JP2012513446A - Drugs for treating spinal stenosis - Google Patents

Abstract

The present invention relates to novel uses of 5-HT _2A and 5-HT _2B receptor antagonists for the treatment or prevention of patients with spinal stenosis and the symptoms caused thereby in these patients.
[Selection figure] None

Description

  The present invention relates to patients with spinal canal stenosis and novel uses of the compounds for treating or preventing the symptoms caused thereby in these patients.

  Spinal stenosis refers to spinal stenosis of the spinal column, which is most often due to degenerative wear-related changes in the spinal joints, ligaments and intervertebral discs. It is characterized by constriction of the spinal canal, which causes compression on the spinal cord and nerve roots contained therein. This spinal stenosis belongs to the most frequently diagnosed and operated spinal disorder.

When this stenosis is at the cervical spine, it is called cervical canal stenosis. Thoracic stenosis is called thoracic canal stenosis. When the lumbar spine is affected, it is called lumbar canal stenosis.
Numerous anatomical causes can cause spinal stenosis. In rare congenital cases, constitutional stenosis occurs (eg, dysplasia, malformation, failure dislocation, spinal bifida, meningocele). However, acquired cervical spine changes are more frequent. These can be caused by trauma, by instability, by inflammatory or neoplastic processes, or by post-surgical changes (eg scars). However, the most clinically relevant cause of spinal stenosis of the spinal column is a degenerative disease, a physiologically occurring wear phenomenon, which occurs secondarily after a degenerative disorder.

  Various anatomical structures that together form the wall of the spinal canal are involved in the development of spinal canal stenosis. These include intervertebral discs, facet joints, and yellow ligaments, ie, strong ligaments extending longitudinally. Direct stenosis occurs when the damaged intervertebral disc bends back or escapes. Intervertebral joint arthritis differs from this by forming a bone protrusion (Spondylophyten, spondylophytes), which in turn affects the width of the spinal canal indirectly by constricting both the spinal canal and nerve openings. Effect. Another cause is thickening of the ligamentum flavum, which closes the dorsal side of the spinal canal.

  Degenerative changes can occur at various locations in the spinal canal, resulting in constriction and stimulation of the spinal cord and / or nerve roots. The formation of serrated bone margins (knoecherne Randzacken, spondylotic osteophytes) from the dorsal limb of the vertebral body results in posterior spondylosis, which occurs mainly inside. Bone anatomy caused by degeneration starting from the sphenoid process results in scaphoid arthritis (Unkarthrose, uncarthrosis) with space requirements constricting to the side. Arthropathy of the spinal joint in the sense of spondyloarthropathy also causes lateral stenosis of the spinal canal and nerve holes. In addition, any form of disc herniation or disc protrusion may occur in the stenosis. A more frequent phenomenon in Asian populations is ossification of the posterior longitudinal ligament (OPPL). This change constricts the spinal canal from the ventral side or side, and thus compresses the spinal cord from the front or side, but there are also rare causes for dorsal space requirements. For example, this occurs due to the enlargement of the yellow ligament, ie the thickening of the lamina ligament, or due to its calcification or ossification.

  Based on epidemiological studies, the incidence is estimated to be 2-8%, and the symptoms are not predominant in any gender but are characteristically manifested in the 50s or 60s. In patients older than 60 years, spinal stenosis is indeed the most frequent reason for spinal surgery. In special risk groups, including those with whiplash, contact sports athletes or pilots, a higher incidence is described even at a younger age.

  The lumbar spine is most frequently affected by spinal stenosis. The main complaints in cases of lumbar stenosis are weight feeling, pain and weakness, especially in walking and standing, and numbness in the buttocks and / or feet, especially in about 90% of patients. Over 85% of patients complain of back pain. Neurogenic intermittent claudication (90%), ie pain after a short walk, occurs in 90% of all patients. At that time, the pain increases when the patient is standing, whereas the bent posture improves the symptoms. Other symptoms describe muscle tone, disruption of coordination (ataxia), and bladder and rectal disorders, ie defecation and urination problems. The most frequent laboratory findings were spinal flexion disorders (40%), back pain (79%), Lazeg signs (12%), sensory abnormalities (32%), paresis (27%), reflex deficits ( 64%) and bladder dysfunction (6%).

  In contrast, cervical spine stenosis, or cervical canal stenosis, can exhibit significantly different clinical symptoms. Scattered and uncharacteristic pain or discomfort in the hands and / or feet and neck pain (Zervikalgien, cervicalgia) or brachial pain (Brachialgien, brachialgia) can occur. Patients often report a marked increase in hand and / or foot weakness, usually to the side. Gait instability with spastic gait is fairly typical; other dysuria can also occur.

Thoracic stenosis is extremely rare compared to lumbar and cervical stenosis.
During diagnostic tests for spinal canal stenosis , noticeable paresis and sensory impairment may occur in the periphery. Often, hyperreflexia can be detected below the affected part of the spine. Locomotor ataxia (spasticity, entanglement) can also be an indicator of this disease. Quite rarely, only patients with cervical canal stenosis have positive pyramidal signs (Babinsky signs) or positive Lermit signs, while flexion of the cervical vertebrae causes an electric shock along the spine or extremities.

  However, in order to identify spinal stenosis as a cause of pain and neurological symptoms, examinations using imaging methods must be performed. Spinal stenosis cannot be directly identified by general radiography. This requires cross-sectional imaging methods, such as CT (Computerized Tomography) and MRT (Nuclear Magnetic Resonance Tomography), which can display the width of the spinal canal by cutting out their cross-sections. MRT is most useful because it not only displays bone structures, but also soft tissue structures in affected areas of the spine can be displayed much better than CT.

  In addition to clinical testing and imaging diagnosis, electrophysiological testing can contribute to the determination and evaluation of the severity of spinal stenosis. Electromyography (EMG), nerve conduction velocity (NLG) and somatosensory evoked potentials (SSEP) can be used to assess in particular the extent and severity of spinal dysfunction and prognosis.

  The natural course of spinal stenosis varies greatly from patient to patient. The onset of this disease is difficult to perceive, and the progression of symptoms changes during the course. The course of deterioration is rarely linear. It can be stagnant at various stages of the disease. As degenerative changes increase, the progression of spinal stenosis occurs and the spinal cord eventually collapses. Unbearable pain and eventually paralysis can occur.

General therapy :
Definitive diagnosis based on medical history, clinical symptoms, imaging methods and / or possibly electrophysiological examinations, especially if there are signs of spasticity with dysfunction (including partial palsy) and severe sensory impairment Surgery is instructed. In so doing, the purpose of any operation is the removal of the stenosis and thus the release of the spinal cord. Various surgical techniques are employed depending on the findings of the imaging method (X-ray, CT, MRT, myelography). The most frequently used methods include ventral decompression with joints, vertebral body replacement as an extension of ventral decompression and corpectomy (Korporektomie, corporectomy), dural incision and expansion Dorsal decompression with or without, and laminoplasty. Surgical orthopedic invasion for removal of lumbar canal stenosis, especially neurosurgical invasion of the cervical spine for removal of cervical canal stenosis, generally involves a relatively high risk and therefore has advanced Only those with staged disease, especially those with imminent paralysis, are employed after a thorough profit and loss analysis by the attending physician. In addition, the risk of non-recoverable spinal cord injury from minor accidents must be considered in such surgical procedures.

  When sensory and / or motor dysfunction is milder or surgical procedures are contraindicated, treatment for spinal stenosis is usually conservative. This includes, on the one hand, cervical spine fixation by external fixation (cervical collar) or fixation by wearing a corsurge or corset in cases of lumbar stenosis. On the other hand, gymnastic therapy is performed to stabilize the muscles and remove the lordosis.

  Pain, the main symptom present in most cases, is often symptomatic and is a pain relieving drug, such as an analgesic (eg, paracetamol, N-acetylsalicylic acid), opioid administration, pain relieving plaster It is treated with agents, pain pump implantation, or invasive therapy using nerve blockade, periradikulaere Therapie, periradicular therapy, pain point infiltration, or transcutaneous electrical stimulation (TENS). In cases of muscle spasticity, drugs such as baclofen or tetrazepam are used. Non-steroidal anti-inflammatory drugs or corticosteroids administered epidurally are also used.

