR ₄ OR ₅ , SNR ₄ R ₇ , NR ₄ SR ₇ , SPR ₄ R ₅ , PR ₄ SR ₇ , NR ₄ PR ₅ R ₆ , PR ₄ NR ₅ R ₇ , N ⁺ R ₅ R ₆ R ₇ ,

인 조건을 만족하고;

Satisfies the condition of;

R ' ₆ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl, unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups;

R ₄ , R ₅ and R ₆ are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, each independently unsubstituted or one or more electron withdrawing groups and / or one or more electron balls Substituted here;

R ₇ is R ₆ , COOR ₈ , or COR ₈ and is unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups;

R ₈ is hydrogen, lower alkyl, or aryl lower alkyl and is substituted with one or more electron withdrawing groups and / or one or more electron donating groups; And

n is 1-4; And

a is a first agent comprising a compound of formula 1-3 or a pharmaceutically acceptable salt thereof, and pain caused by a pain or medical condition associated with a medical condition as compared to the compound of formula (I) alone A therapeutic agent combination comprising a second agent in combination with the first agent to provide increased treatment, wherein the second agent comprises one or more drugs that are not compounds of formula (I).

Item 2 The compound according to item 1, wherein in the compound of formula (I) present in the first agent, one or both of R ₂ and R ₃ are furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, Dazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothier Nil, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, furinyl, indolinyl, pyrazolindinyl, imidazolinyl, imidazolinedinyl, pyrrolidinyl, furazanyl, N-methyl Indolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl and, if present in the heterocycle, N-oxides Heterocycle is independently selected from the group, said heterocycle is independent In unsubstituted or one or more electron-withdrawing group and / or one or more electron-donor would substituted by a combination thereof.

Item 3 The item of item 1, wherein the first agent has the formula (III)

Wherein R ₄ is hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, carboxy, formyl, carboxamido, aryl, quaternary ammonium, haloalkyl, aryl alkanoyl, hydroxy, alkoxy, amino, alkyl One or more substituents independently selected from the group consisting of amino, 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

R ₁ is an alkyl or a combination thereof comprising a pharmaceutically acceptable salt thereof.

Item 4 The compound according to item 3, wherein the compound of formula (III) or a salt thereof

R ₄ is one or more substituents independently selected from the group consisting of hydrogen and halo,

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

R ₁ is lower alkyl.

Item 5 The compound according to item 4, wherein the compound of formula (III) or a salt thereof

R ₃ is lower alkoxy-lower alkyl.

Item 6 The compound of item 3, wherein the compound of formula (III) or a salt thereof

R ₄ is hydrogen,

R ₃ is methoxymethyl, and

R ₁ is methyl.

Item 7 The method according to item 3, wherein the first agent

(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-phenylglycinebenzylamide;

D-1,2- (N, O-dimethylhydroxyamino) -2-acetamide acetic acid benzylamide; And

Combination comprising a compound selected from the group consisting of D-1,2- (O-methylhydroxyamino) -2-acetamide acetate benzylamide.

Item 8 The combination according to item 3, wherein the compound of formula (III) is substantially pure enantiopure.

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

Item 10 The combination of item 9, comprising lacosamide in an amount that provides a dosage of about 100 to about 6000 mg / day.

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

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

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

Item 14 The combination according to item 1, wherein the medical condition is arthritis.

Item 15 The combination according to item 14, wherein the second agent comprises one or more anti-arthritis agents.

Item 16 The combination according to item 15, wherein the one or more anti-arthritis agents is independently selected from the group consisting of opiate and non-opioid analgesics, steroidal and non-steroidal anti-inflammatory agents, DMOAD and DMARD.

