KR20080038408A - Novel use of peptide compounds for treating muscle pain - Google Patents

Abstract

The present invention is directed to the use of a class of peptide compounds for treating non-inflammatory musculoskeletal pain or/and non-inflammatory osteoarthritic pain.

Description

Novel use of peptide compounds for treating muscle pain

The present invention relates to the use of a group of peptide compounds for the treatment of non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritic pain.

Some peptides are known to exhibit central nervous system (CNS) activity and are useful for the treatment of pre-hepatic and other CNS diseases. Such peptides described in US Pat. No. 5,378,729 have the formula (la):

Formula (Ia)

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, lower cycloalkyl lower alkyl, R is Unsubstituted or substituted with one or more electron withdrawing groups or electron donating groups;

R ₁ is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or electron ball Substituted with an excitation or electron withdrawing group; And

R ₂ and R ₃ are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl Lower alkyl, or R ₂ and R ₃ are ZY, which may be unsubstituted or substituted with one or more electron withdrawing groups or electron donor groups;

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

Y is hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, lower alkynyl, halo, heterocyclic, heterocyclic lower alkyl, Y may be unsubstituted or substituted with an electron donor or electron withdrawing group 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 or PR ₄ SR ₇ , NR ₄ PR ₅ R ₆ or PR ₄ NR ₅ R ₇ ,

인 조건을 만족하며;

Satisfy the condition of;

R ₄ , R ₅ and R ₆ are independently hydrogen, lower alkyl, aryl, aryl lower alkyl, lower alkenyl, or lower alkynyl, wherein R ₄ , R ₅ and R ₆ are unsubstituted or electron withdrawing groups or May be substituted with an electron donating group; And

R ₇ is R ₆ or COOR ₈ or COR ₈ ;

R ₈ is hydrogen or lower alkyl, or aryl lower alkyl, wherein the aryl or alkyl group may be unsubstituted or substituted with an electron withdrawing or electron donor group; And

n is 1-4; And

a is 1-3.

US Pat. No. 5,773,475 also discloses additional compounds useful for the treatment of CNS diseases. These compounds are N-benzyl-2-amino-3-methoxy-propionamides having the formula (IIa):

Formula (IIa)

Wherein Ar is unsubstituted or aryl substituted with halo; R ₃ is lower alkoxy; R ₁ is methyl.

U.S. Patent 5,378,729 and U.S. Patent 5,773,475 are incorporated herein by reference. However, none of the above patents uses the use of these compounds to treat certain symptoms of non-inflammatory musculoskeletal pain such as muscle hyperalgesia and allodynia that occur in fibromyalgia, fascia pain syndrome, back pain or osteoarthritis. It is not listed.

WO 02/074297 relates to peripheral neuropathy of compounds of formula (IIa) wherein Ar is phenyl which may be substituted with one or more halo, R ₃ is lower alkoxy containing 1 to 3 carbon atoms and R ₁ is methyl It relates to the use for the manufacture of a pharmaceutical composition useful for the treatment of related allodynia.

WO 02/074784 describes acute and chronic pains of different kinds and symptoms, in particular, non-neuropathic inflammatory pain, for example rheumatoid arthritis pain and / or secondary inflammatory osteo-arthritis pain ( It relates to the use of a compound having formula (Ia) and / or formula (IIa) exhibiting antinociceptive properties for the treatment of secondary inflammatory osteo-arthritic pain.

Non-inflammatory musculoskeletal pain is a specific form of pain. Non-inflammatory musculoskeletal pain is a classic immune system response that is clearly distinguished from pain induced by tissue damage and macrophage infiltration (causing edema).

Non-inflammatory musculoskeletal pain that is not traced to a particular structural or inflammatory cause meets the classification criteria for fibromyalgia syndrome (FMS), fascia pain syndrome (MPS), or low back pain. Non-inflammatory musculoskeletal pain is thought to result from peripheral sensitization and central sensitization (Staud 2002). Knowledge of animal models for evaluating the relevant underlying mechanisms, myalgias and treatment regimens should be enhanced.

Fibromyalgia is a complex syndrome associated with significant impairments in quality of life and function and substantial economic costs (10). Fibromyalgia is also referred to herein as fibromyalgia syndrome (FMS).

Fibromyalgia is a systemic process that induces a tender point (typical local tender areas of tissue that appear normal) in the typical areas of the body and is frequently associated with poor sleep patterns and stressful environments. do. Diagnosis of fibromyalgia is characterized by an extensive history of pain as defined by the bilateral upper and lower limbs, and the spinal cord, and excessive tenderness when pressure is applied to at least 11 of the 18 specific muscle tendon sites. Based on existence. Fibromyalgia is a chronic syndrome that supports bones and joints and causes pain and stiffness throughout the moving tissue.

Treatment of fibromyalgia is typically based on analgesics, NSAIDs, muscle relaxants, sedatives and anti-depressants, but none are particularly useful. Patients with fibromyalgia often experience some relief by sleeping and taking antidepressant amitriptyline at bedtime (JAMA. 2004 Nov 17; 292 (19): 2388-95.Management of fibromyalgia syndrome.Goldberg DL , Burckhardt C1 Crofford L.). The goal of fibromyalgia treatment is to relieve pain and increase function.

Myofascial pain syndrome (MPS) describes chronic non-degenerative, non-inflammatory musculoskeletal conditions. Separate areas in the muscles or their sensitive connective tissue coat (fascia) become abnormally thickened or tight. When the fascia tissue becomes dense and loses elasticity, the ability of the neurotransmitter to send and receive messages between the brain and the body is impaired. Symptoms include muscle stiffness and pain in areas away from the trigger point and sharp blunt pain or tingling and numbness. Discomfort can cause sleep disorders, fatigue, and depression. The most common trigger is in the neck, back or buttocks.

Fascia pain is different from fibromyalgia; Myofascial pain syndrome and fibromyalgia are separate entities, each with their own pathology, but sharing the common path of pain. Fascia pain is a more localized or local pain (along muscle and surrounding fascia tissue) associated with trigger point tenderness. Fascia pain can be treated by various methods (in some cases combined), including stretching, ultrasound, ice spray with stretching, exercise, and injection of anesthetics.

Another non-inflammatory musculoskeletal syndrome is low back pain, in particular low back pain. Low back pain is a common musculoskeletal syndrome that can be acute or chronic. This syndrome can be caused by a variety of diseases and disorders affecting the lumbar spine. Lower back pain is often accompanied by sciatica, which is a pain involving the sciatic nerve and is felt in the back of the lower back, buttocks and thighs.

Non-inflammatory musculoskeletal pain, such as fibromyalgia, fascia pain syndrome and back pain, is an important symptom that includes increased muscle sensitivity. Increased muscle sensitivity is usually characterized by pain caused by non-painful stimuli (allodynia) or increased pain intensity (hyperalgesia) caused by nociceptive stimulation.

Osteoarthritis is considered to be non-inflammatory and non-inflammatory in origin, resulting in cartilage erosion, subchondral bone thickening, and joint damage, which occurs when the rate of cartilage degradation exceeds the regeneration rate. Are acquired musculoskeletal disorders (Wieland, 2005). Less cartilage loses its surface strength, forms cleft, and the cartilage tends to erode more easily with joint motion. As new cartilage is formed, it tends to be more fibrous and less able to withstand mechanical stress. Over time, the underlying bone, which is less capable of withstanding mechanical stress, may be exposed, resulting in microfracture. Localized osteonecrosis can occur below the bone surface, resulting in cysts that can further weaken the bone support of the cartilage.

As osteoarthritis progresses, it can ultimately affect the structures surrounding the joint. Local inflammation, such as synovitis, may occur in response to the secreted inflammatory mediator, for example, during cartilage degeneration. Joint capsules tend to thicken and movement of nutrients into the joints and movement of metabolic waste from the joints may be limited. Ultimately, as osteoarthritis progresses, periarticular muscle wasting becomes evident, and joints are used less or inappropriately. Since cartilage is aneural, the pain of osteoarthritis is thought not to be due to cartilage degeneration itself, but to effects on surrounding structures including bone.

Subchondral bone, periosteum, synovial cord, ligaments and articular capsules all contain abundant nerve endings and nerve endings that may be a source of nociceptive stimuli (Heppelmann, 1997). Mach et al., 2002). In addition to peripheral pain sensitization, central nerve sensitization can occur in osteoarthritis (Schaible et al., 2002).

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

By 2020, it is estimated that 60 million Americans will have arthritis. Arthritis is a leading cause of physical disability (defined as requiring extensive assistance when walking or climbing stairs) and limited daily activities in more than 7 million Americans, reaching more than 11.6 million by 2020. It is expected to increase. See http://www.arthritis.org/ resources / Action PlanInterior.pdf.

Treating arthritis and its complications is very expensive. In 1997, the total cost of arthritis and other rheumatic conditions in the United States was $ 86 billion. Direct medical expenses for arthritis and other rheumatic conditions were $ 511 billion. In 1997, the indirect costs (based on lost wages) for arthritis and other rheumatic conditions were $ 33.5 billion. See http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5318a3.htm.

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

Typical patients with osteoarthritis are middle-aged or elderly and complain of pain in the knees, buttocks, hands or spine. The distal interphalangeal joint or proximal osteoarticular joint of the hand is the most common site of osteoarthritis, but the least likely to be symptomatic. The buttocks and knees are the second and third most common joints observed to be affected on X-rays, and knee pain is more likely to be symptomatic.

Pain is the most prominent symptom of osteoarthritis. Osteoarthritis pain may have one or both inflammatory and non-inflammatory components. Anti-inflammatory agents such as non-sterodial anti-inflammatory agents (NSAIDs) and cyclooxygenase-2 inhibitors may be useful for treating or managing inflammatory components, and opioid analgesics and other analgesics may be non- It may be useful for treating or managing inflammatory components. However, such drug therapies are not always effective and have side effects that are not well tolerated in all patients.

Non-inflammatory pain, especially non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain, is often the absence of swelling or warmth, the absence of inflammatory or systemic features, and minimal stiffness. Or lack of 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.

Non-inflammatory osteoarthritis pain typically results from the effects of osteoarthritis-related morphological changes, such as cartilage degeneration, bone changes on sensory neurons, and vascularization of bone remodeling. Non-inflammatory osteoarthritis refers to inflammatory osteoarthritis pain arising from synovial inflammation following pathological processes in cartilage and bone, including tissue damage and macrophage infiltration (causing edema), associated with the classical immune system response herein. Are distinguished.