  Although the above medications ameliorate pain, the pain-relieving effect is usually only effective for a limited time, and for other effects of the disease, such as muscle stiffness, painless motility disorders, and impaired work performance Almost no effect.

Pathology and molecular targets:
In addition to treatment with symptomatic pain therapy and anti-inflammatory drugs, to date, few drugs have been described that significantly improve the overall clinical symptoms of spinal stenosis by causal treatment to the pathophysiological process.

Experimental indications suggest a combination of various pathologic mechanisms involving the inflammatory process in the multifaceted symptoms of spinal stenosis.
Physiological changes in epidural space pressure and the diameter of blood vessels supplying the spinal cord and ganglia caused by the posture of patients with spinal canal stenosis have been clinically proven, and the occurrence of neurogenic intermittent claudication Correlate. Local vascular endothelial cell dysfunction and changes in the response of body messenger substances have been discussed in this regard. As another mechanism, up-regulation of neurotransmitter receptors in the spinal cord and dorsal and ventral ganglia has been considered, resulting in altered processing of nerve impulses resulting in spinal hypersensitivity and stimulation.

These pathologic mechanisms are related to the therapeutic effects of calcitonin (Calcif Tissue Int 1992 May; 50 (5): 400-3) and treatment of symptoms associated with lumbar disc herniation in the treatment of spinal stenosis It forms a rational for the feasibility of using serotonin antagonists such as sarpogrelate. In particular, it is described that patients with neurogenic intermittent claudication due to lumbar canal stenosis are treated by administration of sarpogrelate as a 5-HT _2A receptor antagonist. In this regard, it is presumed that the mechanism of action is an improvement in blood flow of nerve endings that are chronically constricted due to stenosis ( J Peripher Nerv Syst. 2004 Dec; 9 (4): 263-9). EP 1609480 A1 discloses a medicament for the treatment of spinal stenosis, which consists of a combination of EP2 agonists and EP3 agonists. In Japan, the prostaglandin E1 derivative, limaprost alfadex, was approved to treat low back pain stenosis-related symptoms under the trade name of opalmon (Spine 2008 June; 33 (13): 1465 -9). Furthermore, US 20060058310 A1 describes the use of aldose reductase inhibitors for the treatment of spinal canal stenosis and DE 69919191 T2 discloses the use of pyridazinone compounds for the treatment of spinal canal stenosis. .

  Ergot pathogens cause alkaloids that can cause diseases known as ergot poisoning (St. Antoniusfeuer, Saint Anthony's Fire) with symptoms such as bowel cramps due to circulatory disturbances, necrosis of fingers and toes, and hallucinations. Produce. Ergoline forms the backbone of ergoline alkaloids.

The ergoline skeleton contains structural elements that are the basis for the interaction of various neurotransmitters and their receptors. This basic skeleton mimics the neurotransmitters dopamine, serotonin, noradrenaline and histamine. Depending on the modification of the basic ergoline skeleton by chemical modification, compounds that act as agonists or antagonists at one or more of the neurotransmitter receptors may be obtained. Some ergoline alkaloids are important in medicine because of their pharmacological action, especially for the treatment of migraine, peripheral circulatory disturbance, Parkinson's disease and restless legs syndrome, or they are postpartum uterine regression and postpartum It is used as a drug for supportive treatment of bleeding as well as an antihypertensive drug.

  For example, the ergoline derivative nicergoline has been described for use in the treatment of lumbar canal stenosis in combination with behavioral and physical therapy (Reumatologia 2004, T. 42 (1), 59-63). It is estimated that the microcirculation at the nerve ending is improved by these drugs used. However, the above results are only further unproven findings, the presumed effects of the compounds used have not been confirmed, and the actual properties of the substances used belonging to a significantly different class are not disclosed.

  Nicergoline is known to be an adrenergic antagonist and is used as a vasoactive drug for improving blood flow and in the treatment of vascular disorders and dementia. Nicergoline does not act on the serotonin system in the therapy-related dose range as dopamine agonists such as sarpogrelate or the ergoline derivative terguride act.

The action of ergot alkaloids varies. They can stimulate dopamine receptors and inhibit the release of prolactin and somatotropin. The 8- (R) -diastereomer of lisuride has recently been identified as the most effective agonist at present for the human H1 receptor (Bakker et al., Mol Pharmacol 65: 538-549, 2004). More recent work (Dissertation Gornemann, FU Berlin, 2008) has shown that some ergoline derivatives have a high affinity for α ₂ -adrenergic receptors and 5-HT _2A , 5-HT _2B and 5HT ₇ receptors. It was shown to be an antagonist.

  From WO 07/110047 A2, the use of ergurin derivatives terguride and proterguride is known for treating chronic pain and chronic pain conditions, in particular those caused by fibromyalgia. In view of the dopaminergic effects of terguride on pain management, terguride administration in fibromyalgia was presumed to have a therapeutic effect. The main symptoms of fibromyalgia are non-localized non-specific chronic pain and high pressure point stress, possibly due to central nervous system (CNS) dysfunction. Of the large group of fibromyalgia patients, about 80% report pain in the cervical spine area, while about 20% actually only have cervical canal stenosis.

  Holman and Myers (ARTHRITIS & RHEUMATISM, Vol. 52, No. 8, August 2005, pp. 2495-2505) is a double-blind study using the dopamine agonist pramipexole in patients with fibromyalgia Carried out. In this study, patients with cervical spondylosis were specifically excluded. In a more recent study by Holman, patients with fibromyalgia with cervical stenosis have a poor response to dopamine agonists, so other patients should adopt other treatment options such as pregabalin. It was pointed out (J Pain 2008 Jul; 9 (7): 613-22).

  Further, Example 8 of said WO 07/110047 describes treating patients with chronic pain due to herniated disc herniation by co-administration of terguride and the analgesic oxycodone. Treatment of spinal stenosis, particularly cervical stenosis, with terguride is not described. Intervertebral hernia is usually a limited time event. Intervertebral hernia usually occurs in the lumbar region and much less frequently in the cervical region. Administration of terguride for the treatment of lumbar disc herniation has been used to treat the associated chronic pain. Since terguride is known to have a dopaminergic action, its effect on pain management is expected.

  Intervertebral hernia differs from spinal stenosis in both its symptoms and the cause of the symptoms. Intervertebral disc herniation can be accompanied by intermittent spinal canal stenosis and resulting pain, or intervertebral disc herniation can occur in combination with spinal canal stenosis, but this is due to mechanical suppression of the vertebral body and The occurrence of painful spinal cord compression resulting therefrom is a problem. In various studies, spinal stenosis includes symptoms that are not typical for herniated discs, such as specific limitations in functional motility and sensation of the hands, feet and neck, which are typical gait disorders such as It has been shown to be associated with neurogenic intermittent claudication (Clin. Biomech. 1992 (7), 3-17). Furthermore, spinal canal stenosis alone has not been shown to cause spinal canal stenosis, and conversely, spinal canal stenosis is not the sole cause of spinal canal stenosis, but rather other special cases. It can be concluded that the cause must play a role and this must be taken into account in the treatment (Clin. Biomech. 1992 (7), 3-17). In contrast, spinal canal stenosis is always characterized by vertebral body proliferation or ossification and is therefore a degenerative disorder involving the spine. Such degeneration of the vertebral body is not caused by disc herniation, whereas disc herniation is characterized by mechanical inhibition or damage and so-called “sliding action” as described above. The fact that painful changes in the spinal column can be responsible for a wide variety of symptoms can also be obtained from “Cervical spondylosis and neck pain” (BMJ 2007 (334), 527-531).

  Therefore, it is not possible to speculate that the treatment of intervertebral disc herniation is also successful in the treatment of spinal canal stenosis, since in principle it has to affect different working levers.

