WO2010072774A2 - Agent for treating stenosis of the spinal canal - Google Patents

Abstract

The present invention relates to a novel use of 5-HT2A and 5-HT2B receptor antagonists for therapeutic or prophylactic treatment of patients with stenosis of the spinal canal and of the symptoms thereby caused in these patients.

Description

 , i _

Agent for the treatment of spinal kanolstenosis

BElCHRJElBUNGi

The present invention relates to a novel use of compounds for the Iherapeulic or prophylactic treatment of patients with

Spasmal stenosis and thereby caused in this patient

symptoms

Spinal canal stenosis is a narrowing of the vertebral canal of the spine, usually due to degenerative changes in the vertebral joints, ligaments and intervertebral discs. It is characterized by a narrowing of the spinal canal, which creates pressure on the spinal cord and nerve roots contained in the spinal cord most diagnosed and operated diseases of the spine

If the constriction is at the level of the cervical spine (cervical spine), it is called cervical spinal stenosis. A narrowing of the thoracic spine is called thoracic spinal stenosis. If the lumbar spine is affected, there is talk of a lumbar spinal stenosis

Numerous anatomical causes can cause narrowing of the spinal canal In rare congenital cases, stenosis occurs due to the condition (for example, dysplasia, malformations, subluxations, spina bifida, meningoceles). However, acquired changes in the cervical spine are more common. These can be trauma-related, caused by instability, inflammatory or neoplastic processes or postoperative changes (eg scars). However, by far the greatest clinical significance as a cause of spinal canal stenosis of the spinal column is that of degenerative diseases, ie, physiologically occurring signs of abnuity, which occur secondarily after degenerative disorders

Involved in the development of spinal stenoses are various anatomical structures that together form the wall of the spinal canal. Spinal discs, intervertebral joints, and the ligamentum flavum, a powerful ligament running in the longitudinal direction, pay for this. A direct constriction occurs when a damaged disc protrudes or falls backward. Arthrosis of the intervertebral joints, however, indirectly affect the width of the spinal canal, leading to the formation of bony outbreaks (spondylophytes), which in turn constrict both the spinal canal and the Nervusustπttslocher, Another cause is a thickening of the ligamentum flavum, the vertebral canal ends after a while

Degenerative changes can occur at different points of the spinal canal and thus lead to a constriction and Irπtalion of the spinal cord and / or the nerve roots form bony edge spikes from the posterior edge of the vertebral bodies, leading to a retrospondylosis, which usually plays medial. In a degenerative bone cultivation, starting from the process uncinati, there is an induration with a more lateral constricting mass. Osteoarthritis of the vertebral joints in the sense of spondylarthrosis also causes lateral constriction of the spinal canal and also of the neuroforamina. Furthermore, all forms of spinal disc prolapse or protrusions can lead to stenosis. A phenomenon more common in the Asian population is a calcification or bony ingrowth of the posterior longitudinal ligament, which is referred to as OPLL (ossification of the posterior longitudinal ligament). While the above-mentioned changes narrow the spinal canal from ventrally or laterally, and thus the front or lateral myelon There are also rarer causes for a dorsal mass, which is then due to hypertrophy of the ligamentum flavum, ie, thickening of the intervertebral arches, or due to calcification or ossification thereof.

According to epidemiological studies, the incidence is estimated to be 2 to 8%, with symptoms developing characteristically without gender predominance in the fifth or sixth decade of life. For patients over the age of 60, spinal canal fencing is even the most common cause of spinal surgery Risk groups, which include persons with sputum turbulence, athletes of contact sports or pilots, are described as having a high incidence even at a young age,

The lumbar spine is most often affected by spinal canal stenosis. Painfulness, pain and weakness in the legs, especially when walking and standing as well as numbness in the buttocks and / or in the legs occur in about 90% of the patients in lumbaistenosis. More than 85% of patients complain of back pain. Neurogenic claudicatio Intermittens (90%), d h. Pain conditions after short walking distances occur in 90% of all patients. In the case of upright posture the discomfort is intensified, while conversely a bent posture leads to an improvement of the symptoms. Other symptoms include muscle tension, disorders of movement coordination (ataxia) and bladder / rectal disorders, ie problems with bowel movements and urination. The most common findings are the restricted spinal curl (40%), pain in reclination (79%), Lasegean's sign (1 2%), parasitism (32%), paresis (27%), reflex deficit (64%) and bladder dysfunction ( 6%)

In contrast, spinal stenosis in the area of the cervical spine, a cervical spinal canal stenosis, may have very different clinical manifestations. There may be diffuse and uncharacteristic pain or discomfort on the arms and / or legs as well as cervical or brachial pain. Patients often indicate a slowly increasing weakness in the arms and / or legs, which is mostly lateral. A gait uncertainty with a spastic gait pattern is relatively typical; micturition disorders may also be added.