Item 17 The method according to item 15, wherein the second agent is acetaminophen, alfentanil, allylprodine, alphaprodine, anilredine, benzylmorphine, benzitramide, buprenorphine, butorpanol, claw Nitagen, codeine, cyclazosin, desormorphine, dextromoramide, dextropropoxyphene, dezosin, diazpromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimefetanol, Dimethyl thiambutene, dioxafetyl butyrate, dipipanone, eftazosin, etoheptazine, ethylmethyl thiambutene, ethyl morphine, etonitogen, fentanyl, heroin, hydrocodone, hydromorphone, hydroxy pettidine , Isometadon, ketobemidone, levalorphan, levorpanol, levofenacyl-morphan, lofentanil, meperidine, mephtazinol, metazosin, methadone, methopone, morphine, miropin, nalbuphine, nalofin Lepin, Narcein, Nicomorphine, Norreborg Ol, normethadon, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazosin, phenadoxin, phenazorcin, phenomorphan, phenoferidine, phinodine, pyritramide, From the group consisting of propheptazine, promethol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, NO-naproxen, NCX-701, ALGRX-4975, and pharmaceutically acceptable salts thereof One or more analgesics selected.

Item 18 The method according to item 15, wherein the second agent is alclomethasone, amcinolone, betamethasone, betamethasone 17-valerate, clobetasol, clobetasol propionate, clocortolone, cortisone, Dehydrotestosterone, deoxycorticosterone, desonide, desoximetasone, dexamethasone, dexamethasone 21-isonicotinate, diflorason, fluorinide, fluorine Sinolone, fluorometholone, fluandrenolide, fluticasone, hacinonoid, halobetasol, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone hemisuccinate, hydrocortisone 21-lysinate, hydrocortisone sodium succinate, isoflupredone, isoflupredone acetate, methylprednisolone, methyl Dinisolone acetate, Methylprednisolone sodium succinate, Methylprednisolone sulphateate, mometasone, prednicabate, prednisolone, prednisolone acetate, prednisolone hemisuccinate, prednisolone sodium succinate, prednisolone sodium succinate, prednisolone valericate And one or more steroidal anti-inflammatory agents selected from the group consisting of prednisone, triamcinolone, triamcinolone acetonide, and pharmaceutically acceptable salts thereof.

Item 19 The method according to item 15, wherein the second agent is salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, olsalazine, salsalate, sulfasalazine, indomethacin, etodolak, sulindac, Etopenic acid, meclofenamic acid, mefenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, acemethacin, alclofenac, clidanac, diclofenac, fenclofenac, pentiazac, furofenac, Bufenac, isoxepac, ketorolalac, oxipinac, thiopinac, tolmetin, zidomethacin, zomepirac, alminopropene, benoxapropene, bunoxapropene Bucloxic acid, carpropene, fenbufen, phenopropene, flupropene, flubiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirpro Pen, pranopropene, suprofen, thiapropene acid, thioxapropene, ampyroxoxycam, cinnaxicam, drock Calm, Lormoxicam, Meloxycham, Piroxycham, Sudoxicam, Tenoxycam, Aminopyrin, Antipyrin, Apazone, Dipyrone, Oxyfenbutazone, Phenylbutazone, Nabumethone, Nimesulide, Pro A combination comprising one or more non-steroidal anti-inflammatory agents selected from the group consisting of proguazone, MX-1094, lycopene, and pharmaceutically acceptable salts thereof.

Item 20 The method according to item 15, wherein the second agent is celecoxib, deracoxib, valdecoxib, parecoxib, rofecoxib, etoricoxib, lumiracoxib, PAC-10549, simicoxib, GW -406381, LAS-34475, CS-502 and combinations comprising at least one COX-2 selective inhibitor selected from the group consisting of pharmaceutically acceptable salts thereof.

Item 21 The method according to item 15, wherein the second agent is methotrexate, diacerane, glucosamine, chondroitin sulfate, anakinra, MMP inhibitor, doxycycline, minocycline, misprostole, proton pump inhibitor, non-acetylated Salicylate, tamoxifen, prednisone, methylprednisolone, polysulfated glycosaminoglycan, calcitonin, alledronate, risedronate, zoledronic acid, teriparatide, VX-765, pranacaic acid , SB-462795, CPA-926, ONO-4817, S-3536, PG-530742, CP-544439, and one or more DMOADs selected from the group consisting of pharmaceutically acceptable salts thereof.

Item 22 The item according to item 15, wherein the second agent is etanercept, adalibumab, infliximab, IL-1 receptor antagonist, prednisone, methylprednisolone, penicillamine, Hydroxychloroquine sulfate, chlorambucil, cyclophosphamide, leflunomide, cyclosporin, auranopine, aurothioglucose, azathioprine gold, sodium thiomalate, methotrexate, cyclophosphamide , Minocycline, sulfasalazine, avatacept, rituximab, busylamine, chloroquine, hydroxychloroquine, robbenzit, misoprostol, and pharmaceutically acceptable salts thereof A combination comprising one or more DMARDs selected.