EP 1609480 A1 US 20060058310 A1 DE 69919191 T2 WO 07/110047 A2

Calcif Tissue Int 1992 May; 50 (5): 400-3 J Peripher Nerv Syst. 2004 Dec; 9 (4): 263-9 Spine 2008 June; 33 (13): 1465-9 Reumatologia 2004, T. 42 (1), 59-63 Bakker et al., Mol Pharmacol 65: 538-549, 2004 Dissertation Gornemann, FU Berlin, 2008 Holman and Myers, ARTHRITIS & RHEUMATISM, Vol. 52, No. 8, August 2005, pp. 2495-2505 J Pain 2008 Jul; 9 (7): 613-22 Clin. Biomech. 1992 (7), 3-17 “Cervical spondylosis and neck pain”, BMJ 2007 (334), 527-531

The clinical trial design conducted in connection with this application was first made to test the effect of terguride as a basic dopamine agonist in patients with fibromyalgia. In view of the study by Holman, the patient was further examined for the presence of cervical stenosis and a history with chronic neck pain. The study hypothesis is that-unlike patients with primary fibromyalgia, i.e., patients without cervical stenosis-patients with cervical stenosis or chronic cervical pain will not respond to therapy with terguride. there were. In the meantime, clinical trials have shown that another dopamine agonist, ropinirole, cannot demonstrate a therapeutic effect in patients with fibromyalgia under therapy with this dopamine agonist (http: //ctr.gsk. co.uk/summary/ropinirole/II rof102100.pdf).
Consistent with this, a significant therapeutic effect with terguride over placebo in patients with primary fibromyalgia could not be demonstrated.

Surprisingly, we can selectively improve the symptoms caused by terguride in patients with spinal canal stenosis, while in patients with cervical pain without spinal canal stenosis. It could be shown that no significant effect was achieved. The combination of 5-HT _2A and 5-HT _2B receptor antagonism exists in terguride, which significantly inhibits both receptor isoforms simultaneously in the therapeutically effective dose range. It is considered related. At the same time, it represents a characteristic therapy principle for therapeutic applications.

FIG. 1 shows the effect of terguride on selected patient-oriented scales and questionnaires regarding general status in patients with chronic generalized pain and cervical stenosis (grades 2-4). FIG. 2 shows the effect of terguride on selected patient-oriented measures and questionnaires regarding general status in patients with chronic generalized pain but not cervical stenosis (grade 0-1). FIG. 3 shows the effect of terguride on selected patient-oriented measures and questionnaires regarding general status in patients with chronic generalized pain and neck pain but no signs of spinal stenosis (grade 0-1). Indicates.

Accordingly, the present invention relates to 5-HT _2A and 5-HT _2B receptor antagonists for the treatment or prevention of patients with spinal stenosis, preferably cervical spinal stenosis, and the symptoms caused thereby in these patients Provides a novel use of a compound that is In particular, the present invention provides said use in the early stages of this disease for the prevention and intervention of spinal stenosis. Nonetheless, surgical intervention is unavoidable in some advanced stages, when symptoms of paralysis already appear and the onset of transverse paralysis is imminent. Even at such a stage, the use according to the invention can still be a concomitant treatment in some circumstances.

The use of compounds that are antagonists of both 5-HT _2A and 5-HT _2B receptors in the treatment of patients with spinal stenosis, especially cervical stenosis, is not described in the prior art. Preferably, the compounds are further 5-HT ₇ receptor antagonists and / or α ₂ -adrenergic receptor antagonists, particularly preferably further α ₂ -adrenergic receptor antagonists, especially α _{2 C} -adrenergic receptor antagonists.

Antagonists in the sense of the present invention generally bind to the aforementioned receptors (5-HT _2A , 5-HT _2B and 5-HT ₇ receptors, as well as α ₂ -adrenergic receptors, in particular α _2C -adrenergic receptors). It is a compound that reduces or nullifies the action of the body's messenger substances serotonin and noradrenaline or substances acting as agonists.

pA ₂ valence is often used to represent the characteristics of the antagonist potency of the compound.
pA ₂ valence is the negative common logarithm of the substance concentration of an antagonist that is required to double the concentration of an agonist such as serotonin to achieve the original effect obtained in the absence of the antagonist. Thus, pA ₂ valency is a measure of the affinity of an antagonist for the receptor and is independent of the manner in which the antagonist operates. Preferably, pA ₂ valence method according Arunlakshana and Schild (Arunlakshana O, Schild HO, Some quantitative uses of drug antagonists, Br J Pharmacol 14: 48-58 (1959)) is measured by.

Suitable 5-HT _2A , 5-HT _2B and 5-HT ₇ receptor antagonists and / or α ₂ -adrenergic receptor antagonists, in particular α _2C -adrenergic receptor antagonists, are described in particular in the article by Goernemann, FU Berlin, 2008. It can be determined by the method described in 1.

For example, 5-HT _2A receptor antagonists can be identified by characterizing contractile effects on porcine coronary arteries, particularly under certain experimental conditions (Cushing DJ, Cohen ML (1993), J Pharmacol Exp Ther 264: 193- See also 200).

Appropriate 5-HT _2B receptor antagonists can be identified by characterizing the relaxant action on porcine pulmonary arteries, especially under certain experimental conditions (Glusa E, Pertz HH (2000) Br J Pharmacol 130: 692-698). See also).

Appropriate 5-HT ₇ receptor antagonists can be identified by characterizing the relaxant effect on the pulmonary artery of the weanling piglet, particularly under certain experimental conditions (Jaehnichen et al. (2005) Nauyn-Schmiedebergs Arch Pharmacol 371: 89-98).

Appropriate α ₂ -adrenergic receptor antagonists, particularly α _2C -adrenergic receptor antagonists, can be identified by characterizing the contractile effects on the pulmonary veins of slaughter pigs, particularly under selected experimental conditions (Goernemann et al Br J Pharmacol 2007 May; 151 (2): 186-94). Since there is usually an overlapping interaction between the active substance and the α _2A -receptor and α _2C -receptor, the inhibition constant for the α _2C -receptor is given below as a measure of the α ₂ -anti-adrenergic action of the substance. Define.

Preferred compounds according to the invention have the following pA ₂ values at 5-HT _2A , 5-HT _2B and 5-HT ₇ receptors, as well as α ₂ -adrenergic receptors, in particular α _2C -adrenergic receptors:
Preferably, the compounds according to the invention are 5-HT _2A receptor antagonists with a pA ₂ value ≧ 7.5.

Preferably, the compounds according to the invention are 5-HT _2B receptor antagonists with a pA ₂ value ≧ 7.5.
Particularly preferably, the compounds according to the invention have a pA ₂ ≧ 7.5, more preferably a pA ₂ ≧ 8 at both the 5-HT _2A receptor and the 5-HT _2B receptor.

In a particularly preferred embodiment, the compounds according to the invention have a pA ₂ > 7.5, more preferably a pA ₂ ≧ 8 at both the 5-HT _2A receptor and the 5-HT _2B receptor.
Preferred compounds according to the invention are also preferably 5-HT ₇ receptor antagonists, preferably with a pA ₂ ≧ 7.5.

Furthermore, particularly preferably, the compounds according to the invention, in addition to their properties as 5-HT _2A and 5-HT _2B receptor antagonists, preferably also α ₂ -adrenergic receptor antagonists with a pA ₂ ≧ 7.5, Preferably it is also an [alpha] _2C -adrenergic receptor antagonist.

Further according to the invention, particularly preferably _{5-HT 2A} pA ₂ divalent and maximum ± 1 unit different compounds of the compound pA ₂ valent for _{5-HT 2B} receptor for the receptor. That is, according to the present invention,
| PA ₂ (5-HT _2A ) -pA ₂ (5-HT _2B ) | ≦ 1
Is particularly preferred. This significantly inhibits the pathophysiological processes mediated by one or the other receptor in the same dose range under treatment with a representative drug, thus enhancing the therapeutic efficacy of patients with spinal stenosis with diverse medical history And a wide range of responses can be achieved.

The following table shows the _{5-HT 2A} and _{5-HT 2B} receptor antagonist is exemplified compounds as well as their pA ₂ valence.

This table shows that according to the present invention cyproheptadine, mianserin, ritanserin, methiothepine, methysergide, metergoline, lisuride, terguride, trazodone, pizotifen and nicergoline are preferred: those at 5-HT _2A and 5-HT _2B receptors This is because the pA ₂ of each is ≧ 7.5 and the difference between them is less than one unit (absolute value). Particularly cyproheptadine According to the present invention, ritanserin, methiothepin, methysergide, lisuride, is terguride and pizotifen particularly preferred: a _{5-HT 2A} and _{5-HT 2B} receptor ≧ their pA ₂ respectively in body 8, and respective differences Is less than one unit (absolute value). Of these compounds, terguride and lisuride are particularly preferred.