Non-inflammatory musculoskeletal and / or non-inflammatory osteoarthritis, such as fibromyalgia, allodynia, myofascial pain syndrome, muscular pain and muscular hyperalgesia and allodynia resulting from low back pain or osteoarthritis There is a need to identify treatments with therapeutic efficacy in the treatment of specific manifestations of pain, in particular systemic treatments.

Accordingly, an object of the present invention is to provide a therapeutic for non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain, in particular fibromyalgia, fascia pain syndrome (MPS), or back pain. In particular, the subject of the present invention is increased pain usually caused by non-nociceptive stimuli without physiological causes such as increased pain intensity (hyperalgesia) or inflammatory edema caused by painful stimulation. A non-inflammatory musculoskeletal and / or non-inflammatory osteoarthritis pain, preferably systemic treatment, including fibromyalgia, fascia pain syndrome (MPS), or low back pain characterized by intensity (allodynia).

The development of a second generation antiepileptic drug created an unprecedented opportunity for the treatment of chronic pain. These drugs regulate pain delivery by interacting with specific ion channels. The action of antiepileptic drugs is different in neuropathic pain and non-neuropathic pain, and agents within each drug class have different levels of efficacy. First generation antiepileptic drugs (ie carbamazepine, phenytoin) and second generation antiepileptic drugs (eg gabapentin, pregabalin) are effective in the treatment of neuropathic pain. The efficacy of antidepressants and antiepileptic drugs in the treatment of neuropathic pain is similar; Tolerability is similar, but safety and side effects profiles are different. Tricyclic antiepileptic drugs are associated with less safety concerns in elderly patients. Tricyclic antidepressants have (limited) documented efficacy in the treatment of fibromyalgia and chronic low back pain.

Lacosamide (also referred to as SPM 927 or harcoseride) has a novel mode of action unknown to date (Bialer et al., 2002). The mode of action of the compounds of formulas (Ib) and / or (IIb) differs from the mode of action of common antiepileptic drugs. Compounds of the present invention do not affect ion channels in a similar manner to other known antiepileptic drugs, and enhance GABA-induced currents, but no direct interaction with known GABA receptor subtypes is observed. Glutamate induced currents are attenuated, but the compounds of the present invention do not interact directly with known glutamate receptor subtypes.

Pressure hyperalgesia and TNF-induced grip force reduction can be used as animal models for non-inflammatory musculoskeletal pain. In humans, reduced grip strength is strongly associated with muscle pain. Indeed, alpha- and gamma-motor neurons are inhibited in the agonist muscle after harmful chemical stimulation (6, 7, 8).

The reduction in TNF-induced grip force was found to be actually a measure of hyperalgesia rather than a result of muscle weakness, fatigue or rupture of the contractile apparatus. Rotarod testing indicated the absence of motor damage after TNF injection, and muscle histology showed the absence of abnormalities (1). The withdrawl threshold of pressure applied transdermally to muscle was significantly reduced after TNF injection in most rats. This primary hyperalgesia is similar to tenderness for palpation clinically observed in patients with myalgia, such as fascia pain syndrome and fibromyalgia (3), which is a diagnosis of muscle pain under clinical and experimental human conditions. It is the primary criterion for (4,5).

Since pain upon palpation of muscle without morphological abnormalities is typical for fibromyalgia syndrome in humans (2), a model of intramuscular injection of TNF can be used as a model of muscle pain associated with, for example, fibromyalgia. Intramuscular injection of tumor necrosis factor-alpha (TNF) induces mechanical hyperalgesia in rats. This can be quantified by measuring the avoidance threshold and grip strength of muscle pressure. TNF injections do not cause morphological damage of muscles. Using the TNF injection model into muscle, it was confirmed that lacosamide was effective in reducing anti-nociceptive behavior. Surprisingly, a complete reversal of TNF-induced muscle hyperalgesia in the gastrocnemius muscle was observed with 30 mg / kg lacosamide and 2 mg / kg metamizol. In biceps muscle hyperalgesia, significant reversal of hyperalgesia was observed with 10 mg / kg and 30 mg / kg of lacosamide. A significant decrease in muscle hyperalgesia was also observed with 100 mg / kg of pregabalin and gabapentin and 2 mg / kg of metamizol.

One of the most well-characterized rat models for osteoarthritis is a metabolic inhibitor that inhibits the activity of glyceraldehyde-3-phosphate dehydrogenase in chondrocytes, leading to disruption of glycolysis and ultimately cell death. Injection of monosodium iodoacetate into the joint (Guzman et al., 2003; Kalbhen, 1987). Progressive loss of chondrocytes results in histological and morphological changes of articular cartilage, very similar to those observed in human osteoarthritis patients.

Using the iodoacetate rat model of osteoarthritis pain, it was surprisingly found that lacosamide inhibits mechanical hyperalgesia during the post-inflammatory period, indicating the efficacy of lacosamide in the treatment of non-inflammatory osteoarthritis pain.

The use of the compounds of formula (Ib) and / or formula (IIb) for the treatment of non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain has not been reported. Accordingly, the present invention is directed to non-inflammatory musculoskeletal and / or non-inflammatory osteoarthritis pain, particularly muscular hyperalgesia and / or allodynia that occurs in fibromyalgia, myofascial pain syndrome (MPS), back pain, and / or osteoarthritis. Regarding the use of a compound of formula (Ib) and / or formula (IIb) for the preparation of a pharmaceutical composition for the prevention, alleviation and / or treatment of certain symptoms of non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain will be.

In the context of the present invention, allodynia includes muscular allodynia and non-muscular allodynia. It is preferred that allodynia be muscular allodynia.

Various pathological conditions can be responsible for non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain. Thus, in the present invention, non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain includes non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain associated with and / or caused by a pathological condition. Preferably, this condition is a local pain syndrome such as low back pain or neck pain, rheumatoid arthritis, osteoarthritis, gout, ankylosing spondylitis, lupus erythematosus, fibromyalgia, fibritis, fibromyalitis, fascia pain syndrome, autoimmune disease, Rheumatic polymyalgia, multiple myositis, dermatitis, muscle abscess, nematode, Lyme disease, malaria, Rocky Mountain spotted fever, polio, trauma, joint damage, trauma Joint damage, cartilage degeneration, structural bone changes, and vascularization of areas of osteoarthritic bone remodeling.

As used herein, the term "non-inflammatory osteoarthritic pain" means non-inflammatory pain associated with and / or caused by osteoarthritis. In particular, “non-inflammatory osteoarthritis pain” means non-inflammatory musculoskeletal pain associated with and / or caused by osteoarthritis.

In one embodiment of the invention, the non-inflammatory musculoskeletal pain is non-inflammatory pain associated with and / or caused by osteoarthritis. In another embodiment of the invention, the non-inflammatory musculoskeletal is a non-inflammatory musculoskeletal pain associated with and / or caused by osteoarthritis.

In the present invention, non-inflammatory osteoarthritis pain is associated with and / or by a pathological condition selected from trauma, joint damage, joint damage due to trauma, cartilage degeneration, structural bone changes, and angiogenesis of the osteoarthritis bone remodeling site. It is preferred to be the non-inflammatory osteoarthritis pain caused. The bones are constantly remodeled. Remodeling is the process by which old bone is replaced with new bone to maintain peak bone density. Angiogenesis is caused by the proliferation of capillaries during the remodeling process and can be increased in conditions such as osteoarthritis.

Also preferably, non-inflammatory pain, in particular non-inflammatory musculoskeletal and / or non-inflammatory osteoarthritis pain, in the present invention is edema or absence of warmth, absence of inflammatory and / or systemic manifestations, and / or essentially It is characterized by the absence of early rigidity.

Since the cartilage is anural, osteoarthritis pain can be mediated by the effect of cartilage degeneration on the surrounding structures, including bone and articular capsules. In the present invention, cartilage degeneration includes, but is not limited to, cartilage erosion, loss of surface strength, formation of cleft, and increased erosion following joint motion.

In the present invention, structural bone changes include, but are not limited to, subchronicral bone thickening, microfracture, osteonecrosis, osteonecrosis beneath bone surface, and weakened bone support of cartilage. It is not limited.

In the present invention, osteoarthritis pain includes, but is not limited to, osteoarthritis pain of the knee, buttocks, hands, and / or spine.

Non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain can be the cause of a number of symptoms, which symptoms can be treated or at least alleviated by treatment of non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain. have. Accordingly, non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain in the present invention includes conditions associated with and / or caused by non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain. Preferably, the condition is fatigue, sleep disorders, irritable bowel syndrome, chronic headache, temporomandibular joint dysfunction syndrome, multiple chemical sensitivity, painful menstrual periods Dysmenorrhea, chest pain, early stiffness, cognitive or memory disorders, numbness and numbness, muscle twitching, irritable bladder, feeling of swollen extremities, skin sensitivities ), Dry eyes and mouth, frequent changes in eye prescription, dizziness and impaired coordinaiton.

As used herein, the term "non-inflammatory arthritic pain" refers to non-inflammatory pain associated with and / or caused by conditions associated with arthritis and / or arthritis. In particular, "non-inflammatory arthritis pain" refers to non-inflammatory musculoskeletal pain associated with or caused by conditions associated with arthritis such as arthritis and / or osteoarthritis.

For example, the pain associated with arthritis in osteoarthritis may be inflammatory, non-inflammatory, or both. In one embodiment of the invention, non-inflammatory musculoskeletal pain refers to non-inflammatory pain associated with or caused by conditions associated with arthritis such as arthritis and / or osteoarthritis.

In another embodiment of the invention, the non-inflammatory musculoskeletal is a non-inflammatory musculoskeletal pain associated with or caused by a condition concomitant with arthritis such as arthritis and / or osteoarthritis.

As used herein, an "arthritic condition" or "arthritis" is a musculoskeletal disorder of one or more joints of an individual, usually accompanied by pain, associated with or not necessarily associated with a condition that is not necessarily primarily arthritis. Includes incidental arthritis. The most important arthritic condition is osteoarthritis, which may be idiopathic or primary in origin, or incidental to other conditions.