Item 23. The combination according to item 14, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat arthritis conditions and / or associated pain thereof.

Item 24 The combination according to item 14, wherein the second agent comprises an anti-inflammatory agent in an amount effective to treat inflammation occurring in arthritis conditions.

Item 25 The method according to item 14, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat non-inflammatory and inflammatory components of pain associated with or caused by the arthritis condition. Combination.

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

 Item 27 The combination of item 26, wherein the increased treatment is treatment of non-inflammatory pain.

Item 28 The combination of item 26, wherein the second agent comprises one or more drugs independently selected from the group consisting of analgesics, anticonvulsants, antidepressants and NMDA receptor antagonists.

Item 29. The method according to item 26, wherein the second agent is acetaminophen, alfentanil, allylprodine, alphaprodine, aniliredine, benzylmorphine, benzitramide, buprenorphine, butorpanol, claw Nitagen, codeine, cyclazosin, desormorphine, dextromoramide, dextropropoxyphene, dezosin, diazpromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimefetanol, Dimethyl thiambutene, dioxafetyl butyrate, dipipanone, eftazosin, etoheptazine, ethylmethyl thiambutene, ethyl morphine, etonitogen, fentanyl, heroin, hydrocodone, hydromorphone, hydroxy pettidine , Isometadon, ketobemidone, levalorphan, levorpanol, levofenacylmorphan, lofentanil, meperidine, meftazinol, metazosin, methadone, methopone, morphine, miropin, nalbuphine, nallopine , Narcein, Nicomorphine, Norreborg , Normetadon, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazosin, phenadoxin, phenazosin, phenomorphan, phenoferidine, phinodine, pyritramide, pro Selected from the group consisting of heptazine, promethol, properidine, propyram, propoxyphene, sufentanil, tilidine, tramadol, NO-naproxen, NCX-701, ALGRX-4975, and pharmaceutically acceptable salts thereof A combination comprising one or more analgesics.

Item 30 The method according to item 26, wherein the second agent is acetylpheneturide, albutoin, aminoglutetimide, 4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate , Carbamazepine, pyrromid, clomeththiazole, clonazepam, decimemid, dietadione, dimethadione, doxenitoin, etorobab, etadione, etosuccimid, etootoin ), Felbamate, fluoresone, phosphenitoin, gabapentin, ganoxolone, lamotrigine, levetiracetam, lorazepam, mefenytoin, mepobarbital, metabital, methetoin, metsuximide ), Midazolam, narcobarbital, nitrazepam, oxcarbazepine, paramethadione, phenacemide, penetharbital, phenturide, phenobarbital, pensuccimid, phenylmethylbarbituric acid, phenytoin, phenethylate , Pregabalin, primidone, pro Beads, remasemide, lufinamide, suclofenide, sulthiame, talampanel, tetratoin, tiagabine, topiramate, trimetadione, valproic acid, valpromide, bivitatrin, johnny A combination comprising one or more anticonvulsants selected from the group consisting of samides, and pharmaceutically acceptable salts thereof.

Item 31 The item according to item 26, wherein the second agent is adinazolam, adrafinyl, aminephthine, amitriptyline, amitriptylinoxide, amoxapine, befloxatone, bupropion, butacetin, butleaf Tilin, caroxazone, citalopram, clomipramine, cotinine, demexiptiline, decipramine, dibenzepine, dimethacrine, dimethazane, dioxadol, dotipine, doxepin, Duloxetine, etoferidone, phenoxetine, phencarmine, fenpentadiol, fluasizin, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, imipramine, imipramine N-jade Seeds, indalpins, indeloxazines, ifrindol, ifroclosidide, inproniazide, isocarboxides, levopacetoferran, lofepramine, maprotilin, medipoxamine, melitracene, metafrafra Min, metallindol, Mianserine, Milnasifran, Minafrin, Mirtazapine, Moclovemi , Nefazodone, nepofam, nialamide, nomifensin, nortriptyline, oxycipylin, octamoxin, opipramol, oxaflozan, oxytriphtan, oxyfertin, paroxetine, phenelzin , Fiberalline, pizotylline, prolinetan, propipine, protriptiniline, pyrisuccideanol, quinupramine, reboxetine, ritanserine, roxindole, rubidium chloride, sertraline, sulfi Reed, ballistican, thiazime, tozalinone, thianephthine, tophenasin, toloxatone, tranilcipromin, trazodone, trimipramine, tryptophan, venlafaxazine, viloxazine, gimel Dean and one or more antidepressants selected from the group consisting of pharmaceutically acceptable salts thereof.