  The compounds used in accordance with the present invention are useful for treating patients with spinal stenosis and the symptoms caused thereby in these patients. Particularly preferably, the compounds used according to the invention are useful for treating patients with cervical stenosis and related symptoms. As already described in detail at the outset, spinal stenosis represents spinal stenosis, in particular degenerative changes or stenosis of the spinal canal. Preferably in the case of cervical canal stenosis treated according to the invention, this is in the region of the cervical spine. Therefore, the result is a difference between the size of the spinal cord (Rueckenmark, spinal cord) (Myelon, myelon) and the spinal canal, making the spinal canal relatively small. As a result, the spinal cord and / or nerve roots are compressed. Relative stenosis is referred to as absolute stenosis when the sagittal diameter of the cervical spine is narrowed to 10-12 (13/14) mm, based on radiological criteria, and less than 10 mm. The clinical manifestations of cervical myelopathy can be quite diverse. Scattered and uncharacteristic pain or discomfort in the hands and / or feet, and neck or brachial pain can occur. Patients often report a marked increase in hand and / or foot weakness, usually to the side. Gait instability with spastic gait is fairly typical. In addition, dysuria may further occur.

  In contrast, as already explained, disc herniation is characterized by mechanical displacement of the vertebral body or so-called disc slippage, which places painful compressions on the spinal cord. Such symptoms are clearly different from the vertebral body degenerative changes characteristic of spinal stenosis. Unlike spinal stenosis, so-called cauda equina are rarely affected in cases of herniated discs. In spinal canal stenosis, clinical symptoms are not caused directly by the stenosis itself, but rather by additional degenerative deformation of the vertebral body, which may remain asymptomatic without spinal canal stenosis (Clin. Biomech. 1992 (7), 3-17).

Thoracic stenosis:
The thoracic vertebra is integrated into the dense support structure due to its anatomical relationship with the ribs, and therefore has less longitudinal and lateral freedom of movement than the cervical and lumbar vertebrae, thus reducing the risk / possibility of wear and bone mutation Fewer. Significantly, thoracic spinal stenosis is rarer; diagnostic and therapeutic options correspond to other spinal stenosis.

Lumbar stenosis:
Typical complaint: “Sole” pain along the skin sensation zone of a specific hip root (mostly L3-L5). Often accompanied by paralysis of the hip flexor, anterior thigh muscles, rarely raised legs, and very rarely. In classical pathology, so-called “intermittent claudication” (neurogenic claudication); that is, the patient has to sit after a short time, eventually pain relief occurs, then he can walk a few meters again, then sit again, etc. .

  Diagnosis of all of the above mentioned spinal stenosis includes detailed neurological laboratory tests (optionally accompanied by evoked potentials) by specialists (neurologists), detailed medical history, and more specific tests (EMG, nerve conduction velocity) , Measurement of evoked potentials, etc.) as well as imaging methods (MRT, CT, and possibly myelography) in particular; of these, MRT is the most preferred diagnostic method, thereby sagittal direction of the spinal canal The existence of diameter stenosis and spinal stenosis can be determined without question.

Preferably, said compounds are used for the treatment of cervical and / or lumbar canal stenosis, preferably cervical canal stenosis.
Use according to the invention includes treatment of all symptoms that may be associated with spinal stenosis.

  In addition to the symptoms already mentioned above, these include symptoms of paresis, hyposensory, sensory abnormalities, pain and / or sensory disturbances, such as sensory paralysis, which are alleviated or ameliorated by the administration of the compounds according to the invention. be able to.

  Furthermore, the use according to the invention is also useful for improving physical dysfunction, in particular movement disorders of the affected part of the spine. Thus, the use according to the invention also achieves an improvement in muscle weakness, an improvement in gait disturbance, an improvement in ant running and / or an ataxia. In particular, the use of the compounds of the present invention in the treatment of spinal canal stenosis can achieve improved painless motility and reduced heading abnormalities. Such abnormal head orientation due to pain usually results in additional muscular stiffness and spastic muscle abnormalities resulting in worse motility and increased pain. Furthermore, the use according to the invention improves urinary and fecal incontinence when the cause is due to spinal stenosis.

In a particularly preferred use according to the invention, this is useful for the treatment of whiplash, other traumatic changes or spinal stenosis which is the chronic prognosis of disc herniation.
In another particularly preferred embodiment of the use according to the invention, this serves to prevent a patient with whiplash to prevent the chronic effects of spinal stenosis as its prognosis.

  In another particularly preferred embodiment of the use according to the invention, this serves for the prophylactic treatment of patients with spinal stenosis and the symptoms thereby caused in these patients to prevent the chronicity of the syndrome.

The present invention further provides for the treatment or prevention of patients with spinal stenosis, in particular patients with cervical stenosis, and the symptoms caused thereby in these patients, as already detailed above. To the ergoline derivatives, preferably the aforementioned compounds, which are 5-HT _2A and 5-HT _2B receptor antagonists as detailed above. According to the present invention, an ergoline derivative is a compound derived from ergoline in the formula:

That is, its 4,6,6a, 7,8,9,10,10a-octahydro-indolo [4,3-fg] quinoline skeleton is optionally dehydrogenated in the formula as well. The dehydrogenated form specifically includes the basic skeleton of lisuride:

This is a 4,6,6a, 7,8,9-hexahydro-indolo [4,3-fg] quinoline skeleton. Thus, all ergoline derivatives in the sense of the present invention are derivatives obtained by substitution of at least one hydrogen atom in ergoline or dehydroergoline in the formula.

  Preferred ergoline derivatives are compounds of the formula:

In the formula:
R ¹ and R ⁴ independently of one another represent hydrogen, alkanoyl, (preferably —CHO, —COCH ₃ , —COC ₂ H ₅ , —COC ₃ H ₇ , —CO-cyclo-C _{3 H 5, -COCH (CH 3)} 2, -COC (CH 3) 3), carboxyl (-COOH), alkoxycarbonyl _{(preferably, -COOCH 3, -COOC 2 H 5} , -COOC 3 H 7, -COO - cyclo _{-C 3 H 5, -COOCH (CH} 3) 2, -COOC (CH 3) 3), alkoxythiocarbonyl, alkyl thio thiocarbonyl, carbamoyl (-CONH _2,), a mono - or dialkylamino carbonyl (preferably _{, -CONHCH 3, -CONHC 2 H 5} , -CONHC 3 H 7, -CONH- cyclo -C _{H 5, -CONH [CH (CH} 3) 2], - CONH [C (CH 3) 3], - CON (CH 3) 2, -CON (C 2 H 5) 2, -CON (C 3 H 7 ) ₂ , —CON (cyclo-C ₃ H ₅ ) ₂ , —CON [CH (CH ₃ ) ₂ ] ₂ , —CON [C (CH ₃ ) ₃ ] ₂ ), amino (—NH ₂ ), mono- or dialkylamino _{(preferably, -NHCH 3, -NHC 2 H 5} , -NHC 3 H 7, -NH- cyclo _{-C 3 H 5, -NHCH (CH} 3) 2, -NHC (CH 3) 3, -N _{(CH 3) 2, -N (} C 2 H 5) 2, -N (C 3 H 7) 2, -N ( cyclo _{-C 3 H 5) 2, -N} [CH (CH 3) 2] 2, _{-N [C (CH 3) 3} ] 2), alkylsulfoxyl (preferably, -SO _{H 3, -SOC 2 H 5,} -SOC 3 H 7, -SO- cyclo _{-C 3 H 5, -SOCH (CH} 3) 2, -SOC (CH 3) 3), alkylsulfonyl (preferably, -SO _{2 CH 3, -SO 2 C 2} H 5, -SO 2 C 3 H 7, -SO 2 - cyclo _{-C 3 H 5, -SO 2 CH} (CH 3) 2, -SO 2 C (CH 3) 3 ), Sulfo (—SO ₃ H,), alkyl sulfonate (preferably —SO ₃ CH ₃ , —SO ₃ C ₂ H ₅ , —SO ₃ C ₃ H ₇ , —SO ₃ -cyclo-C ₃ H ₅ , —SO ₃ CH (CH ₃ ) ₂ , —SO ₃ C (CH ₃ ) ₃ ), halogen alkyl (preferably —CH ₂ F, —CHF ₂ , —CF ₃ , —CH ₂ Cl, —CH ₂ Br _{, -CH 2 I, -CH 2 -CH} 2 F, -CH _{2 -CHF 2, -CH 2 -CF 3} , -CH 2 -CH 2 Cl, -CH 2 -CH 2 Br, -CH 2 -CH 2 I), alkyl _(preferably, -CH 3, _-C 2 H _{5, -C 3 H 7, -CH} (CH 3) 2, -C (CH 3) 3, -C 4 H 9, -CH 2 -CH (CH 3) 2, -CH (CH 3) -C 2 _{H 5, -C 5 H 11,} -C 6 H 13, -C 7 H 15, -C 8 H 17, - cyclo _-C 3 _{H 5,} - cyclo _-C 4 _{H 7,} - cyclo _-C 5 _{H 9} , -Cyclo-C ₆ H ₁₁ ), aryl (preferably phenyl), arylalkyl (preferably —CH ₂ —Ph, —CPh ₃ ), alkenyl (preferably —CH═CH ₂ , —CH ₂ —CH _{= CH 2, -C (CH 3} ) = CH 2, -CH = CH-CH _{, -C 2 H 4 -CH = CH} 2, -CH = C (CH 3) 2), alkynyl _{(preferably, -CoCH, -CoC-CH 3,} -CH 2 -CoCH);
R ² and R ³ independently represent:
hydrogen,
Optionally substituted linear, branched or cyclic, saturated or unsaturated hydrocarbon residues; for example:
-Optionally substituted alkyl,
An optionally substituted alkenyl,
An optionally substituted aryl,
An optionally substituted alkylaryl,
Preferably defined below.