Compounds according to the invention have the general formula (Ib)

Formula (Ib)

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, lower cycloalkyl lower alkyl, respectively Unsubstituted or substituted with one or more electron donating groups and / or one or more electron withdrawing groups; And

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, is ZY, which may be 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, lower alkyl heterocyclic, Y is unsubstituted or one or more electron balls And may be substituted with one or more electron withdrawing 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 or N ⁺ R ₅ R ₆ R ₇ ,

인 조건을 만족하고;

Satisfies the condition of;

R ' ₆ is hydrogen, lower alkyl, lower alkenyl, or lower alkenyl, 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, wherein R ₄ , R ₅ and R ₆ are independently unsubstituted or one May be substituted with one or more electron withdrawing groups and / or one or more electron donating groups; And

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

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

n is 1-4; And

a is 1-3.

Preferably, the compounds of the present invention have the general formula (IIb)

Formula (IIb)

In the formula,

Ar is aryl, in particular phenyl unsubstituted or substituted with one or more halo; R ₃ is —CH ₂ —Q, wherein Q is lower alkoxy; R ₁ is lower alkyl, in particular methyl.

The invention is also useful for the prevention, alleviation, and / or treatment of myalgia, in particular myalgias associated with and / or caused by a pathological condition, and / or conditions associated with and / or caused by myalgias. , To a pharmaceutical composition comprising a compound of formula (Ib) and / or formula (IIb).

When used alone or in combination with other groups, a "lower alkyl" group is lower alkyl comprising 1 to 6 carbon atoms, in particular 1 to 3 carbon atoms, and may be straight or branched. have. These groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, hexyl and their equivalents.

A "lower alkoxy" group is lower alkoxy containing 1 to 6 carbon atoms, in particular 1 to 3 carbon atoms, and may be straight or branched. These groups include methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy and the like.

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

When used alone or in combination, the term "aryl" means an aromatic group containing from 6 to 18 ring carbon atoms and up to 25 carbon atoms in total and comprising polynuclear aromatics do. These aryl groups are monocyclic, bicyclic, tricyclic or polycyclic and fused rings. As used herein, multinuclear aromatic compounds are intended to include bicyclic or tricyclic fused aromatic ring systems comprising 10-18 ring carbon atoms and up to 25 carbon atoms in total. Aryl groups include phenyl, and polynuclear aromatics include, for example, naphthyl, anthracenyl, phenanthrenyl, azulenyl and equivalents thereof. Aryl groups also include groups such as ferrocenyl. Aryl groups may be unsubstituted or mono- or multiply substituted with electron withdrawing groups and / or electron donor groups as described below.

The term "monosubstituted amino", alone or in combination with another term (s), 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. do. An example of a monosubstituted amino substituent is an N-alkoxyamino group. Examples of di-substituted amino substituents are N-alkoxy-N-alkylamino groups.

"Lower alkenyl" is an alkenyl group containing 2 to 6 carbon atoms and one or more double bonds. These groups may be straight or branched and may be Z or E. Such groups include vinyl, propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z) -2-pentenyl, (E) -2-pentenyl, (Z)- 4-methyl-2-pentenyl, (E) -4-methyl-2-pentenyl, pentadienyl such as 1,3-, or 2,4-pentadienyl and equivalents thereof.

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

When used alone or in combination, the term "lower cycloalkyl" is a cycloalkyl group comprising from 3 to 18 ring carbon atoms and up to 25 carbon atoms in total. Cycloalkyl groups can be monocyclic, bicyclic, tricyclic, or polycyclic and the rings are fused. Cycloalkyls can be fully saturated or partially saturated. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl, cyclooctenyl, cycloheptenyl, decalinyl, hydroindanyl, indanyl, Fenkill, pinenyl, adamantyl and equivalents thereof. 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.

The terms "electron-withdrawing and electron donating" refer to the ability of a substituent to attract or donate electrons compared to hydrogen when the hydrogen atoms occupy the same position in the molecule. These terms are fully understood by those skilled in the art and discussed in Advanced Organic Chemistry, by J. March, John Wiley and Sons, New York, NY, pp. 16-18 (1985), the discussion of which Inc. is incorporated herein by reference. Electron attractors include halo, including bromo, fluoro, chloro, iodo and the like; Nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxamido, aryl, quaternary ammonium, haloalkyl such as trifluoromethyl, aryl lower alkanoyl, carvalcoxyl and the like. Electron donor groups include lower alkoxy including hydroxy, methoxy, ethoxy and the like; Lower alkyl including methyl, ethyl and the like; Amino, lower alkylamino, di (lower alkyl) amino, aryloxy such as phenoxy, mercapto, lower alkylthio, lower 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 "halo" includes fluoro, chloro, bromo, iodo, and the like.

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 lower alkanoyls containing 1 to 6 carbon atoms and may be straight or branched. These groups include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, tertiary butyryl, pentanoyl and hexanoyl.

As used herein, heterocyclic groups include one or more sulfur, nitrogen, or oxygen ring atoms, but may also include several such atoms in the ring. Heterocyclic groups contemplated in the present invention include heteroaromatic and saturated heterocyclic compounds and partially saturated heterocyclic compounds. This heterocyclic compound is a monocyclic, bicyclic, tricyclic or polycyclic and fused ring. They may preferably comprise up to 18 ring atoms and up to 17 ring carbon atoms and up to 25 carbon atoms in total. Heterocyclic groups are intended to include so-called benzoheterocyclics. Representative heterocyclics are furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, py Ferrazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, furinyl, indolinyl, pyrazolindinyl , Imidazolinyl, imidazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, epoxy, aziridino, jade N-oxides of cetanyl, azetidinyl, nitrogen-containing heterocycles such as pyridyl, pyrazinyl, and pyrimidinyl. Heterocyclic groups can be unsubstituted or monosubstituted or polysubstituted with electron withdrawing groups and / or electron donors.

Preferred heterocyclic groups are thienyl, furyl, pyrrolyl, benzofuryl, benzothienyl, indolyl, methylpyrrolyl, morpholinyl, pyridylyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl . Preferred heterocyclics are 5 or 6-membered heterocyclic compounds consisting of 5 or 6 atoms. Particularly preferred heterocyclics are furyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl. Most preferred heterocyclics are furyl and pyridyl.

In another preferred embodiment, the heterocyclic is furyl, preferably at least one lower alkyl group containing 1 to 3 carbon atoms, for example furyl substituted by methyl, pyrrolyl, imidazolyl, pyri Selected from dill, pyrazinyl, pyrimidinyl, oxazolyl, and thiazolyl, more preferably from furyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl and thiazolyl, most preferably furyl , Pyridyl, pyrimidinyl, and oxazolyl.

Preferred compounds are those wherein n is 1, but di (n = 2), tri (n = 3) and tetra (n = 4) peptides are also contemplated as being within the scope of the present invention.

Preferred values of R are aryl lower alkyl, in particular benzyl, 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 F).

Preferred R ₁ is H or lower alkyl. Most preferred R ₁ group is methyl.

Preferred electron donating substituents and / or electron withdrawing substituents are halo, nitro, alkanoyl, formyl, arylalkanoyl, aryloyl, carboxyl, carvalcoxyl, carboxamido, cyano, sulfonyl, sulfoxide, hetero Cyclic, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di (lower alkyl) amino, amino lower alkyl, mercapto, Mercaptoalkyl, alkylthio, and alkyldithio. The term "sulfide" includes mercapto, mercapto alkyl, and alkylthio, and the term disulfide includes alkyldithio. Particularly preferred electron donor or / and electron withdrawing groups are halo or lower alkoxy, most preferred is fluoro or methoxy. Such preferred substituents are one of the groups in formula (Ib) or in formula (IIb), for example R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R as defined herein. ₆ , R ′ ₆ , R ₇ , R ₈ and / or R ₅₀ .

R ₂ And representative ZY groups of R ₃ are hydroxy, methoxy, alkoxy such as ethoxy, aryloxy such as phenoxy; Thioalkoxy such as thiomethoxy, thioethoxy; Thioaryloxy such as thiophenoxy; Amino; Alkylamino such as methylamino, ethylamino; Arylamino, such as anilino; Lower dialkylamino such as dimethylamino; Trialkyl ammonium salts, hydrazino; Alkylhydrazinos and arylhydrazinos, such as N-methylhydrazino, N-phenylhydrazino, carvalcoxyl hydrazino, aralkyloxycarbonyl hydrazino, aryloxycarbonyl hydrazino, N-hydroxylamino (-NH Hydroxylamino, such as -OH), lower alkoxy amino [R ₁₈ is lower alkyl (NHOR ₁₈ )], N-lower alkylhydroxy amino [R ₁₈ is lower alkyl (NR ₁₈ ) OH], N-lower alkyl -O-lower alkylhydroxyamino, ie [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; Lower alkoxyaminos (eg, NH (OCH ₃ )) and heterocyclic aminos such as pyrazoylamino;

R ₂ And preferred heterocyclic groups representing R ₃ are a monocyclic 5- or 6-membered heterocyclic moiety consisting of 5 or 6 atoms having the formula:

Or a corresponding partially or fully saturated form thereof, wherein n is 0 or 1;

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 heteroaromatic moiety is a ring of 5 atoms, and when n is 1, the heterocyclic moiety is a monocyclic heterocyclic moiety of 6 atoms. Preferred heterocyclic moieties are heterocyclics which are monocyclic as described above.

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 is heterocyclic 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 such as phenyl, aryl alkyl such as benzyl and alkyl.

It will be appreciated that the preferred groups of R ₂ and R ₃ may be unsubstituted or monosubstituted or polysubstituted with an electron donor group and / or an electron withdrawing unit. Lower alkyl, N-hydroxylamino, 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 (e.g., methoxy, ethoxy, etc.) , N-lower alkylhydroxyamino, N-lower alkyl-O-lower alkyl and alkylhydroxyamino.

R ₂ and R ₃ One of Hydrogen is preferred.

It is preferable that n is 1.

n = 1 and R ₂ and R ₃ One of It is more preferable that it is hydrogen. In this embodiment, R ₂ is hydrogen and R ₃ is lower alkyl or ZY;

인 것이 특히 바람직하다. 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 , ON _R 4R ₇ ,

Is particularly preferred.