Item 32. The method according to item 26, wherein the second agent is amantadine, D-AP5, aftiganel, CPP, dexanabinol, dextromethorphan, dextrosepropoxyphene, 5,7-dichlorokinuric acid (5 , 7-dichlorokynurenic acid), gavestinel, fendopril, ketamine, ketobemidone, lycostinel, LY-235959, memantine, methadone, MK-801, penciclidine, remasemide, selpotel, til Combination comprising at least one NMDA receptor antagonist selected from the group consisting of retamine, and pharmaceutically acceptable salts thereof.

Item 33 The combination according to item 1, wherein the first agent and the second agent are provided in separate dosage forms for administration by the same route or different routes at the same time or at different time points.

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 claim 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 drug dosage form comprising a combination of item 1 and one or more pharmaceutically acceptable excipients.

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

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

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

Item 41 The method according to item 40, wherein the medical condition or pain associated therewith is acute inflammatory pain, acute pain, alcoholism-associated or alcoholism-induced neuropathic pain, allodynia, arthritis state, back pain, cancer-related neuropathic pain, Central neuropathic pain, chronic headache, chronic inflammatory pain, chronic pain, chronic pain caused by peripheral nerve damage, diabetes-associated or diabetes-induced neuropathic pain, diabetic distal sensory neuropathy, diabetic distal sensory polyneuropathy, diabetic Pain, fibromyalgia, headache, hyperalgesia, hyperesthesia, hyperpathia, migraine, myalgia, myofascial pain syndrome, neuralgia, neuroma, non-inflammatory osteoarthritis pain , Non-neoplastic inflammatory pain, neuropathic pain, pain associated with or induced by chemotherapy or radiation therapy, traumatic kidney Pain associated with or induced by injury or compression or traumatic injury to the brain or spinal cord, painful diabetic neuropathy, peripheral neuropathic pain, persistent clinical pain, phantom pain, rheumatism Arthritic pain, secondary inflammatory osteoarthritic pain, trigeminal neuralgia, vascular headache, and combinations thereof.

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

Item 43 A method of treating arthritis condition and / or pain associated therewith comprising administering to a subject a combination of the therapeutic agents of item 15.

Item 44. The method of item 43, wherein the arthritis condition and pain associated therewith are treated.

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

Item 46 The method according to item 45, wherein the lacosamide is administered according to a treatment regime wherein the daily dose is increased until a predetermined daily dose is reached that will be maintained for further treatment.

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

Item 48 The method according to item 47, wherein the lacosamide has a plasma concentration of about 0.1 to about 15 μg / ml (lowest) and about 5 to about 18.5 μg / ml (highest) calculated as an average for the plurality of treated subjects. Administered in an amount to provide a daily dosage effective to provide.

Item 49. The method according to item 43, wherein the arthritis condition is idiopathic osteoarthritis, secondary osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, infectious arthritis, ankylosing spondylitis, neuroarthritis, multiple joint pain ( polyarthralgia), and Sjogren's syndrome, Behcet's syndrome, Reiter syndrome. At least one disease selected from systemic lupus erythematosus, rheumatic fever, gout, pseudogout, Lyme disease, sarcoidosis and arthritis associated with ulcerative colitis.

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

Item 51 The method according to item 43, wherein the arthritis condition comprises rheumatoid arthritis or combustible rheumatoid arthritis.