For the present invention as a whole, ie with respect to other substituents, the optionally substituted alkyl preferably includes the following:
Linear or branched alkyl having 1 to 8, preferably 1 to 6 carbon atoms, cycloalkyl having 3 to 8, preferably 5 or 6 carbon atoms, or 1 to 4 carbon atoms Each having an alkyl and substituted with cycloalkyl; each optionally has preferably 1 to 3 substituents, which are preferably selected from the group consisting of hydroxy, halogen and cyano . Here and in the context of the present invention, halogen includes fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine. Furthermore, one or more, preferably 1 to 3 carbon atoms may be replaced by a hetero-analogous group containing nitrogen, oxygen or sulfur. This means in particular that, for example, one or more methylene groups in the alkyl residue may be substituted by NH, O or S.

  Examples of alkyl residues having 1 to 8 carbon atoms include: methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec -Butyl group, t-butyl group, n-pentyl group, i-pentyl group, sec-pentyl group, t-pentyl group, 2-methylbutyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group 3-methylpentyl group, 4-methylpentyl group, 1-ethylbutyl group, 2-ethylbutyl group, 3-ethylbutyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl Group, 1-ethyl-1-methylpropyl group, n-heptyl group, 1-methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group 1-ethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, 4-ethylpentyl group, 1,1-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 4, 4-dimethylpentyl group, 1-propylbutyl group, n-octyl group, 1-methylheptyl group, 2-methylheptyl group, 3-methylheptyl group, 4-methylheptyl group, 5-methylheptyl group, 6-methyl Heptyl group, 1-ethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 5-ethylhexyl group, 1,1-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl Group, 4,4-dimethylhexyl group, 5,5-dimethylhexyl group, 1-propylpentyl group, 2-propylpentyl group Such as. Preference is given to groups having 1 to 6 carbon atoms, in particular methyl, ethyl and n-propyl. Most preferred is methyl.

  Examples of alkyl groups obtained by exchanging with one or more hetero-analogous groups, for example -O-, -S- or -NH-, preferably have one or more methylene groups substituted by -O-. Those formed with an ether group, such as methoxymethyl, ethoxymethyl, 2-methoxyethylene and the like. According to the invention, the definition of alkyl includes polyether groups.

  Cycloalkyl residues having 3 to 8 carbon atoms preferably include the following: cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and the like. Preferred are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Heterocyclic alkyl residues formed by methylene exchange from cycloalkyl to hetero-analogous groups are, for example, 5- or 6-membered heterocyclic residues, such as tetrahydrofuryl, pyrrolidinyl, piperidinyl or tetrahydropyranyl, these May optionally be condensed with an aromatic ring or the like.

  In particular, examples of halogen-substituted linear or branched alkyl residues having 1 to 8 carbon atoms include: fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl Group, dichloromethyl group, trichloromethyl group, bromomethyl group, dibromomethyl group, tribromomethyl group, 1-fluoroethyl group, 1-chloroethyl group, 1-bromoethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2 -Bromoethyl group, 1,2-difluoroethyl group, 1,2-dichloroethyl group, 1,2-dibromoethyl group, 2,2,2-trifluoroethyl group, heptafluoroethyl group, 1-fluoropropyl group, 1-chloropropyl group, 1-bromopropyl group, 2-fluoropropyl group, 2-chloropropyl group, 2-bromopropylene Group, 3-fluoropropyl group, 3-chloropropyl group, 3-bromopropyl group, 1,2-difluoropropyl group, 1,2-dichloropropyl group, 1,2-dibromopropyl group, 2,3-difluoropropyl Group, 2,3-dichloropropyl group, 2,3-dibromopropyl group, 3,3,3-trifluoropropyl group, 2,2,3,3,3-pentafluoropropyl group, 2-fluorobutyl group, 2-chlorobutyl group, 2-bromobutyl group, 4-fluorobutyl group, 4-chlorobutyl group, 4-bromobutyl group, 4,4,4-trifluorobutyl group, 2,2,3,3,4,4,4 -Heptafluorobutyl group, perfluorobutyl group, 2-fluoropentyl group, 2-chloropentyl group, 2-bromopentyl group, 5-fluoropentyl group, 5-chloropente Group, 5-bromopentyl group, perfluoropentyl group, 2-fluorohexyl group, 2-chlorohexyl group, 2-bromohexyl group, 6-fluorohexyl group, 6-chlorohexyl group, 6-bromohexyl group, perfluoro Hexyl group, 2-fluoroheptyl group, 2-chloroheptyl group, 2-bromoheptyl group, 7-fluoroheptyl group, 7-chloroheptyl group, 7-bromoheptyl group, perfluoroheptyl group and the like.

  Examples of hydroxy substituted alkyl residues having 1 to 3 hydroxyl residues include, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.

  For the purposes of the present invention, optionally substituted alkenyl preferably includes: straight chain or branched alkenyl having 2 to 8 carbon atoms, and 3 to 8 carbon atoms. Cycloalkenyl; these may optionally be substituted with preferably 1 to 3 substituents such as hydroxy, halogen or alkoxy. Examples include: vinyl, 1-methylvinyl, allyl, 1-butenyl, isopropenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl. Vinyl or allyl are preferred.

  For the present invention as a whole, the optionally substituted aryl preferably includes: 6 to 14 carbon atoms (not counting the carbon atoms of the substituents) and the series S, O, N selected 5- to 10-membered aromatic heterocyclic residues having up to 3 heteroatoms, which may be monocyclic or bicyclic, preferably hydroxy, halogen, cyano, alkyl, acyl And optionally substituted by 1 to 3 substituents selected from alkoxy. In so doing, the above definitions or examples can be referred to for the definitions of alkyl and halogen.

  Alkoxy as a substituent for aryl includes, for example and below, here and below: an alkyl residue as described above attached to aryl via an oxygen atom, eg a straight chain having up to 6 carbon atoms Or branched alkoxy residues such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, sec-butyloxy, t-butyloxy, n-pentyl Oxy group, i-pentyloxy group, sec-pentyloxy group, t-pentyloxy group, 2-methylbutoxy group, n-hexyloxy group, i-hexyloxy group, t-hexyloxy group, sec-hexyloxy group 2-methylpentyloxy group, 3-methylpentyloxy group, 1-ethylbutyloxy group, 2 Ethyl butyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethyl-1-methylpropyl group. Preferred are methoxy group, ethoxy group, n-propyloxy group, i-propyloxy group, n-butyloxy group, i-butyloxy group, sec-butyloxy group, t-butyloxy group and the like.