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

In another particularly preferred 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 hydroxy or lower alkoxy, wherein R ₄ , R ₅ and R ₇ are independently hydrogen or lower alkyl, R is aryl lower alkyl, wherein the aryl group may be unsubstituted or substituted with an electron withdrawing group and R ₁ is lower alkyl. In this embodiment, aryl is most preferably unsubstituted or phenyl substituted with halo.

It is preferred that R ₂ is hydrogen and R ₃ is hydrogen, unsubstituted or an alkyl group substituted with one or more electron donor groups or electron withdrawing groups or ZY. In this preferred embodiment, R ₃ is hydrogen, an alkyl group such as methyl, unsubstituted or substituted with an electron donor, or NR ₄ OR ₅ , wherein R ₄ , R ₅ and R ₇ are independently hydrogen or lower alkyl or it is more preferred that ONR ₄ R _7. The electron donating group is preferably lower alkoxy, in particular methoxy or ethoxy.

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

인 것이 바람직하다.ZY is NR ₄ R ₅ R ₇ , NR ₄ 0R ₅ , ONR ₄ R ₇ ,

Is preferably.

In addition, R is preferably aryl lower alkyl. Most preferred aryl for R is phenyl. Most preferred R group is benzyl. In a preferred embodiment, the aryl group can be unsubstituted or substituted with an electron donor group or an electron withdrawing group. When the aryl ring of R is substituted, it is most preferred that it is substituted with an electron withdrawing group, especially on the aryl ring. The most preferred electron withdrawing group for R is halo, in particular fluoro.

Preferred R ₁ is lower alkyl, in particular methyl.

More preferably, R is aryl lower alkyl and R ₁ is lower alkyl.

Further preferred compounds are n is 1; R ₂ is hydrogen; R ₃ is hydrogen or lower alkyl group, in particular methyl or ZY substituted with an electron donor group or an electron withdrawing group; R is an aryl, a compound of formula (Ib) wherein aryl is unsubstituted or substituted with an electron donor or electron withdrawing group, aryl lower alkyl such as benzyl and R ₁ is lower alkyl. 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 donating group such as hydrogen, lower alkoxy (eg methoxy, ethoxy etc.) Or ON ₄ R ₇ is preferred.

Most preferred compounds used are as compounds of formula (IIb):

Formula (IIb)

Wherein Ar is unsubstituted or aryl, in particular phenyl, substituted by one or more electron donating groups or electron withdrawing groups, in particular halo,

R ₁ is lower alkyl, especially lower alkyl comprising 1 to 3 carbon atoms;

R ₃ is as defined herein, but in particular, lower alkyl or ZY substituted with hydrogen, unsubstituted or substituted with one or more electron donor groups or electron substituents. In this embodiment, it is even more preferred that R ₃ is hydrogen, an unsubstituted or substituted alkyl group, NR ₄ OR ₅ or ONR ₄ R ₇ . R ₃ is CH ₂ -Q wherein Q is lower alkoxy, especially lower alkoxy containing 1 to 3 carbon atoms; R ₄ is hydrogen or alkyl containing 1 to 3 carbon atoms, R ₅ is hydrogen or alkyl containing 1 to 3 carbon atoms, and R ₇ is hydrogen or 1 to 3 carbon atoms Most preferably, it is NR ₄ OR ₅ or ONR ₄ R ₇ which is alkyl.

Most preferred R ₁ is CH ₃ . Most preferred R ₃ is CH ₂ -Q, wherein Q is methoxy.

Most preferred aryl is phenyl. Most preferred halo is fluoro.

Another preferred embodiment is n = 1 and R ₁ is lower alkyl comprising 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, more preferably methyl; R ₂ is H and R in formula (Ib) is unsubstituted or substituted benzyl, in particular halosubstituted benzyl, or Ar in formula (IIb) is unsubstituted or substituted phenyl, in particular halosubstituted phenyl do.

In another embodiment, the compounds of the invention, in particular the compounds of formula (lb), are formula (III)

Formula (III)

Or a pharmaceutically acceptable salt thereof, wherein

R ₉ 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-alkylamino; And

R ₁ is alkyl.

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

In certain embodiments, the R ₉ substituents in the compound of formula (III) are independently selected from hydrogen and halo, more particularly fluoro substituents.

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

In a particular embodiment, in the compound of formula (III) R ₁ is a C _{1 -3} alkyl.

In a more particular embodiment, no more than one R ₉ substituent is fluoro and all others are hydrogen; R ₃ is selected from the group consisting of methoxymethyl, N-methoxy-N-methylamino and N-methoxyamino, and R ₁ is methyl.

Most preferred compounds are:

(R) -2-acetamido-N-benzyl-3-methoxy-propionamide (lacosamide);

(R) -2-acetamido-N-benzyl-3-ethoxy-propionamide

O-methyl-N-acetyl-D-serine-m-fluorobenzyl-amide;

O-methyl-N-acetyl-D-serine-p-fluorobenzyl-amide;

N-acetyl-D-phenylglycine benzylamide;

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

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

Various combinations and permutations of the Markush groups of R ₁ , R ₂ , R ₃ , R and n described herein are contemplated as being within the scope of the present invention. The invention also includes compounds and compositions comprising one or more elements of each of the Markush groups of R ₁ , R ₂ , R ₃ , n and R and various combinations thereof. Thus, for example, in the present invention, R ₁ may be one or more substituents described above in the combination having all substituents of R ₂ , R ₃ and R for each n value.

The compounds used in the present invention may comprise one or more asymmetric carbons and may exist in racemic and optically active forms. The arrangement around each asymmetric carbon may be Form D or Form L. It is known in the art that the arrangement around chiral carbons can also be described as R or S in the Cahn-Prelog-Ingold nomenclature system. All various arrangements around each asymmetric carbon are contemplated by the present invention, including racemic mixtures and mixtures comprising various enantiomers and diastereomers and enantiomers, diastereomers or both.

In the main chain, there is asymmetry in the carbon atom to which R ₂ and R ₃ are attached. When n is 1, the compound of the present invention is a compound of formula (IV)

식 (IV)

Formula (IV)

Wherein R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ' ₆ , R ₇ , R ₈ , R ₅₀ , Z and Y are as defined above.

As used herein, the term configuration will mean an arrangement around a carbon atom to which R ₂ and R ₃ are bonded, although other chital centers may be present in the molecule. Thus, when referring to specific arrangements such as D or L, it will be understood that R ₂ and R ₃ refer to D or L stereoisomers at the bonded carbon atom. However, if there are other chiral centers in the compound, the arrangement also includes all possible enantiomers and diastereomers at other chiral centers.

The compounds of the invention relate to all optical isomers, ie the compounds of the invention are L-stereoisomers or D-stereoisomers (at the carbon atoms to which R ₂ and R ₃ are bonded). Stereoisomers may be found as mixtures of L stereoisomers and D stereoisomers, eg racemic mixtures. D stereoisomers are preferred.

More preferably substituent R is benzyl unsubstituted or substituted with one or more halo groups, R ₃ is CH ₂ -Q wherein Q is lower alkoxy containing 1 to 3 carbon atoms, and R ₁ is methyl It is a compound of formula (IV) in the R configuration, and is preferably substantially pure enantiopure. Preferably R is benzyl substituted with one or more halo groups which are unsubstituted benzyl or fluoro groups.

The "substantially enantiopure" compounds of the invention have an enantiomeric purity of at least 88%, preferably at 90%, more preferably at 95, 96, 97, 98, or 99%. Can have

Depending on the substituents, the compounds of the present invention may also form addition salts. All such forms, including mixtures of stereoisomers, are contemplated as being within the scope of this invention.

The preparation of the compounds used is described in US Pat. No. 5,378,729 and US Pat. No. 5,773.475, incorporated herein by reference.

The compounds used in the present invention as described by formula (Ib) or / and (IIb) may be useful on their own or in the form of salts in view of the basicity due to the presence of free amino groups. Thus, the compounds of formula (Ib) or / and (IIb) form salts with a wide range of inorganic and organic acids, including pharmaceutically acceptable acids. Salts with pharmaceutically acceptable acids are of course useful in the preparation of formulations in which increased water solubility is most advantageous.

This pharmaceutically acceptable salt also has therapeutic efficacy. 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, aryl sulfonic acid (e.g. Salts of organic acids such as p-toluene sulfonic acid, benzenesulfonic acid), phosphoric acid, malonic acid and the like.

The invention also provides a method of preventing, alleviating or / and treating a disease or condition as described above in a mammal, including a human, comprising administering at least one compound of formula (Ib) or / and (IIb). It is about.

The compound used in the present invention is preferably used in a therapeutically effective amount.

The physician will determine the most suitable dosage of the therapeutic agent of the invention, which will depend on the particular compound and dosage form chosen, and also on the patient being treated, the age of the patient, the type of disease being treated. The physician will generally want to start treatment at a dose substantially lower than the optimal dose of the compound and increase the dose in small amounts until the optimum effect is reached. When the composition is administered orally, higher amounts of active agent will be required to produce the same effect as the less parentally administered amount. The compounds are useful in the same manner as similar therapeutic agents and the dosage level is as generally applied to such other therapeutic agents.

In a preferred embodiment, the compound of the present invention is administered in an amount of about 1 mg to about 100 mg / 1 kg / day, more preferably in an amount of about 1 mg to about 10 mg / 1 kg / day body weight. This dosage regimen can be adjusted by the physician to provide the optimum therapeutic response. Patients in need of administration are treated with a dose of a compound of the invention of at least 50 mg / day, preferably at least 200 mg / day, more preferably at least 300 mg / day and most preferably at least 400 mg / day. In general, patients in need of administration can be treated at a dose of up to 6 g / day, more preferably at a dose of up to 1 g / day, and most preferably at a dose of up to 600 mg / day. In some cases, however, higher or lower dosages may be required.

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

In another preferred embodiment, several divided doses may be administered daily. For example, three doses per day, preferably twice a day, may be administered. More preferably, once daily administration.

In another preferred embodiment, the compounds of the present invention result in plasma concentrations of 0.1-15 μg / ml (lowest) and 5-18.5 μg / ml (highest), calculated as averages for the plurality of treated subjects. Amounts may be administered.

The compound of formula (Ib) or / and (IIb) may be administered in a convenient manner such as oral, intravenous (if water soluble), intramuscular, intrathecal or subcutaneous route of administration. Oral or / and intravenous administration is preferred.