Claims (55)

  Having the following formula (I):

In the above, R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl or lower cycloalkyl lower alkyl, R is Unsubstituted or substituted with one or more electron-withdrawing groups and / or one or more electron-donating groups; R ₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, lower alkyl heterocyclic, heterocyclic, lower cycloalkyl, or lower cycloalkyl lower alkyl, Unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups; R ₂ and R ₃ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, halo, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower Cycloalkyl lower alkyl, or R ₂ and R _3, are each independently ZY unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups; Z is 0, S, S (O) _a , NR ₄ , NR ′ ₆ , PR ₄ or a chemical bond; Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, or lower alkyl heterocyclic, unsubstituted or one or more electron withdrawing groups and And / or substituted with one or more electron donor groups and Y is halo, Z is a chemical bond, or ZY taken together is NR ₄ NR ₅ R ₇ , NR ₄ OR ₅ , ONR ₄ R ₇ , OPR ₄ R ₅ , PR ₄ OR ₅ , SNR ₄ R ₇ , NR ₄ SR ₇ , SPR ₄ R ₅ , PR ₄ SR ₇ , NR ₄ PR ₅ R ₆ , PR ₄ NR ₅ R ₇ , N ⁺ R ₅ R ₆ R ₇ ,

Satisfies the condition of; R ' ₆ is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl, unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups; R ₄ , R ₅ and R ₆ are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, each independently unsubstituted or one or more electron withdrawing groups and / or one or more electron balls Substituted here; R ₇ is R ₆ , COOR ₈ , or COR ₈ and is unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups; R ₈ is hydrogen, lower alkyl, or aryl lower alkyl and is substituted with one or more electron withdrawing groups and / or one or more electron donating groups; And n is 1-4; And a is a first agent comprising a compound of formula 1-3 or a pharmaceutically acceptable salt thereof, and pain caused by a pain or medical condition associated with a medical condition as compared to the compound of formula (I) alone A therapeutic combination comprising a second agent effective for combining with the first agent to provide increased treatment, wherein the second agent comprises one or more drugs, not a compound of formula (I) ). The compound of formula (I) present in the first agent, wherein one or both of R ₂ and R ₃ are furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imide. Zolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl , Morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, furinyl, indolinyl, pyrazolindinyl, imidazolinyl, imidazolininyl, pyrrolidinyl, furazanyl, N-methylin From the group consisting of N-oxides when N is present in the doryl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, oxetanyl, azetidinyl and heterocycles Heterocycle is independently selected, and said heterocycle is unsubstituted independently Or at least one electron-withdrawing group and / or one or more electron-in the donor will be replaced by a combination thereof. The compound of claim 1, wherein the first agent has the formula (III)