Thoracic spinal stenosis is extremely rare compared to lumbar and cervical spinal canal stenosis Diagnosis of spinal stenosis

Distally emphasized paresis and sensibility disorders can be detected Frequently a reflex increase can be detected underneath the affected part of the spinal column A gait ataxia (spastic legs stumble) can also indicate the disease Rarer and limited to patients with cervical spinal canal stenosis one finds positive pyramidal tract signs ( Babinski's sign) or a positive midway sign whereby an electrifying feeling is triggered along the spine or extremities during flexion of the cervical spine

For the specific clarification of a spinal stenosis as a cause of pain or neurological abnormalities, however, a study with imaging techniques durchzufuhren The spinal canal stenosis itself can not be directly detected in conventional radiographs For this Schnitfbildvorfahren as CT (computed tomography) and MRI (magnetic resonance imaging) necessary by their transversal Schnittfuhrung The most valuable feature of MRI is that, in addition to the bony structures, it is significantly better than the CT also shows the soft-tissue structures in the affected spinal column area

In addition to clinical examination and diagnostic imaging, electrophysiological examinations can also contribute to the assessment and estimation of the severity of spinal canal stenosis. By means of electromyography (EMG) nerve conduction velocity (NLG) and somatosensory evoked potentials (SSEP) the extent and severity of spinal dysfunction as well as prognosis can be evaluated be estimated

The spontaneous course of spinal canal stenosis varies greatly from patient to patient. The onset of the disease is almost imperceptible and the progression of symptoms varies. Rarely, there is a linear course of deterioration. Em stagnation is possible in various stages of the disease Degenerative changes lead to a progressive narrowing of the vertebral body, and the spinal cord is finally squeezed unbearable pain and finally lameness can occur.

Usual therapy:

If there is a definite diagnosis based on the history, clinic, imaging, and / or susceptible electrophysiological examination, and if there are signs of spasticity (including partial paresis) and high-grade sensory disturbances, the clinical indication for surgery is the target of every operation Depending on the imaging findings (X-ray, CT, MRI, myelography) different surgical techniques are used. The most common procedures are ventral decompression with fusion, corpectomy as an extension of ventral decompression by vertebral body replacement and fusion, dorsal decompression with or without opening and extension of the dura and laminoplasty, such surgical procedures as surgical orthopedic procedures for the removal of lumbar spinal canal stenoses, but especially also neurosurgical procedures in the abdomen cervical spinal canal stenoses are generally associated with relatively high risks and are therefore usually used only in advanced disease, especially in imminent paralysis, as well as after a comprehensive benefit-risk consideration by the attending physician application in such surgical procedures is beyond also consider the risk of suffering irreparable spinal cord damage from a minor accident

If there are only minor degrees of sensory and / or motor failure, or if surgery is contraindicated, therapy of spinal canal stenosis is usually conservative. This includes, on the one hand, immobilization of the cervical spine by external fixation (cervical collar) or by wearing corsets or corsets in the case of lumbosacosis On the other hand, therapeutic exercises will be carried out to stabilize the musculature and to remove the lungs

The leading symptom in most cases of pain is usually symptomatic by the administration of analgesics such as analgesics (eg paracetamol, N-acetylsahcylic acid), opioids, pain plasters, implanted pain pumps, or nerve block infiltration therapy, periradicular therapy, initial point infiltration or transcutaneous electrical nerve stimulation ( In muscle spasms, drugs such as baclofen or tetrazepam are used as well as non-steroidal anti-inflammatory agents or epidurally administered corticosteroids are used

Although the medicines mentioned alleviate the pain, the pain-relieving effects are generally limited in time and the other effects of the disease such as muscle stiffness, limited pain-free movement and impairment of work ability are hardly affected

Pathobiology and Molecular Targets:

Apart from symptomatic pain therapies or treatments with anti-inflammatory drugs, so far only a few drugs have been described, the administration of which leads to a holistic marked improvement in the clinical appearance of spinal stenosis by causal intervention in the pathophysiological processes,

Experimental evidence suggests a combination of different pathomechanisms involving inflammatory processes in the multifaceted symptoms of spinal stenosis.