  Acyl as a substituent for aryl includes here and below, for example: aliphatic acyl, aromatic acyl, eg C1-C6 alkanoyl, eg formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl , Pivaloyl, hexanoyl, and the like, and C6-C10 aroyl such as benzoyl, toluoyl, xyloyl, and the like.

  Aromatic hydrocarbon residues having 6 to 14 carbon atoms include, for example: phenyl, naphthyl, phenanthrenyl, and anthracenyl; these may be optionally substituted. Phenyl is preferred.

  Heteroaromatic residues include, for example: pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl, Benzo [b] thienyl, benzo [b] furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl. 5- or 6-membered aromatic heterocycles such as pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, furyl and thienyl are preferred.

  For the present invention as a whole, the optionally substituted alkylaryl preferably includes the following: 1-8, preferably 1-4, said straight-chain or branched alkyl having 1 to 4 carbon atoms Substituted with aryl. A preferred arylalkyl is benzyl.

-CO-R ^8: wherein, R ⁸ is a straight-chain optionally substituted, branched or cyclic, saturated or unsaturated hydrocarbon residue, which may be of the;
-NH-CO-R ^9: wherein R ⁹ is a straight-chain optionally substituted, branched or cyclic, is saturated or unsaturated hydrocarbon residue; it may be of the ;
^{-NH-CO-NR 11 R 12} : ^{wherein, R 11} and ^{R 12} is a straight-chain optionally substituted hydrogen and / or independently of each other, branched or cyclic, saturated or unsaturated hydrocarbon Hydrogen residues, which may be as described above, or R ¹¹ and R ¹² together with the nitrogen atom to which they are attached a 5- or 6-membered optionally substituted ring. Formed, which may optionally further comprise 1 or 2 heteroatoms: for example piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, pyrrolidin-1-yl, oxazolidine-3 -Yl, thiazolidin-3-yl, 2-carboxyl-pyrrolidin-1-yl (prolyl), 3- or 4-hydroxy-carboxyl-pyrrolidin-1-yl 3- or 4-hydroxy - prolyl) like.

^{-R 13 -O-CO-R 14} : ^{wherein, R 13} is a straight-chain optionally substituted bivalent, branched or cyclic, substituted saturated or unsaturated hydrocarbon residue, for example optionally Optionally substituted alkenediyl; optionally substituted alkanediyl preferably includes: a divalent linear or branched alkanediyl residue comprising 1 -7, preferably 1-6, more preferably 1-4 carbon atoms; these can optionally have 1-3 substituents selected from hydroxy, halogen and cyano; And preferably include the following: methylene, 1,2-ethanediyl, ethane-1,1-diyl, 1,3-propylene, propane-1,1-diyl, propane 1,2-diyl, propane-2,2-diyl, 1,4-butylene, butane-1,2-diyl, butane-1,3-diyl, butane-2,3-diyl, pentane-1,5- Diyl, pentane-2,4-diyl, 3-methyl-pentane-2,4-diyl and hexane-1,6-diyl; preferred substituted alkanediyl residues are hydroxy-substituted alkanediyl residues. The optionally substituted alkenediyl is preferably a divalent linear or branched alkenediyl residue having 2 to 7, preferably 2 to 6, more preferably 2 to 4 carbon atoms. Yes, they can optionally have 1 to 3 substituents selected from hydroxy, halogen and cyano. For example, the following are preferred: ethene-1,1-diyl, ethene-1,2-diyl, propene-1,1-diyl, propene-1,2-diyl, propene-1,3-diyl , But-1-ene-1,4-diyl, but-1-ene-1,3-diyl, but-2-ene-1,4-diyl, buta-1,3-diene-1,4-diyl Penta-2-ene-1,5-diyl, hexa-3-ene-1,6-diyl and hexa-2,4-diene-1,6-diyl. In the context of the present invention, R ¹³ is particularly preferably alkanediyl, more preferably alkanediyl having 1 to 3 carbon atoms, more preferably 1,2-ethanediyl (—CH ₂ CH ₂ —) or 1,3. - propanediyl _{(-CH 2 CH 2 CH 2 -} ) a ^{and, R 14} is a straight-chain optionally substituted, branched or cyclic, saturated or unsaturated hydrocarbon residue, which when Can have one or more of the above defined heteroatoms; and —CO—NR ¹⁵ R ^16, wherein R ¹⁵ and R ¹⁶ are each independently hydrogen and / or as defined above linear optionally substituted as, branched or cyclic, saturated or unsaturated hydrocarbon residue, or R ¹⁵ and R ^16, the nitrogen source which they are attached Together with, the 5 or 6-membered, optionally form a ring substituted, can these also containing one or two heteroatoms optionally as defined above;
R ⁵ is hydrogen, halogen, cyano or nitro;
R ⁶ and R ⁷ are, independently of one another, hydrogen or alkoxy, with reference to the above definition of alkyl for the alkyl moiety or together representing a bond to form a double bond between carbon atoms ( That is, it has the following structure:

And its salts;
To treat or prevent patients with spinal stenosis, especially cervical canal stenosis, and the symptoms caused thereby.

  The compounds used according to the invention include stereoisomers (racemates, enantiomers, diastereomers) when asymmetric carbon atoms are present, as in the case of ergoline derivatives. Accordingly, the present invention includes the use of all stereoisomeric forms, such as enantiomers, diastereomers, and mixtures thereof, such as racemates. Enantiomerically pure forms can optionally be obtained from them by reaction with optically active compounds by means of common optical resolution methods, for example by fractional crystallization of diastereomers. Where the compounds according to the invention can exist in tautomeric forms, the present invention includes all tautomeric forms.

  The compounds used according to the invention can exist as salts, and the invention includes all such salts. The compounds of the present invention can be used in the form of their pharmaceutically acceptable salts. Compounds containing basic groups are particularly salts with pharmaceutically acceptable acids, such as salts with inorganic acids, carboxylic acids and sulfonic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, Tartaric acid, methanesulfonic acid, hydroxyethanesulfonic acid, sulfonic acid, acetylglycine (Acetursaeure, acetyl glycine), maleic acid, propionic acid, fumaric acid, toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, naphthalene-1,5- It can be used as a salt with disulfonic acid, salicylic acid, benzoic acid, lactic acid, malic acid, 3-hydroxy-2-naphthoic acid, citric acid or acetic acid. The compounds containing acidic groups used according to the invention can be used as pharmaceutically acceptable salts with pharmaceutically acceptable bases: for example alkali metal hydroxides (such as sodium salts), alkaline earth metal hydroxides ( Calcium salts, magnesium salts, etc.), amines, etc.

  Ergoline derivatives are described, for example, in WO_92020339_A1, WO_08061805_A1, WO_08043601_A2, WO_07110047_A2, WO_070657713_A2, WO_05025546_A1, WO_03076439_A2, WO_0215890_A1, WO_021589_. Accordingly, the entire document is considered part of this specification.

  Particularly preferred are compounds of the following formula:

In the formula:
R ¹ and R ⁴ are independently of each other hydrogen, alkyl, alkenyl,
R ² and R ³ mean the following:
hydrogen,
^{-NH-CO-NR 11 R 12} : ^{wherein, R 11} and ^{R 12} are hydrogen and / or alkyl independently of one another, or ^{R 11} and ^{R 12} 5 together with the nitrogen to which they are attached - or 6-membered ring is formed, and they can further contain one heteroatom optionally; and / or ^-CO-NR 15 ^{R 16: wherein, R 15} and ^{R 16} are, independently of one another Hydrogen and / or optionally substituted linear, branched or cyclic, saturated or unsaturated hydrocarbon residues, or R ¹⁵ and R ¹⁶ together with the nitrogen atom to which they are attached. Form a 5- or 6-membered, optionally substituted ring, which may optionally further comprise 1 or 2 heteroatoms;
R ⁵ is hydrogen;
R ⁶ and R ⁷ are independently of each other hydrogen, or together represent a bond to form a double bond between carbon atoms;
Among these, preferred substituents are those described above.

  Particular preference is given to the use of compounds according to the following formula:

These are preferably selected from:

Each 8β-derivative is an 8α-derivative, for example an epimer of 8α-lisuride or 8α-terguride.
Of these compounds, the use of 8α-lisuride or 8α-terguride is particularly preferred, and the use of terguride or 8α-terguride is most preferred.