In the above, R ₄ is hydrogen, halo, alkyl, alkenyl, alkynyl, nitro, carboxy, formyl, carboxamido, aryl, quaternary ammonium, haloalkyl, aryl alkanoyl, hydroxy, alkoxy, amino, alkylamino, di At least one substituent independently selected from the group consisting of alkylamino, 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 R ₁ is an alkyl or a combination thereof comprising a pharmaceutically acceptable salt thereof. The compound of claim 3, wherein the compound of formula (III) or a salt thereof R ₄ is one or more substituents independently selected from the group consisting of hydrogen and halo, R ₃ is selected from the group consisting of lower alkoxy-lower alkyl, aryl, N-lower alkoxy-N-lower alkylamino, and N-lower alkoxyamino, and R ₁ is lower alkyl. The compound of formula (III) or a salt thereof according to claim 4, R ₃ is lower alkoxy-lower alkyl. The compound of claim 3, wherein the compound of formula (III) or a salt thereof R ₄ is hydrogen, R ₃ is methoxymethyl, and R ₁ is methyl. The method of claim 3, wherein the first agent is (R) -2-acetamido-N-benzyl-3-methoxypropionamide; (R) -2-acetamido-N-benzyl-3-ethoxypropionamide; O-methyl-N-acetyl-D-serine-m-fluorobenzylamide; O-methyl-N-acetyl-D-serine-p-fluorobenzylamide; N-acetyl-D-phenylglycinebenzylamide; D-1,2- (N, O-dimethylhydroxyamino) -2-acetamide acetic acid benzylamide; And Combination comprising a compound selected from the group consisting of D-1,2- (O-methylhydroxyamino) -2-acetamide acetate benzylamide. The combination according to any one of claims 3 to 7, wherein the compound of formula (III) is substantially pure enantiopure. The combination of claim 3, wherein the first agent comprises lacosamide. The combination of claim 9 comprising lacosamide in an amount that provides a dosage of about 100 to about 6000 mg / day. The combination of claim 9 comprising lacosamide in an amount that provides a dosage of about 200 to about 1000 mg / day. The combination of claim 9 comprising lacosamide in an amount that provides a dosage of about 300 to about 600 mg / day. The combination of any one of the preceding claims, wherein said second agent comprises one or more drugs independently selected from the group consisting of analgesics, anticonvulsants, antidepressants and NMDA receptor antagonists. The method of claim 13, wherein the second agent is acetaminophen, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, benzitramide, buprenorphine, buttorpanol, clonita Zen, codeine, cyclazosin, desormorphine, dextrosemoramide, dextropropoxyphene, dezosin, diopramide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxaldol, dimefetanol, dimethyl Thiabutene, dioxafetyl butyrate, dipipanone, eftazosin, etoheptazine, ethylmethylthiambutene, ethylmorphine, etonitogen, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypettidine, Isometadon, Ketobemidone, Levalorphan, Levorpanol, Levofenacyl-Morpan, Lofentanil, Meperidine, Mephtazinol, Metazosin, Methadone, Metophon, Morphine, Miropine, Nalbuphine, Nalopin , Narcein, Nicomorphine, Norreborganol, Nord Methadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazosin, phenadoxone, phenazosin, phenomorphan, phenoferidine, piminodine, pyritramide, proheptazine Selected from the group consisting of, promethol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, naproxen, NO-naproxen, NCX-701, ALGRX-4975, and pharmaceutically acceptable salts thereof A combination comprising one or more analgesics. The method of claim 13, wherein the second agent is acetylpheneturilide. Albuto Phosphorus, Aminoglutetimide, 4-Amino-3-hydroxybutyric Acid, Atrolactamide, Beclamide, Buramate, Carbamazepine, Cyramide, Chlomethiazole, Clonazepam, Decimemid , Diethadione, dimethadione, doxenitoin, etherobarb, etadione, etosuccimid, etotoin, felbamate, fluoresone, phosphphenytoin, gabapentin, ganaxolone, lamotrigine , Levetiracetam, lorazepam, mefenitoin, mepobarbital, metabital, metetoin, metsuccimid, midazolam, narcobarbital, nitrazepam, oxcarbazepine, paramethadione, phenacemid, peneta Lebital, pheneturide, phenobarbital, pensuccimid, phenylmethylbarbituric acid, phenytoin, phenethylate, pregabalin, primidone, progabide, remasemid, lupinamide, suclufenide, sulphate Sulthiame, talampanel, tetratoin, tiaga Combination, topiramate, tri meta-dione, Valproic acid, valproic imide ratio trim bar, comprises four Johnny imide and at least one anticonvulsant is selected from the group consisting of pharmaceutically acceptable salts. The method according to any one of claims 13 to 15, wherein the second agent is adinazolam, adrafinyl, aminephthine, amitriptyline, amitriptylinoxide, amoxapine, befloxatone, Bupropion, butetacetin, butyriftyline, caroxazone, citalopram, clomipramine, cotinine, demexiptiline, decipramine, dibenzepine, dimethacrine, dimethazane, dioxadol, Dothiepine, doxepin, duloxetine, etoferidone, pemoxetine, phencarmine, fenpentadiol, fluasigin, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, imipramine , Imipramine N-oxide, indalpine, indel oxazine, ifrindol, iproclozide, iproniazide, isocarboxide, levopacetoferan, lofepramine, maprotiline, medipoxamine , Melitracene, metapramine, methalindol, myan