The pharmaceutical composition of the present invention may be treated with a treatment regimen as described above, in particular with a duration of administration and / or route of administration as specified in embodiments of the invention as described above at the above-mentioned dosages. It may be prepared for a method of treatment for obtaining a plasma concentration as such.

In another preferred embodiment, the method of the invention as described above for treating a mammal, including a human in need thereof, comprises non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain, in particular fibromyalgia, fascia pain. Prevention, alleviation and / or treatment of certain symptoms of non-inflammatory musculoskeletal and / or non-inflammatory osteoarthritis pain such as muscular hyperalgesia and / or allodynia resulting from syndrome (MPS), back pain and / or osteoarthritis, in particular systemic Together with the administration of additional active agents for treatment, administration of the compounds of the invention. Compounds of the invention and additional active agents can be administered simultaneously, ie in a single dosage form, or separately, ie in separate dosage forms. Accordingly, the pharmaceutical compositions of the present invention may comprise a compound of the present invention as defined above and may include non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain, in particular fibromyalgia, fascia pain syndrome (MPS), Additional for the prevention, alleviation and / or treatment of certain symptoms of non-inflammatory musculoskeletal and / or non-inflammatory osteoarthritis pain, such as muscular hyperalgesia and / or allodynia resulting from low back pain and / or osteoarthritis, in particular for systemic treatment It may further comprise an active agent. The pharmaceutical composition of the present invention may comprise a single dosage form or may be a separate dosage form comprising a first composition comprising a compound of the invention as defined above and a second composition comprising an additional active agent. It may include.

In another preferred embodiment, the methods of the invention comprise the administration of a compound of the invention, in combination with the administration of an additional active agent for the prevention, alleviation and / or treatment of non-inflammatory arthritis pain. The pharmaceutical composition of the present invention may comprise a compound of the present invention as defined above and prevent, alleviate and / or treat non-inflammatory arthritis pain, such as pain associated with and / or caused by osteoarthritis. It may include additional active agents for.

Two or more active agents of the aforementioned combinations are formulated into one pharmaceutical formulation (single dosage form), or are administered to the individual substantially simultaneously, or at different times or frequencies, eg, sequentially, for simultaneous administration to the individual. It may be formulated into two or more separate agents for administration. Two separate formulations may be formulated for administration by the same route or by different routes.

Individual dosage forms can optionally be packaged together, for example in one container, or presented together in separate packages (“common presentation”). As an example of co-packaging or common presentation, a compound of formula (Ib), (IIb), or (III) in a first container, and a second active agent or one or more anti-osteoarthritis agents (anti-) in a second container Kits containing osteoarthritis agents are contemplated. In another embodiment, the compounds of formula (Ib), (IIb) or (III) and the second active agent or one or more anti-osteoarthritis agents may be packaged separately and sold independently of each other, but according to the invention It can be co-sold or co-promote for. Separate dosage forms can also be presented separately and independently to the subject for use according to the invention.

Formula (Ib), (IIb), depending on the same or different dosage formulations, for example fast release form, controlled release dosage form or depot formulation. The compound of) or (III) and the second active agent or anti-osteoarthritis may be administered on the same schedule or on different schedules, eg, on a daily, weekly or monthly basis.

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. Can be.

Additional active agents for the prevention, alleviation and / or treatment of certain symptoms of non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain, in particular, non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain, may be selected from formula (Ib) and And / or a compound different from the compound of (IIb), in particular an anticonvulsant, wherein the anticonvulsant is preferably a first generation anticonvulsant such as carbamazepine and phenytoin, and gabapentin, pregabalin, lamotrigine, And second generation anticonvulsants such as levetiracetam.

Additional active agents for the prevention, alleviation, and / or treatment of non-inflammatory musculoskeletal and / or non-inflammatory osteoarthritis pain as described herein are also intended for the prevention, alleviation and / or treatment of non-inflammatory arthritis pain. It can be used as an additional active agent.

The compounds of the present invention can be used for the preparation of pharmaceutical compositions as described above.

The additional active agent for the prevention, alleviation, and / or treatment of non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain may be one or more anti-osteoarthritis agents, ie, the additional active agent may also be osteoarthritis or any aspect thereof, It may be effective for the prevention, alleviation and / or treatment of symptoms or underlying causes. In the present invention, the one or more anti-osteoarthritis agents may be agents which are not compounds of formulas (Ib) and / or (IIb), in particular agents which are not anticonvulsants.

In one embodiment, additional agents for the prevention, alleviation and / or treatment of non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain, in particular anti-osteoarthritis agents, are effective for the treatment of pain, ie analgesics. . Suitable analgesics include certain anti-inflammatory drugs and opioid analgesics and non-opioid analgesics (see immediately below).

As described herein, osteoarthritis pain can include both non-inflammatory and inflammatory components. Thus, in another embodiment, additional active agents, in particular anti-osteoarthritis agents, are effective for the treatment of inflammation and / or pain associated therewith. Suitable anti-inflammatory agents include steroidal and non-steroidal anti-inflammatory drugs. Non-steroidal anti-inflammatory agents (NSAIDs) include traditional NSAIDs and cyclooxygenase-2 (COX-2) selective inhibitors.

Opiate and non- that may be useful as additional active agents, especially anti-osteoarthritis agents, to be administered in combination or adjuvant therapy with a compound of formula (Ib), (IIb) or (III), for example lacosamide Non-limiting examples of opiate analgesics include acetaminophen, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, benzitramide, buprenorphine, butorpanol, clonitogen, Codeine, Cyclazosin, Desomorphine, Dextromoramide, Dextropropoxyphene, Dezosin, Diampromide, Diamorphone, Dihydrocodeine, Dihydromorphine, Dimenoxadol, Dimefetanol, Dimethylthiambu Ten, dioxafetyl butyrate, dipipanone, eftazosin, etoheptazine, ethylmethylthiambutene, ethylmorphine, etonitogen, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypettidine, isometadon , Ketobemidone, levalorphan, levorpan Ol, levofenacylmorphan, lofentanil, meperidine, meftazinol, metamizol, metazosin, methadone, metophon, morphine, myropin, nalbuphine, nalopine, narcane, nicomorphine, norreborpanol , Normetadon, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazosin, phenadoxin, phenazosin, phenomorphan, phenoferidine, phinodine, pyritramide, pro Heptazine, promedol, properidine, propyram, propoxyphene, sufentanil, tilidine, tramadol, NO-naproxen, NCX-701, ALGRX-4975, and combinations thereof.

The ratio of additional active agents to be administered in combination with a compound of formula (Ib), (IIb) or (III), for example lacosamide or in adjuvant therapy, in particular steroidal anti-inflammatory agents which may be useful as anti-osteoarthritis agents. Restrictive examples include alclomethasone, amcinolone, betamethasone, betamethasone 17-valerate, clobetasol, clobetasol propionate, clocortolone, cortisone, dehydrotestosterone, deoxy Corticosterone (deoxycorticosterone), desonide, desoximetasone, dexamethasone, dexamethasone 21-isonicotinate, diflorasone, fluorosinide, fluorinolone, fluorometholone, flulan Drenolide, fluticasone, hacinonoid, halobetasol, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone hemisuccinate , Hydrocortisone 21-lysinate, hydrocortisone sodium succinate, isoflupredone, isoflupredon acetate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisolone sulfentanate, mometasone , Prednicabate, prednisolone, prednisolone acetate, prednisolone hemisuccinate, prednisolone sodium phosphate, prednisolone sodium succinate, prednisolone valerate-acetate, prednisolone, triamcinolone, triamcinolone acetonide and combinations thereof.

NSAIDs and COX-2, which may be useful as additional active agents, in particular anti-osteoarthritis agents, to be administered in combination or adjuvant therapy with a compound of formula (Ib), (IIb) or (III), for example lacosamide Non-limiting examples of selective inhibitors include salicylic acid derivatives (e.g. salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, olsalazine, salsalate and sulfasalazine), indole and indene acetic acid (e.g. For example, indomethacin, etodolak and sulindac), phenamate (e.g., etophenic acid, meclofenamic acid, mefenamic acid, flufenamic acid, niflumic acid and tolphenamic acid), heteroaryl Acetic acid (e.g. acemethacin, alclofenac, clidanac, diclofenac, fenclofenac, pentiazac, furofenac, ibufenac, isoxepac, ketorolalac, oxipinac , Thiopinac, tolmetin, zidomethacin and zomepirac), Reyl acetic acid and propionic acid derivatives (e.g. aminopropene, benoxapropene, bucloxic acid, carpropene, fenbufen, phenopropene, flupropene, flubiprofen, ibuprofen , Indoprofen, ketoprofen, miroprofen, naproxen, naproxen sodium, oxaprozin, pyrpropene, pranopropene, suprofen, thiapropene acid and thioxapropene), enolic acid (e.g. , Oxycamp derivatives such as ampyroxicam, cynoxycam, doxycampum, romoxicam, meloxycamp, pyloxicam, sudoxicam and tenoxycam, and pyrazolone derivatives aminopyrin, antipyrine, apazone, di Pyrone, oxyfenbutazone and phenylbutazone), alkanones (eg nabumethone), nimesulide, proguazone, MX-1094, lycopene, and combinations thereof.

In another embodiment, the additional active agent, in particular the anti-osteoarthritis agent, is an anti-inflammatory agent of the COX-2 selective inhibitor family, for example celecoxib, deracoxib, valdecoxib, parecoxib, rofecoxib , Etoricoxib, lumiracoxib, 2- (3,5-difluorophenyl) -3- [4- (methylsulfonyl) phenyl] -2-cyclopenten-l-one, (S) -6 , 8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid, 2- (3,4-difluorophenyl) -4- (3-hydroxy-3-methyl- 1-butoxy) -5- [4- (methylsulfonyl) phenyl] -3- (2H) -pyridazinone, 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, PAC-10549, Simi Anti-inflammatory agent selected from coxive, GW-406381, LAS-34475, CS-502, and combinations thereof.

In another embodiment, additional agents for the prevention, alleviation and / or treatment of non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain, in particular anti-osteoarthritis agents, are one or more antidepressants. Such combinations or adjuvant therapies are also non-inflammatory in some cases, rather than monotherapy with a compound of formula (Ib), (IIb) or (III), eg, lacosamide, or antidepressant alone. It may be more effective in the treatment of musculoskeletal pain and / or non-inflammatory osteoarthritis pain and / or have reduced adverse side effects.