  The present invention further provides the use of a combination of said compound with one or more other active substances. Such preferred other active substances include in particular other active substances known for the treatment of spinal stenosis, such as in particular: aldose reductase inhibitors known from US_20060058310_A1; DE 69919191 Pyridazinone compounds known from T2; and particularly preferably EP2 agonists and EP3 agonists known from EP 1609480 A1 or combinations thereof, such as prostaglandin E1 derivatives, approved under the trade name opalmon.

  Other active substances that can be used in combination with the compounds according to the invention include, for example: prostaglandins, prostaglandin derivatives, so-called “nonsteroidal anti-inflammatory drugs” (NSAIDs), vitamins, muscle relaxation Drugs, antidepressants, poly-ADP-ribose polymerase (PARP) -inhibitors, excitatory amino acid receptor antagonists (eg NMDA receptor antagonists and AMPA receptor antagonists), radical scavengers, astrocyte modulators, IL-8 -Receptor antagonists, immunosuppressants (eg cyclosporine and FK506), and aldose reductase inhibitors. Examples of prostaglandins (abbreviated as PG) include PG receptor agonists, PG receptor antagonists, and the like. Examples of PG receptors include PGE receptors (EP1, EP2, EP3 and EP4), PGD receptors (DP, CRTH2), PGF receptors (FP), PGI receptors (IP), TX receptors (TP) Etc. are included. Examples of prostaglandin derivatives further include limaprost, iloprost and beraprost.

  Examples of NSAIDs include: sasapyrine, sodium salicylate, aspirin, aspirin dialuminate, diflunisal, indomethacin, suprofen, ufenamate, dimethyl dimethyl (Dimethylisopropylazole), bufexamac, felbinac, diclofenac, tolmetin sodium, crinoril, gourfen (fenbene), fenbufene (fenbufene) oglemetacin, indomethacin-farnesyl, acemetacin, acemetacin maleate, profenacin maleate, amfenacol, mofezolac , Ibuprofen-piconol, naproxen, flurbiprofen, flurbiprofenaxetil, ketoprofen (ketoprofen), fenoprofen oprofen calcium, thiaprofenic acid, oxaprozin, pranoprofen, loxoprofen sodium, lominoprofen, altoprofen, altoprofenic acid, altoprofenic acid, altoprofenic acid Aluminum acid, tolfenamic acid, flocafenin, ketophenylbutazone, oxyphenbutazone, piroxicam, tenoxicam cam), ampiroxicam, felbinac, epirizol, tiaramid hydrochloride, rinorin hydrochloride (nin), morphizone (ul), morpholzone (in) saridon, cedes G, amipylo-N (amipylo-N), sorbon, acetaminophen, acetaminophen, phenacetin, dimethothiazine mesylate, and the like. Examples of muscle relaxants include the following: tolperisone hydrochloride, chlorozoxazone, chloromezanone, methocacarbamol, fenprobamine phenprobamololate mesylate), chlorophenesine carbamate, baclofen, eperisone hydrochloride, afloqualon, tizanidine hydrochloride, tizaindine hydrochloride. De (alcuronium chloride), Suki shark door chloride (suxamethonium chloride), pot-class link Lori de (tubocurarin chloride), dantrolene sodium (dantrolen sodium), pancuronium bromide (pancuronium bromide), Velcro bromide (vecuronium bromide) and the like. Examples of antidepressants include tricyclic antidepressants such as imipramine hydrochloride, desipramine hydrochloride, chloramine hydrochloride, ), Nortriptyline hydrochloride, iofepramine hydrochloride, amoxapine, dosulepin hydrochloride, etc. included. Examples of tetracyclic antidepressants include maprotiriline, mianserine, and the like.

  Such combinations include various types of administration, eg, simultaneous or sequential administration of separate active agents, or simultaneous administration of a combination formulation of active agents. Such combinations also include arbitrarily provided combinations of related offerings, such as so-called “part kits”.

The present invention is further a 5-HT _2A and 5-HT _2B receptor antagonist and 5-HT _2A for the treatment or prevention of patients with spinal stenosis and the symptoms caused thereby in these patients It relates to a compound whose pA ₂ value of the compound at the 5-HT _2B receptor is ≧ 7.5.

  The invention further relates to patients with spinal stenosis, in particular cervical canal stenosis, and ergoline derivatives for treating or preventing the symptoms caused thereby in these patients, As described above.

  Furthermore, the present invention provides a formula for treating or preventing a patient with spinal stenosis and the symptoms caused thereby in these patients.

And the salts thereof.
The present invention further preferably relates to patients with spinal stenosis and 8α-lisuride or 8α-terguride, more preferably 8α-terguride, for treating or preventing the symptoms caused thereby in these patients.

Particularly preferably, the invention relates to 8α-terguride for the treatment or prevention of patients with cervical canal stenosis and the symptoms caused thereby in these patients.
The invention further comprises one or more compounds as defined above together with one or more other active substances for the treatment or prevention of patients with spinal stenosis and the symptoms caused thereby in these patients. It relates to a combination preparation.

  The compounds defined above are preferably administered according to the invention in the form of pharmaceutical compositions together with one or more common pharmaceutical auxiliaries. Accordingly, the present invention further comprises a compound as defined above and one or more general pharmaceutical auxiliaries for the treatment or prevention of patients with spinal stenosis and the symptoms caused thereby in these patients. To a pharmaceutical composition.

  Said pharmaceutical composition is for example inhaled or intravenous, intraperitoneal, intramuscular, intravaginal, intraoral, transdermal, subcutaneous, mucocutaneous, oral, rectal, transdermal, topical, intradermal, intragastric or dermal Suitable for internal administration, such as pills, tablets, enteric tablets, film tablets, laminated tablets, oral delayed-release preparations, subcutaneous or dermal administration (especially as patches), depot preparations, sugar-coated tablets, suppositories, gels Agent, ointment, syrup, powder for inhalation, granule, suppository, emulsion, dispersion preparation, microcapsule, micro-preparation, nano-preparation, liposome preparation, capsule, enteric capsule, powder, powder for inhalation, microcrystal Present in the form of formulations, sprays for inhalation, powders, drops, nasal drops, nasal sprays, aerosols, ampoules, solutions, juices, suspensions, emulsions, injectable solutions or injectable solutions . Oral, dermal and transdermal dosage forms are preferred.

  The compounds according to the invention can be administered in pharmaceutical compositions, which can contain various organic or inorganic carriers and / or auxiliaries, which are customary for pharmaceutical use, especially in solid pharmaceutical formulations: Excipients (eg sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate), binders (eg cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene) Glycol, sucrose, starch), disintegrants (eg starch, hydrolyzed starch, carboxymethylcellulose, calcium salt of carboxymethylcellulose, hydroxypropyl starch, glycol starch sodium Sodium bicarbonate, calcium phosphate, calcium citrate), glidants and lubricants (eg, magnesium stearate, talc, sodium lauryl sulfate), flavoring agents (eg, citric acid, menthol, glycine, orange powder), preservatives ( Eg sodium benzoate, sodium sulfite, methylparaben, propylparaben), stabilizers (eg citric acid, sodium citrate, acetic acid and titriplex polyvalent carboxylic acids such as diethylenetriaminepentaacetic acid (DTPA)), suspending agents ( For example, methyl cellulose, polyvinyl pyrrolidone, aluminum stearate), dispersant, diluent (for example, water, organic solvent), beeswax, cocoa butter, polyethylene glycol, white petrolatum and the like.

  Liquid pharmaceutical formulations such as solutions, suspensions and gels usually contain a liquid carrier such as water and / or a pharmaceutically acceptable organic solvent. In addition, such liquid preparations may also contain pH adjusters, emulsifiers or dispersants, buffers, preservatives, wetting agents, gelling agents (eg methylcellulose), colorants and / or flavoring agents. The compositions may be isotonic, i.e. they can have the same osmotic pressure as blood. The isotonicity of the composition can be adjusted by the use of sodium chloride or other pharmaceutically acceptable agents such as dextrose, maltose, boric acid, sodium tartrate, propylene glycol, or other inorganic or organic soluble materials. The viscosity of the liquid composition can be adjusted by the use of a pharmaceutically acceptable thickener, such as methylcellulose. Other suitable thickening agents include, for example, xanthan, carboxymethylcellulose, hydroxypropylcellulose, carbomer, and the like. The preferred concentration of thickener will depend on the agent selected. Pharmaceutically acceptable preservatives can be used to increase the shelf life of the liquid composition. Benzyl alcohol is suitable, but many preservatives can be used equally, including parabens, thimerosal, chlorobutanol or benzalkonium chloride.