serine, milnacipran, minafrine, mirta Pin, moclobemid, nefazodone, nepofam, nialamide, nomiphenine, nortriptyline, oxycipyline, octamoxin, opipramol, oxaflozan, oxytriptan, oxyfer Tin, paroxetine, phenelzin, fiberalline, pizotillin, prolinetan, propizepine, protriphthylline, pyrisuccideanol, quinupramine, reboxetine, ritataneline, roxindole, rubidium chloride , Sertraline, sulfide, ballistic spiron, thiazime, tozalinone, thianephthine, tofenacin, toloxatone, tranilcipromine, trazodone, trimimipramine, tryptophan, venlafaxazine, biljade Combination comprising at least one antidepressant selected from the group consisting of viloxazine, gimeldine and pharmaceutically acceptable salts thereof. The method according to claim 13, wherein the second agent is amantadine, D-AP5, aftiganel, CPP, dexanabinol, dextromethorphan, dextrosepropoxyphen, 5, 7-dichlorokinuric acid, gavestinel, ifendorfril, ketamine, ketobemidone, lycostinel, LY-235959, memantine, methadone, MK-801, penciclidine, remasemide, selpotel, tileta And one or more NMDA receptor antagonists selected from the group consisting of Min, and pharmaceutically acceptable salts thereof. The method of claim 1, wherein the second agent comprises one or more drugs independently selected from the group consisting of gabapentin, duloxetine, morphine, naxproxen, and memantine. Combination. The combination of claim 18, wherein the second agent comprises one or more drugs independently selected from the group consisting of duloxetine, morphine, naproxen, and memantine. 20. The combination according to any one of claims 1 to 19, wherein said medical condition involves non-inflammatory pain or has non-inflammatory pain as a symptom thereof. The combination of claim 1, wherein the pain associated with the medical condition comprises non-inflammatory pain. 22. The combination according to any one of the preceding claims, wherein said medical condition is an arthritic condition and / or associated pain thereof. The combination of claim 22, wherein the arthritis 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 arthritis conditions and / or associated pain thereof. 25. The absolute amount of any of claims 22-24, wherein the first agent and the second agent are effective to treat non-inflammatory and inflammatory components of pain associated with or caused by the arthritis condition. And combinations present in relative amounts. 26. The combination of any one of claims 22-25, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat non-inflammatory pain associated with arthritis conditions. 27. The combination of any one of claims 22-26, wherein the first agent and the second agent are present in absolute and relative amounts effective for treating non-inflammatory osteoarthritis pain. 26. The combination of any one of claims 22-25, wherein the first agent and the second agent are present in absolute and relative amounts effective for treating inflammatory pain associated with arthritis conditions. 29. The combination of any one of claims 22-25 and 28, wherein the first agent and the second agent are present in absolute and relative amounts effective to treat inflammatory osteoarthritis pain. The combination of claim 27 or 29, wherein the osteoarthritis pain is associated with cartilage degeneration, structural bone changes, and / or vascularization of areas of osteoarthritic remodeling. 31. The method according to any one of claims 22 to 30, wherein the arthritic condition is idiopathic osteoarthritis, secondary osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, infectious arthritis, ankylosing spondylitis, Neuroarthritis, polyarthralgia, and Sjogren's syndrome, Behcet's syndrome, Reiter syndrome. One or more diseases selected from systemic lupus erythematosus, rheumatic fever, gout, pseudogout, Lyme disease, sarcoidosis and arthritis associated with ulcerative colitis. 32. The combination of any one of claims 22-31, wherein the arthritic condition comprises rheumatoid arthritis or combustible rheumatoid arthritis. 20. The combination according to any one of the preceding claims, wherein said medical condition is pain in painful diabetic neuropathy. The combination of claim 33, wherein the painful diabetic neuropathy is painful diabetic neuropathy is diabetic distal sensory polyneuropathy. 35. The method of claim 33 or 34, wherein the first agent and the second agent are in combination to average daily pain, overall pain, present pain intensity, pain. Pain with sleep, subject's perception of disturbance of general activity by pain, patient's overall impression of pain change, subject's perception of different neuropathic pain quality, quality of life and painlessness The combination effective for the treatment of an aspect of pain selected from the group consisting of the number of days. 36. The combination of any one of claims 33 to 35, wherein the painful diabetic neuropathy is associated with type I or type II diabetes. 