Physiological changes in the epidural pressure and diameter of blood vessels supplying the spinal cord and nerve nodes due to the posture of patients with spinal canal stenosis have been clinically proven and correlated with Development of Neurogenic Clαudicαtio Intermittens A dysfunction of endothelial cells of local blood vessels and an altered response also endogenous messenger substances are discussed in this context. As another mechanism, the upregulation of neurotransmitter receptors in the spinal cord and in the dorsal and ventral nerve nerves is discussed, which mutated Processing of nerve impulses and in a sense of hypersensitivity and irritation of the spinal cord,

These pathomechanisms constitute the rationale for a therapeutic effect of calcitonin (Calcif Tissue Int 1 992 May; 50 (5) 400-3) in the treatment of spinal stenosis and for the potential use of serotonin antagonists such as sarpogrelate for the treatment of symptoms associated with In particular, the treatment of patients with neurogenic claudication Intermittens due to lumbar spinal stenosis by administration of sarpogrelate, as a 5-HT, _Λ receptor antagonist, described. The mechanism of action is considered to be the improvement of the blood circulation in the nerve endings chronically constricted due to the stenosis (J Peripher Nerv. Syst. 2004 Dec, 9 (4) 263-9). EP 1 609480 A1 discloses an agent for the treatment of spinal canal stenosis, which comprises a combination of an EP2 agonist and an EP3 agonist. In Japan, limaprost alfadex, a prostaglandin El derivative, is marketed under the trade name Opalmon for the treatment of symptoms associated with lumbisthinosis (Spine 2008 June; 33 (13) '1 465-9). Furthermore, US 2006005831 0 A1 describes the use of aldose redulphase inhibitors for the treatment of spinal canal sienosis and DE 6991 91 91 T2 discloses the use of a pyridazone compound for the treatment of spinal cord canal stenosis.

The ergot fungus produces alkaloids, which can lead to the disease ergotism (Antony's fire), with symptoms such as intestinal spasms, dying of fingers and toes due to circulatory disorders and hallucinations. Ergolin forms the basic skeleton of ergot alkaloids

The ergoline framework contains structural elements that are the basis of interactions with various neurotransmitters and their receptors. The basic body emulates structures of the neurotransmitters dopamine, serotonin, norepinephrine, and histamine. Depending on the modification of the basic body of ergoline by chemical modification, compounds may arise which act as agonist or as antagonist at one or more of the above-mentioned neurotransmitter receptors. Because of their pharmacological effects, some ergot alkaloids in medicine are ua. For the treatment of migraine, peripheral circulatory disorders, Parkinson's disease and Restless Legs Syndrome relevant or have been used as a means of CPR postpartum and for supportive treatment in postpartum rebleeding and as antihypertensive agents

For example, the use of the ergoline derivative nicergoline in the treatment of lumbar spinal canal stenosis in combination with a behavioral or physiotherapeutic treatment is described (Reumatologia 2004, T. 42 (1), 59-63). It is believed that the drugs used to improve the microcirculation in the nerve endings However, the results shown here are only non-verified observations that prove neither vei mutete effect of the compounds used, nor specific properties of the substances used, which belong to the most diverse substance classes.

Nicergoline is known to be an adrenergic antagonist and is used as a vasoactive drug to improve blood circulation and in vascular and dementia restrictions. In the therapeutically relevant dose range, nicergoline does not affect the serotonergic system such as dopamine agonists such as sarpogrelate or the ergoline derivative Terguπd

The effects of mother comal alkaloids are manifold. They can stimulate the dopamine RozeplOren and inhibit the release of prolactin and somatotropm. The 8- (R) -diastereomer of lisuride has recently been identified as the currently most potent agonisi at human H 1 receptors (Bakker et al., Mol Pharmacol 65 ¹ 538-549, 2004), Recent Investigations (Dissertation Gornemann, FU Berlin , 2008) show that some ergoline derivatives have a high affinity for a _? Having adrenoceptors and 5 HT _2Λ , 5-HT ₂₈ and 5-HT ₇ receptor antagonists,

From WO 07/1 1 0047 A2 the use of the ergoline derivatives Terguπd and Proterguπd for the treatment of chronic pain and chronic states of pain u.a. known in fibromyalgia. In the context of the dopaminergic effect of Terguπd on pain processing, treatment success with terguride in fibromyalgia was assumed. The main symptoms of fibromyalgia are non-regionalized, nonspecific chronic pain as well as a high pressure point load presumably based on a malfunction of the central nervous system (CNS) In the large group of fibromyalgia patients, about 80% report cervical pain, but only about 20% of patients also have cervical spinal canal stenosis