  The active substance can be administered 1 to 4 times a day, for example, in a unit amount of 0.25 mg to 50 mg, preferably 0.25 to 5.0 mg. However, doses can be increased or decreased depending on the patient's age, condition, disease severity, or mode of administration.

Furthermore, particularly preferably, the present invention relates to said compounds and compositions for the treatment or prevention of patients with cervical canal stenosis and the symptoms caused thereby.
The invention is illustrated in more detail by the following examples. The examples merely constitute a description of the invention and those skilled in the art can extend this embodiment to other compounds of the invention.

  Patients with chronic systemic pain were recruited for clinical trials. One subgroup of patients meets the definition of primary fibromyalgia. Other patient groups are characterized by a diagnosis of chronic neck pain. In most patients participating in the study, examination of the cervical spine was performed during the course of the study by magnetic resonance imaging (MRI) as an imaging method. At that time, generally, a condition was selected that enables imaging of the transverse section of the vertebral canal in the cervical vertebra region in the normal position with no contrast agent. This measurement was performed with a 1.5 Tesla magnetic resonance scanner. In all analyzable images, spinal canal diameter and nerve fiber (so-called spinal cord) thickness were measured by a blind evaluator working as an independent expert. In addition, findings were evaluated according to an internationally recognized standard catalog (NJNR Am J Neuroradiol 1998 Oct; 19 (9): 1763-71) for the presence of cervical stenosis. This consists of a scale of five grades. Grade 0 represents a normal width spinal canal with no signs of stenosis of the anterior or posterior subarachnoid space in the spinal canal. In grade 1, there are signs of partial stenosis of the anterior or posterior subarachnoid space or both subarachnoid spaces. In grade 2, the spinal cord eventually completely fills the subarachnoid space of the spinal canal. Grade 3 ultimately represents cervical spine compression or spinal cord twist, and grade 4 represents spinal cord excess strength as a sign of spinal cord injury. Based on this evaluation, approximately 20% of all patients evaluated in this study have a test grade 2-4 change, which describes this patient group as patients with cervical stenosis.

Patients were treated with ergoline compound terguride (1 tablet = 0.5 mg), which was a partial dopamine agonist and also a 5-HT _2A and 5-HT _2B receptor antagonist, as described above, or placebo. The study drug was gradually increased from half a day to 6 tablets over 21 days and then further treated at a fixed dose for 9 weeks. The medicine was taken in the morning and evening. Patient-oriented after 3, 7 and 12 weeks of therapy, according to pain intensity, fatigue, deep sleep, muscle stiffness, anxiety, nervousness and depression, health status and work ability, and questionnaires on activities of daily living Inspected on a scale. At that time, a decrease in the scale value or a decrease in the score in the questionnaire indicates an improvement in the reference value at that time, and thus a therapeutic effect.

  Surprisingly, among patients with chronic generalized pain, only the patient group with cervical stenosis (grade 2-4) showed significant therapeutic effect after 3 months (FIG. 1). With respect to the sum of all questions asked (total score), the majority of this patient group responded with a more or less noticeable general status improvement. In that case, the reduction of pain intensity, anxiety and nervousness, and especially the improvement of subjective disability and workload tolerance are particularly significant. In contrast, a group of patients with chronic systemic pain but normal cervical spinal canal and no damage did not change significantly despite treatment with terguride (FIG. 2). Only muscle stiffness and depressive behavior tended to improve, but the pain response was assessed as unchanged. In summary, for patients without cervical canal stenosis, patients treated with terguride showed no significant improvement compared to the group of patients treated with placebo.

  Similarly, an analysis of a group of patients with chronic neck pain but no signs of cervical stenosis showed no therapeutic effect when treated with terguride (FIG. 3). In contrast, several effect parameters of treatment in patients have been described, in particular, disability, health, pain perception, muscle stiffness and anxiety / nervation exacerbation.

  In summary, it should be noted that terguride provided a therapeutic effect only in patients with cervical spinal stenosis.

Claims (21)

5-HT _2A and 5-HT _2B receptor antagonists and 5-HT _2A and 5 for the manufacture of patients with spinal stenosis and medicaments for treating or preventing the symptoms caused thereby in these patients use of a compound pA ₂ divalent compound in -HT _2B receptor is ≧ 7.5. Use according to claim 1, wherein the pA ₂ valence for the 5-HT _2A receptor differs from the pA ₂ valence of the compound for the 5-HT _2B receptor by up to ± 1 unit.   Use according to any one of claims 1 to 2, wherein the compound is selected from the group comprising cyproheptadine, mianserin, ritanserin, methiothepine, methysergide, metergoline, lisuride, terguride, trazodone, pizotifen and nicergoline.   4. Use according to any one of claims 1 to 3, wherein the compound is terguride and / or lisuride.   The use according to any one of claims 1 to 4, wherein the compound is selected from 8α-lisuride or 8α-terguride.   The use according to any one of claims 1 to 5, wherein the spinal stenosis is cervical canal stenosis.   7. Use according to any one of claims 1 to 6, which acts to ameliorate symptoms of paresis, hyposensory, sensory abnormalities, pain, and / or sensory disturbances, such as feelings of sensory paralysis.   Improve physical dysfunction, especially painless motor impairment, reduce head orientation abnormalities, improve muscle weakness, improve gait disturbance, improve ant running, and / or ataxia, and urinary incontinence and / or Or use of any one of claims 1-7 for the improvement of fecal incontinence.   Use according to any one of claims 1 to 8, wherein the spinal stenosis is whiplash, other traumatic changes or the chronic prognosis of disc herniation.   Prophylactic treatment of patients with spinal stenosis and symptoms caused thereby in these patients to prevent chronicity of the syndrome, and chronic prognosis of spinal stenosis as a result of patients with whiplash 10. Use according to any one of claims 1 to 9, comprising prophylactic treatment to prevent.   11. Use according to any one of claims 1 to 10, wherein the compound is administered to the patient in combination with one or more other active substances. 5-HT _2A and 5-HT _2B receptor antagonists and 5-HT _2A and 5-HT _2B receptors for the treatment or prevention of patients with spinal stenosis and the symptoms caused thereby in these patients compound pA ₂ dihydric of the compound in the body is ≧ 7.5.   8α-Lisuride and 8α-Telguride for the treatment or prevention of patients with spinal stenosis and the symptoms caused thereby in these patients.   8α-Telguride for the treatment or prevention of patients with spinal stenosis and the symptoms caused thereby in these patients.   8α-Telguride for the treatment or prevention of patients with cervical canal stenosis and the symptoms caused thereby in these patients.   A patient with spinal stenosis and one or more other active substances as claimed in any one of the preceding claims for the treatment or prevention of symptoms caused thereby in these patients Combination preparation containing in combination.   Use according to any one of the preceding claims, wherein the compound according to any one of the preceding claims is administered in the form of a pharmaceutical composition together with one or more common pharmaceutical auxiliaries.   A compound according to any one of the preceding claims and one or more general pharmaceutical auxiliaries for the treatment or prevention of patients with spinal stenosis and the symptoms caused thereby in these patients A pharmaceutical composition.   19. The pharmaceutical composition according to claim 18, wherein the composition is suitable for oral, sublingual, parenteral, dermal, buccal, transdermal, subcutaneous, inhalation or intranasal administration.   The composition is a tablet, laminated tablet, capsule, slow-acting oral preparation, transdermal system, suppository, micro-formulation, nano-formulation, liposomal preparation, instillation, nasal drop, intranasal spray, aerosol, ampoule The pharmaceutical composition according to any one of claims 18 to 19, which is present in the form of a liquid formulation, emulsion, dispersion formulation, powder, inhalation powder, microcrystalline formulation, inhalation spray, transdermal system or subcutaneous formulation. object.   21. A pharmaceutical composition according to any one of claims 18 to 20 for the treatment or prevention of patients with cervical spinal stenosis and the symptoms caused thereby in these patients.

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