Non-limiting examples of antidepressants that may be useful in combination with a compound of formula (Ib), (IIb) or (III), for example lacosamide or in adjuvant therapy, are not limited to bicyclic ), Tricyclic and tetracyclic antidepressants, hydrazide, hydrazine, phenyloxazolidinone and pyrrolidone. Specific examples include adinazolam, adrafinil, aminephthine, amitriptyline, amitriptylinoxide, amoxapine, befloxatone, bupropion, butetacetin, butliprifrin, caroxazone, citalopram, Clomipramine, cotinine, demexiptiline, decipramin, dibenzepine, dimethacrine, dimethazane, dioxadol, dotipine, doxepin, duloxetine, etoferidone, pemoxetine, Phencarmine, fenpentadiol, fluasizin, fluoxetine, fluvoxamine, hematoporphyrin, hypericin, imipramine, imipramine N-oxide, indalpine, indeloxazine, Ifrindol, Iproclozid, Iproniazide, Isocarboxide, Levopacetoferan, Lofepramine, Mapprotilin, Medipoxamine, Melitracene, Metapramine, Metralline, Mianserine, Milnacipran, minafrin, mirtazapine, moclobemid, nefazodone, nepofam, nialamide, Nomiphenine, nortriptyline, oxycitiline, octamoxin, opipramol, oxaflozan, oxytriphtane, oxyfertin, paroxetine, phenelzin, fiberalline, fizotilin, prolinetan, Propizepine, protriphthylline, pyrisuccideanol, quinupramine, reboxetine, ritanserine, roxindole, rubidium chloride, sertraline, sulfide, ballidospiron, thiazime, tozalinone , Thianephthine, tofenacin, toloxatone, tranilcipromin, trazodone, trimimipramine, tryptophan, venlafaxazine, viloxazine, gimeldine and combinations thereof.

In another embodiment, additional agents, in particular anti-osteoarthritis agents, for the prevention, alleviation, and / or treatment of non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain are one or more NMDA receptor antagonists. Such combinations or adjuvant therapies are, in some cases, more non-inflammatory than monotherapy with a compound of formula (Ib), (IIb) or (III), eg, lacosamide or NMDA receptor antagonist alone. It may be more useful for the treatment of musculoskeletal pain and / or non-inflammatory osteoarthritis pain, and / or may have reduced adverse side effects.

Non-limiting examples of NMDA receptor antagonists to be administered in combination or adjuvant therapy with a compound of formula (Ib), (IIb) or (III), for example lacosamide, are atiganel, dexanabinol, ricoh Stinel, memantine, remasemide, and combinations thereof.

In another embodiment, the additional active agent, in particular, the anti-osteoarthritis agent, is a disease-modifying Osteoarthritis Drug (DMOAD). As used herein, the term "DMOAD" refers to drugs that are not the aforementioned drugs that have utility in the treatment of osteoarthritis or symptoms thereof. Non-limiting of additional active agents, in particular DMOAD, which may be useful as an anti-osteoarthritis agent in combination with a compound of formula (Ib), (IIb) or (III), for example lacosamide or for administration in adjuvant therapy Typical examples include methotrexate, diacerane, glucosamine, chondroitin sulfate, anakinra, MMP inhibitors, doxycycline, minocycline, misoprostol, proton pump inhibitors, non-acetylated salicylates, tamoxifen, prednisone, methyl Prednisolone, polysulfated glycosaminoglycan, calcitonin, allredonate, risedronate, zoledronic acid, teriparatide, VX-765, pranacaic acid, SB-462795, CPA-926, ONO-4817, S-3536, PG-530742, CP-544439, and combinations thereof.

In another embodiment, the additional active agent, in particular the anti-osteoarthritis agent, is a symptom modifying osteoarthritis drug other than the aforementioned drug. Non-limiting of additional active agents, in particular DMOAD, which may be useful as an anti-osteoarthritis agent in combination with a compound of formula (Ib), (IIb) or (III), for example lacosamide or for administration in adjuvant therapy Illustrative examples include ADL-100116, AD-827, HOE-140, DA-5018, and combinations thereof.

Suitable regimens, including dosages and routes of administration for specific anti-osteoarthritis agents, are readily available in reference to such agents, for example, Physicians' Desk Reference (PDR), 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 (Ib), (IIb) or (III), for example lacosamide, anti-osteoarthritis agents may be used in full dosage, but the physician may at least Initially, one may choose to administer less than a full dose of anti-osteoarthritis.

One or more anti-osteoarthritis agents may be administered in combination or adjuvant therapy with a compound of formula (Ib), (IIb) or (III), for example lacosamide. 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; And

(iv) DMOAD.

The compound of formula (Ib) and / or (IIb) may be administered orally, for example, with an inert diluent or with an absorbable edible carrier, or in a hard or soft gelatin capsule. It may be enclosed, compressed into tablets, or directly included in the diet. For oral therapeutic administration, the active compound of formula (Ib) and / or (IIb) may be combined with excipients for ingestible tablets, buccal tablets, troches, capsules, elixirs (elixir), suspensions, syrups, wafers and the like. Such compositions and preparations should comprise at least 1% of the active compounds of formula (Ib) or / and (IIb). The percentage of compositions and formulations may of course vary and may conveniently be between about 5% and about 80% of the unit weight. The amount of active compound of formula (Ib) and / or formula (IIb) in such therapeutically useful compositions is determined such that a suitable dosage can be obtained. Preferred compositions or preparations according to the invention comprise about 10 mg to 6 g of the active compound of formula (Ib) and / or formula (IIb).

Tablets, troches, pills, capsules and the like may also include the following: binders such as tragacan gum, acacia, corn starch or gelatin; Excipients such as dicalcium phosphate; Disintegrants such as corn starch, potato starch, alginic acid and the like; Lubricants such as magnesium stearate; And sweetening agents such as sucrose, lactose or saccharin can be added or flavorings such as peppermint, methyl salicylate (oil of wintergreen), or cherry flavor can be added. When the dosage unit form is a capsule, it may comprise a liquid carrier, in addition to the substances of the aforementioned kind.

Various other materials may be present in the coating or to modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar or both. Syrups or elixirs may include active compounds, sucrose as a sweetening agent, methylparabens and propylparabens as preservatives, dyes and flavoring agents such as cherry or orange flavors. Of course, the materials used to prepare any dosage unit formulations must be pharmaceutically pure and non-toxic in practically the amount used. The active compounds can also be mixed into sustained release formulations and compositions. For example, sustained release dosage forms are contemplated in which the active ingredient is bound to an ion exchange resin that can be optionally coated with a diffusion barrier coating to modify the release characteristics of the resin.

The active compound may be administered parenterally or intraperitoneally. Disperisons can be prepared in glycerol, liquids, polyethylene glycols, and mixtures and oils thereof. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical formulations suitable for injection use include sterile aqueous solutions (if water soluble) or dispersants and sterile powders for the instant preparation of sterile injectable solutions or dispersants. In all cases, the formulation must be sterile and fluid to the extent that easy syringability in the syringe is possible. It 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, and 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. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be more desirable to include isotonic agents, for example, sugars or sodium chloride. 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 desired amount of active compound with a suitable solvent containing the various ingredients described above as needed and subject to filtered sterilization. Generally, dispersants are prepared by mixing the various sterilized active ingredients into a sterile vehicle that contains the desired ingredients from the basic dispersion medium and those described above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying, lyophilization of additional desired components from the previous sterile-filtered solution.

As used herein, "pharmaceutically acceptable carrier" isotonicity for all solvents, dispersion media, coatings, antibacterial and antifungal agents, pharmaceutically active substances known in the art to which this invention pertains. Agonists and absorption retardants. Except insofar as conventional media or agents are incompatible with the active ingredient, their use in therapeutic compositions is contemplated. Supplementary active ingredients can also be mixed into the compositions.

It is particularly advantageous to prepare parenteral compositions in dosage unit dosage forms or in dosage forms and in dosages that are uniform. Dosage unit dosage form as used herein refers to physically discrete units suited as unitary dosages for the mammal to be treated; Each unit contains a predetermined amount of active substance calculated to produce the desired therapeutic effect in combination with the desired pharmaceutical carrier. Details of the novel dosage unit formulations of the present invention are directed to (a) the unique properties of the active substance for the particular therapeutic effect to be achieved, and (b) a disease state in which physical health is impaired as described in detail herein. It is determined and directly depends on the limitations inherent in the art of preparing such active substances for the treatment of diseases in living subjects.

The main active ingredients are formulated in dosage unit formulations as described above with pharmaceutically acceptable carriers suitable for convenient and effective administration in effective amounts. Unit dosage formulations may comprise a major active compound, eg, in an amount from about 10 mg to about 6 g. Expressed in proportions, the active compound is generally present in about 1 to about 750 mg of the formulation per ml of carrier. In the case of compositions comprising supplementary active ingredients, the dosage is determined with reference to the usual dosages and modes of administration of the above ingredients.

The term "patient" or "subject" as used herein includes warm blooded animals, preferably cats, dogs, horses, cattle, pigs, mice, mice, and humans, for example. Means mammals such as primates. Preferred patients are humans.

The term "treat" means alleviating pain associated with a disease or condition, or treating or alleviating a disease or condition of a patient, or prolonging survival.

The compounds of the present invention are administered in an effective amount to a patient suffering from a disease of the aforementioned kind. These amounts correspond to the therapeutically effective amounts described above.

Example 1 below shows the ability of lacosamide to inhibit mechanical hyperalgesia following TNF induced musculoskeletal pain in rats. Lacosamide also attenuates mechanical allodynia measured by grip strength in the same model. The model reflects musculoskeletal pain that occurs in fibromyalgia, fascia pain syndrome or back pain.

Example 2 below shows that lacosamide inhibited mechanical hyperalgesia during the post-inflammatory period in the iodoacetate rat model of osteoarthritis pain, which is a Lacosa treatment for non-inflammatory osteoarthritis pain. It shows the efficacy of the mead.

The material used in Examples 1 and 2 is lacosamide (nonproprietary name) which is synonymous with Harkoseride or SPM 927. Standard chemical designation is (R) -2-acetamide-N-benzyl-3-methoxypropionamide.