37. The method of any one of claims 1 to 36, wherein the second agent is present in combination with the first agent in an amount effective to provide increased treatment of pain as compared to the first agent alone. Combination. The method of claim 1, wherein the medical condition or pain associated therewith is acute inflammatory pain, acute pain, alcoholism-associated or alcoholism-induced neuropathic pain, allodynia, arthritis state, low back pain. , Cancer-related neuropathic pain, central neuropathic pain, chronic headache, chronic inflammatory pain, chronic pain, chronic pain due to peripheral nerve damage, diabetes-associated or diabetes-induced neuropathic pain, diabetic distal sensory neuropathy, diabetes Sexual distal polyneuropathy, diabetic pain, fibromyalgia, headache, hyperalgesia, hyperesthesia, hyperpathia, migraine, myalgia, myofascial pain syndrome, neuralgia Or associated with or induced by neuroma, non-inflammatory osteoarthritis pain, non-neuropathic inflammatory pain, neuropathic pain, chemotherapy or radiation therapy Is associated with or induced by pain, traumatic nerve injury or compression or traumatic injury to the brain or spinal cord, painful diabetic neuropathy, peripheral neuropathic pain, persistent clinical pain, or annular pain ( a combination selected from the group consisting of phantom pain, rheumatoid arthritis pain, secondary inflammatory osteoarthritic pain, trigeminal neuralgia, vascular headache, and combinations thereof. The combination of any one of claims 1-38, wherein the first agent and the second agent are provided in separate dosage forms for administration by the same route or different routes at the same time or at different times. 40. The combination of any one of the preceding claims, wherein at least the first agent is provided in a dosage form adapted for oral or parenteral administration. 41. The combination of 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. 42. The combination of any one of the preceding claims, wherein said second agent is orally bioavailable and is provided in a dosage form adapted for oral administration. A pharmaceutical dosage form comprising a combination of claims 1 to 19 and one or more pharmaceutically acceptable excipients. The dosage form of claim 43, wherein the first agent comprises lacosamide. 45. The dosage form of claim 43 or 44 which is adapted for oral or parenteral administration. 20. A method of treating a painful medical condition and / or pain associated therewith in a subject comprising administering to the subject a combination of the therapeutic agents as defined in any one of claims 1 to 19. 47. The method of claim 46, wherein the painful medical condition and / or pain associated therewith is selected from the conditions defined in any one of claims 20-38. 47. The method of claim 46, wherein the medical condition or pain associated therewith is acute inflammatory pain, acute pain, alcoholism-associated or alcoholism-induced neuropathic pain, allodynia, arthritis state, back pain, cancer-related neuropathic pain, central Neuropathic pain, chronic headache, chronic inflammatory pain, chronic pain, chronic pain due to peripheral nerve damage, diabetes-associated or diabetes-induced neuropathic pain, diabetic distal sensory neuropathy, diabetic distal sensory polyneuropathy, diabetic pain , Fibromyalitis, headache, hypersensitivity, tactile hypersensitivity, hyperalgesia, migraine, myalgia, myofascial pain syndrome, neuralgia, neuroma, non-inflammatory osteoarthritis pain, non-neuropathic inflammatory pain, neuropathic pain, chemotherapy or radiation therapy Associated with or induced by pain, traumatic nerve injury or compression, or traumatic injury to the brain or spinal cord Or pain induced thereby, painful diabetic neuropathy, peripheral neuropathic pain, persistent clinical pain, annular pain, rheumatoid arthritis pain, secondary inflammatory osteoarthritis pain, trigeminal neuralgia, vascular headache and combinations thereof How to be. 49. The method of any one of claims 46-48, wherein in said combination, said first agent comprises lacosamide. 50. The method according to any one of claims 46 to 49, wherein the lacosamide is administered according to a treatment regime wherein the daily dose is increased until a predetermined daily dose is reached that will be maintained for further treatment. How to be. 51. The method of any one of claims 46-50, wherein the lacosamide is administered orally. 52. The method according to any one of claims 46 to 51, wherein the lacosamide is calculated as an average for the plurality of treated individuals from about 0.1 to about 15 μg / ml (lowest) and from about 5 to about 18.5 μg / ml. Administered in an amount to provide a daily dosage effective to provide a (maximum) lacosamide plasma concentration. 20. The method of any one of claims 1 to 19 for the manufacture of a medicament for increased prevention, alleviation and / or treatment of pain associated with or caused by a medical condition, compared to the compound of formula (I) alone. Use of a defined combination, wherein the second agent comprises one or more drugs that are not compounds of formula (I). 54. The use of claim 53, wherein said medical condition is selected from the conditions defined in any one of claims 20-38. The use of claim 54, wherein the first agent comprises lacosamide.

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