Symptom 1 shows the effects of 3 mg / kg, 10 mg / kg, and 30 mg / kg of lacosamide on paw withdrawl after muscle pressure after TNF-induced myalgia.

FIG. 2 shows the effect of 3 mg / kg, 10 mg / kg, and 30 mg / kg of lacosamide on foot withdrawal after muscle pressure after TNF-induced myalgia versus pregabalin, gabapentin and metamizol. MPE: maximum possible effect.

3 shows the effect of 3 mg / kg, 10 mg / kg, and 30 mg / kg of lacosamide on grip strength after TNF-induced myalgia.

FIG. 4 shows the effect of 3 mg / kg, 10 mg / kg, and 30 mg / kg of lacosamide on grip strength after TNF-induced myalgia relative to pregabalin, gabapentin and metamizol. MPE: maximum possible effect.

5A-C are graphical depictions of the results for tactile allodynia obtained in the iodoacetate rat model of Example 2 after administration of lacosamide and morphine on days 3, 7, and 14 of the study, respectively.

6A-C are graphical depictions of the results for tactile allodynia obtained in the iodoacetate rat model of Example 2 after administration of diclofenac on days 3, 7, and 14 of the study, respectively.

7A-C are graphical depictions of the results for mechanical hyperalgesia obtained in the iodoacetate rat model of Example 2 after administration of lacosamide and morphine on Days 3, 7, and 14 of the study, respectively.

8A-C are graphical depictions of the results for mechanical hyperalgesia obtained in the iodoacetate rat model of Example 2 after administration of diclofenac on Days 3, 7, and 14 of the study, respectively.

Example 1

Intramuscular injection of tumor necrosis factor-alpha (TNF) was used as a model of muscle mechanical hyperalgesia that occurs in human fibromyalgia, fascia pain syndrome, back pain or osteoarthritis.

Intramuscular injection of TNF induces mechanical muscle hyperalgesia in rats. This can be quantified by measuring the withdrawal threshold for muscle pressure and grip strength. TNF injection does not cause muscle morphological damage (1).

Pain upon palpation of muscles without morphological abnormalities is typical in human fibromyalgia, fascia pain syndrome or back pain (2). Thus, a model of intramuscular injection of TNF can be used as a model of myalgia associated with fibromyalgia, fascia pain syndrome or back pain. In this model, the antinociceptive action of the novel anticonvulsant lacosamide (LCM) was tested. Control drugs were metamizol (comparative), a non-opioid analgesic, and pregabalin and gabapentin, anticonvulsants.

Mechanical withdrawal thresholds for muscle pressure were measured with an analgesimeter that exerts pressure on the gastrocnemius muscle previously injected with TNF. Forelimb grip strength was measured with a digital grip force meter after TNF injection into the biceps.

Animals, Induction of Muscle Pain

Mature male Sprague Dawley rats weighing 250 g to 300 g were used (School River, Charles 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 (referred to herein as TNF) was obtained from R & D Systems of Minneapolis, Minnesota, USA. TNF was diluted in 0.9% NaCl and used at a concentration of 1 μg / 50 μl. Injections were performed bilaterally with gastrocnemius or brachial biceps with a 30 g needle under short halotane anesthesia. Behavioral tests were performed on all animals prior to injection and baseline values recorded during the 3 day test period.

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 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. The drug was applied and grip strength was tested again after 30-60 minutes.

Application protocol

10 rats per group were treated with 3, 10 or 30 mg / kg lacosamide or vehicle intraperitoneally (i.p.). 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.

Table 1: Injection of TNF into the gastrocnemius muscle

Table 2: Injection of the TNF into the brachial biceps

Data presentation and statistics

Data is plotted on a graph showing mean value and SEM. Pre- and post-treatment data were compared using Analysis of Variance (ANOVA) and Turkey post hot test. Mean values of treatment groups were compared using one-way ANOVA and Dunnett's post hoc test. Maximum possible effects (MPE) were 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 mechanical hyperalgesia of 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.

Biceps muscle 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 drag 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, gabapentin 100 mg / kg, and metamizol 2 mg / kg, MPE (FIG. 4) differed significantly from vehicle. Vehicle did not work.

Review

The withdrawal threshold for pressure applied subcutaneously to muscle was significantly reduced after TNF injection in most rats. This primary muscular hyperalgesia is similar to the tenderness to palpitation observed clinically in patients with myalgia, such as fascia pain syndrome, fibromyalgia and back pain (3). Pain for palpation is a major criterion for the diagnosis of myalgia in clinical and experimental human conditions (4, 5).

Lacosamide dose dependency improves 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 has a stronger effect on muscle pain. Neither pregabalin nor gabapentin induces complete reversal of muscle hyperalgesia. In the grip strength test, lacosamide reverses the effect of TNF on muscle already at 10 mg / kg. Lacosamide is also more potent than pregabalin and gabapentin, which only improve grip strength at 100 mg / kg.

In conclusion, lacosamide was effective in relieving muscle hyperalgesia induced by intramuscularly injected TNF. Thus, lacosamide and related compounds as disclosed in formulas (Ib) and (IIb) are useful for non-inflammatory musculoskeletal pain, such as muscular hyperalgesia and / or allodynia resulting from fibromyalgia, fascia pain syndrome, back pain or osteoarthritis, and And / or have therapeutic efficacy in the treatment of certain symptoms of non-inflammatory osteoarthritis pain, in particular systemic treatment.

Example 2:

A Study on the Nociceptive Effect of Lacosamide in the Iodoacetate Rat Model.

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.

Evaluate the effects of compound pain

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 (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 invasive macrophages, neutrophils, plasma cells and lymphocytes, and swelling of the synovial 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 at 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 groups 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.

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

Reference

Schafers M, Sorkin LS1 Sommer C. Intramuscular injection of tumor necrosis factor-alpha induces muscle hyperalgesia in rats. Pain 2003; 104 (3): 579-588.

2. Pongratz DE, Spath M. Morphologic aspects of fibromyalgia. Z Rheumatol 1998; 57 Suppl 2: 47-51.

3. McCain GA. Fibromyalgia and myofascial pain. In: PD Wall and R Melzack (Eds.). Textbook of pain: Churchill Livingstone, New York, 1994.pp. 475-493.

Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL. The American College of Rheumatology 1990 criteria fo the classification of fibromyalgia: report of the multicenter criteria committee. Arthritis Rheum 1990; 33: 160-172.

5.Arendt-Nielsen L. Induction and assessment of experimental pain from human skin, muscle, and viscera. In: TS Jensen, JA Turner and Z Wiesenfeld-Hallin (Eds.). Proceedings of the 8th World Congress of Pain: IASP Press, Seattle, 1997.

6.Nordenskiold UM1 Grimby G. Grip force in patients with rheumatoid arthritis and fibromyalgia and in healthy subjects. A study with the o Grippit instrument. Scand J Rheumatol 1993; 22: 14-9.

7. Kniffki KD, Mense S, Schmidt RF. Responses of group IV afferent units from skeletal muscle to stretch, contraction and chemical stimulation. Exp Brain Res 1978; 31: 511-22.

8.Mense S, Skeppar P. Discharge behavior of feline gamma- motoneurones following induction of an artificial myositis. Pain 1991; 46: 201-10.

9. Gur A, Karakoc M, Nas K, Remzi, Cevik, Denli A, et al. Cytokines and depression in cases with fibromyalgia. J Rheumatol 2002; 29: 358-61.

10. Nampiaparampil DE1 Shmerling RH (2004) A review of fibromyalgia. Am. J. Manag. Care 10: 794-800. 5

Guzman R.E., Evans M.G., Bove S., Morenko B., Kilgore K., 2003. Mono-iodoacetate-induced histologic changes in subchondral bone and articular cartilage of rat femorotibial joints: an animal model of osteoarthritis. Toxicol Pathol. 31 (6), 619-624.

12. Kalbhen D.A., 1987. Chemical model of osteoarthritis- a pharmacological evaluation. J Rheumatol. 14 Spec No: 130-131.

13.Wieland, H.A., Michaelis, M., Kirschbaum, BJ. , Rudolphi, K.A. 2005. Osteoarthritis-an untreatable disease? Nature Reviews Drug Discovery 4, 331-344.

14. Heppelmann B., 1997. Anatomy and histology of joint innervation. J Peripher Nerv Syst. 2 (1), 5-16.

15. Mach D.B., Rogers S.D., Sabino M.C., Luger N. M., Schwei M.J., Pomonis J. D., Keyser C.P., Clohisy D.R., Adams DJ. , O'Leary P., Mantyh P.W., 2002. Origins of skeletal pain: sensory and sympathetic innervation of the mouse femur. Neuroscience 113 (1), 155-166.

16. Schaible H. G., Ebersberger A., Von Banchet G. S., 2002. Mechanisms of pain in arthritis. Ann N Y Acad Sci. 966, 343-354.

17. Bialer M., Johannessen, S.I., Kupferberg, HJ., Levy, R.H., Loiseau, P., Perucca, E., 2002, Progress report on new antiepileptic drugs: a summary of the Sixth Eilat Conference (EILAT Vl). Epilepsy Res 51, 31-71.

18. Staud R., Smitherman, L. 2002. Peripheral and central sensitization in fibromyalgia: pathogenetic role. Current pain and headache reports 6, 259-266.

Claims (47)

 Having the following formula (lb):

Formula (Ib) 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, lower cycloalkyl lower alkyl, respectively Unsubstituted or substituted with one or more electron donating groups and / or one or more electron withdrawing groups; And 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, is ZY, which may be unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups; Heterocyclic in R ₂ and R ₃ is furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl , Pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, furinyl, Indolinyl, pyrazolindinyl, imidazolinyl, imidazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl, Epoxy, aziridino, oxetanyl, azetidinyl or, if present in the heterocyclic N, is an N-oxide thereof 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, lower alkyl heterocyclic, Y is unsubstituted or one or more electron balls And may be substituted with one or more electron withdrawing groups, wherein the heterocyclic has the same meaning as in R ₂ or R ₃ , If 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 or N ⁺ R ₅ R ₆ R ₇ ,

Satisfies the condition of being; 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, wherein R ₄ , R ₅ and R ₆ are independently unsubstituted or one May be substituted with one or more electron withdrawing groups and / or one or more electron donating groups; And R ₇ is R ₆ or COOR ₈ or COR ₈ , wherein R ₇ may be unsubstituted or substituted with one or more electron withdrawing groups and / or one or more electron donating groups; R ₈ is hydrogen or lower alkyl, or aryl lower alkyl, wherein the aryl or alkyl group may be unsubstituted or 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 non-inflammatory musculoskeletal system and / or such as muscle hyperalgesia and / or allodynia resulting from fibromyalgia, fascia pain syndrome, back pain and / or osteoarthritis of the compound or a pharmaceutically acceptable salt thereof Use in the manufacture of a pharmaceutical composition for the prevention, alleviation and / or treatment of non-inflammatory osteoarthritis pain. The method of claim 1, wherein the non-inflammatory musculoskeletal pain is a regional pain syndrome such as back pain or neck pain, rheumatoid arthritis, osteoarthritis, gout, ankylosing spondylitis, lupus erythematosus, fibromyalgia, fibritis, fibromyalitis, fascia pain Syndrome, autoimmune diseases, rheumatic polymyalgia, multiple myositis, dermatitis, muscle abscess, trichinosis, Lyme disease, malaria, Rocky Mountain spotted fever, poliomyelitis, trauma , Associated with and / or caused by a pathological condition selected from joint injury, joint damage due to trauma, cartilage degeneration, structural bone changes, and vascularization of areas of osteoarthritic bone remodeling. Non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain. 3. The non-inflammatory osteoarthritis pain of claim 1 or 2, wherein the non-inflammatory osteoarthritis pain is from trauma, joint injury, joint injury due to trauma, cartilage degeneration, structural bone change, and angiogenesis of the osteoarthritis bone remodeling site. And non-inflammatory osteoarthritis pain associated with and / or caused by the selected pathological condition. The method of claim 1, wherein the non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain is edema or absence of warmth, absence of inflammatory and / or systemic manifestations, and / or Use characterized by the inherent absence of morning stiffness. The method of claim 1, wherein the non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain is fatigue, sleep disorders, irritable bowel syndrome, chronic headache, jaw joint disorder syndrome. (temporomandibular joint dysfunction syndrome), multiple chemical sensitivity, painful menstrual periods, dysmenorrhea, chest pain, early stiffness, cognitive or memory disorders, numbness and numbness, muscle twitching ), Irritable bladder, feeling of swollen extremities, skin sensitivities, dry eyes and mouth, frequent changes in eye prescription, dizziness and impaired coordination ( and a condition associated with and / or caused by non-inflammatory musculoskeletal pain and / or non-inflammatory osteoarthritis pain selected from impaired coordinaiton). The non-inflammatory musculoskeletal pain of claim 1, wherein the non-inflammatory musculoskeletal pain is associated with and / or caused by osteoarthritis, in particular associated with and / or caused by osteoarthritis. Use is a non-inflammatory musculoskeletal pain. Use according to claim 6, wherein the non-inflammatory pain is non-inflammatory osteoarthritis pain. 8. Use according to any of the preceding claims, wherein one of R ₂ and R ₃ is hydrogen. The use according to any one of claims 1 to 8, wherein n is one. The use according to any one of claims 1 to 9, wherein one of R ₂ and R ₃ is hydrogen and n is 1. The use according to any one of claims 1 to 10, wherein R is aryl lower alkyl and R ₁ is lower alkyl. The compound of claim 1, wherein 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; ZY is NR ₄ NR ₅ R ₇ , NR ₄ 0R ₅ , ONR ₄ R ₇ ,

Use that is. The compound of claim 12, wherein R ₂ is hydrogen and R ₃ is lower alkyl or ZY; 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 ,

Use that is. 14. Lower alkyl, NR ₄ according to any one of claims 1 to 13, wherein R ₂ is hydrogen and R ₃ is unsubstituted or substituted with one or more electron donor groups and / or one or more electron withdrawing groups. 0R ₅ , or ONR ₄ R ₇ . Any one of claims 1 to 14. A method according to any one of claims, wherein R ₃ is unsubstituted or or a hydroxy or lower alkyl which may be substituted by lower alkoxy, NR ₄ 0R _5, or ONR ₄ R _7, wherein R ₄ R ₅ and R ₇ are independently hydrogen or lower alkyl, R is aryl lower alkyl, wherein the aryl group is unsubstituted or can be substituted with one or more electron withdrawing groups and R ₁ is lower alkyl . Use according to claim 1, wherein the aryl is phenyl and unsubstituted or substituted with halo. The compound of claim 1, wherein the compound is (R) -2-acetamido-N-benzyl-3-methoxy-propionamide; (R) -2-acetamido-N-benzyl-3-ethoxy-propionamide; 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; or D-1,2- (O-methylhydroxyamino) -2-acetamido acetate benzylamide. The compound according to any one of claims 1 to 16, wherein the compound has the formula (IIb)

Formula (IIb) In the above, Ar is unsubstituted or phenyl substituted with one or more halo; R ₃ is CH ₂ -Q wherein Q is lower alkoxy containing 1 to 3 carbon atoms, and R ₁ is lower alkyl containing 1 to 3 carbon atoms, or a compound thereof Use is a pharmaceutically acceptable salt. 19. The use of claim 18, wherein Ar is unsubstituted phenyl. The use according to claim 18, wherein said halo is fluoro. 20. The use of claim 18 or 19, wherein R ₃ is CH ₂ -Q wherein Q is alkoxy comprising 1 to 3 carbon atoms and Ar is unsubstituted phenyl. The compound of any one of claims 1 to 16, wherein the compound is of R type

R Has, In the above, R is unsubstituted or benzyl substituted with one or more halo; R ₃ is CH ₂ -Q, wherein Q is lower alkoxy containing 1 to 3 carbon atoms and R ₁ is methyl; or a pharmaceutically acceptable salt thereof. The use of claim 22, which is substantially pure enantiopure. Use according to claim 22 or 23, wherein R is unsubstituted benzyl. 24. The use according to claim 22 or 23, wherein said halo is fluoro. 25. The method of any one of claims 22 to 24, wherein R ₃ is CH ₂ -Q, wherein Q is alkoxy containing 1 to 3 carbon atoms, and R is unsubstituted benzyl The compound of any one of claims 1 to 7, wherein the compound of formula (Ib) is (R) -2-acetamido-N-benzyl-3-methoxypropionamide or a pharmaceutically acceptable salt thereof. Use. The use of claim 27, wherein the compound is a substantially pure mirror image. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is at least 100 mg / day, preferably at least 200 mg / day, more preferably at least 300 mg / day, most preferably 400 mg For use by a dosage of said compound per day or more. The method of claim 1, wherein the pharmaceutical composition is administered at a dose of up to 6 g / day, more preferably up to 1 g / day and most preferably up to 600 mg / day. Use prepared for treatment. 32. The pharmaceutical composition of any one of claims 1 to 30, wherein the pharmaceutical composition is prepared for treatment with a dose that is increased until a predetermined daily dose is reached and maintained for subsequent treatment. Use that is. 32. The method according to any one of claims 1 to 31, wherein the pharmaceutical composition is for treatment by three doses per day, preferably twice a day, more preferably a single daily dose. To be prepared. 33. The pharmaceutical composition of any one of claims 1-32, wherein the pharmaceutical composition is 0.1-15 μg / ml (lowest) and 5-18.5 μg / ml (highest) calculated as an average for the plurality of treated subjects. And is prepared for administration resulting in a plasma concentration of. 34. The use according to any one of claims 1 to 33, wherein said pharmaceutical composition is prepared for oral or intravenous administration. 35. The method according to any one of claims 1 to 34, wherein the pharmaceutical composition comprises non-inflammatory musculoskeletal pain such as muscular hyperalgesia and / or allodynia resulting from fibromyalgia, fascia pain syndrome, back pain and / or osteoarthritis. And / or active agent for the prevention, alleviation and / or treatment of non-inflammatory osteoarthritis pain. 36. The pharmaceutical composition of claim 35, wherein the pharmaceutical composition comprises a first composition comprising a compound as defined by any one of claims 1 and 8 to 28 and a second composition comprising said additional active agent. Use comprising a single dosage form or separate dosage forms. 37. The use according to any one of claims 1 to 36, wherein said pharmaceutical composition is prepared for administration in a mammal. 38. The use of claim 37, wherein the pharmaceutical composition is prepared for administration in humans. (a) a compound as defined in any one of claims 1 and 8 to 28, and (b) preventing, alleviating and / or treating non-inflammatory musculoskeletal and / or non-inflammatory osteoarthritis pain, such as myofascial hypersensitivity and / or allodynia resulting from fibromyalgia, fascia pain syndrome, back pain and / or osteoarthritis. A pharmaceutical composition comprising an additional active agent for the preparation. 40. The pharmaceutical composition of claim 39, wherein the compound of (a) is (R) -2-acetamide-N-benzyl-3-methoxypropionamide. 41. The composition of claim 39 or 40, comprising a first composition comprising a compound as defined in any one of claims 1 and 8 to 28 and a second composition comprising said additional active agent (b). A pharmaceutical composition comprising a single dosage form or comprising separate dosage forms. The pharmaceutical composition of any one of claims 39-41, wherein the additional active agent is an anticonvulsant. The pharmaceutical composition of claim 42, wherein the anticonvulsant is selected from the group consisting of carbamazepine, phenytoin, gabapentin, pregabalin, lamotrigine, and levetiracetam. The pharmaceutical composition of any one of claims 39-41, wherein the additional active agent is one or more anti-osteoarthritis agents, not anticonvulsants. 45. The method according to any one of claims 39 to 41 and 44, wherein said additional active agent, in particular said anti-osteoarthritis agent, is an opioid analgesic or non-opioid analgesic, a steroidal anti-inflammatory agent, an NSAID. Or COX-2 selective inhibitor, or DMOAD. (a) a compound as defined in any one of claims 1 and 8 to 28, and (b) a pharmaceutical composition comprising additional active agents for the prevention, alleviation and / or treatment of non-inflammatory arthritis pain, such as pain associated with and / or caused by osteoarthritis. 47. The pharmaceutical composition of claim 46, wherein the compound of (a) is (R) -2-acetamide-N-benzyl-3-methoxypropionamide.

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