Holman and Myers (ARTHRITIS & RHEUMATISM, VoI 52, No 8, August 2005, pp 2495-2505) conducted a double blmd study of pramipexole, a dopamine agonist, in patients with fibromyalgia, specifically excluding patients with cervical myelopathy , In a recent work by Holman, it is stated that fibromyalgia patients with cervical stenosis respond poorly to dopamine agonists and therefore should be given other treatment options such as pregabalin (J Pain 2008 JuI, 9 (7) 61 3-22). In the above-mentioned WO 07/1 1 0047, the treatment of a patient with chronic pain due to a Bandschoibenunterfalls in the lower I endenbereichs by simultaneous administration of Terguπd and the analgesic oxycodone is described in Example 8 treatment of Spinalkanalslenosen, especially of cervical spinal stenoses, Terguπd is not described A disc herniation is usually a temporary event. Herniated discs are usually found in the lumbar spine area and much less often in the cervical cervical area. Terguπd has been used in lumbar disc herniations to treat the associated chronic pain Pain processing is expected insofar as Terguπd is known to have a dopaminergic effect

Although disc herniation may be accompanied by an intermittent constriction of the spinal cord canal and resulting pain sensation, spinal disc prolapses may occur in combination with spinal stenosis, but this is a mechanical arrest of the spinal canal stenosis Vertebral bodies and resulting painful pressure development on the spinal cord It has been shown in various studies that spinal canal stenoses include symptoms that are atypical of disc herniations, such as specific limitations in functional mobility and sensation in the arms and neck associated with typical gait disturbances. in particular, the neurogenic claudication of intermittens (Clin Biomech 1 992 (7), 3-1 7) In addition, it could be shown that a narrowing of the spinal canal alone is not necessarily often leads to a spinal canal stenosis, from which the inference can be drawn that a narrowing of the spinal canal is not the sole cause of spinal canal stenosis but rather that other specific causes play a role, which should be taken into account in a treatment (Clin Biomech 1 992 (7) 3-1 7) On the other hand, spinal canal stenosis always results from an obstruction or ossification of the spinal canal stenosis Vertebral body characterized and thus represents a vertebrate degenerative disease is Such a degenerative change of the Wirbelkorper does not originate from a herniated disc, in contrast, as stated by a mechanical locking or impairment and a so-called "hatching effect" is characterized painful spinal column alteration can also be based on very different sympi- tomatics, as is clear from "Cervical spondylosis and neck pain" (BMJ 2007 (334), 527-531).

Thus, it can not be assumed that a treatment of herniated discs is in principle successful in the treatment of Spinalkanalstenosen, since in principle must be applied to unierschiedlichen action levers

The design of the clinical trial conducted in the context of this application was initially directed to investigating the effect of Terguπd as a prototypic dopamine agonist in patients with fibromyalgia. In addition to the above-mentioned work by Holman, patients were also examined for the presence of cervical stenosis and a history of chronic neck pain. The working hypothesis was that, in contrast to patients with primary fibromyalgia, d h. without cervical stenosis - straight patient mι1 cervical stenosis or chronic neck pain do not respond to therapy with terguπd For another dopamine agonist, ropinirole, it has meanwhile been demonstrated in a clinical study that no therapeutic effects could be demonstrated under therapy with this dopamine agonist in fibromyalgia patients ( http; // ctr gsk co uk / summary / ropιnirole / ll_rof l 021 00. pdf). Consistent with this, no significant therapeutic effect of terguride in patients with primary fibromyalgia was demonstrated compared to placebo However, the inventors of the present invention have surprisingly been able to show that terguride can selectively relieve spinal canal stenosis in patients, thereby alleviating symptoms caused in this patient, while no significant effect has been achieved in neck pain patients without spinal canal stenosis. The combination of 5 HT _{? A} and 5-HT _2B re-ester antagonism present in terguride, which at the same time significantly inhibits both receptor isoforms in the therapeutically effective dose range, is held responsible for this surprising therapeutic effect and thus at the same time describes a characteristic active principle for therapeutic applications

The present invention thus provides a novel use of compounds which are 5-HT _2A and 5-HT _{? B} - Receptor agonists are ready for the therapeutic or prophylactic treatment of patients with spinal stenosis, preferably with cervical spasmal stenosis, and the symptoms thereby caused in this patient. In particular, the invention provides such use at an early stage of the disease for the preventive and interventional treatment of spinal stenosis. In an advanced late stage, in which there is already lameness and threatens the occurrence of paraplegia, surgery may still be necessary. The use according to the invention may at some stage constitute an accompanying treatment

A use of compounds which are both 5 H1 _2A and 5-HT _2B receptor antagonists for the treatment of patients with spinal stenosis, in particular cervical spinal stenosis, has not been described in the prior art. Preferably, the compounds are additionally 5-HT ₇ - Receptor antagonists and / or a ₂ - adrenoceptor antagonists, particularly preferably additionally a ₂ - adrenoceptor fanfists, in particular a _2C- adrenoceptor antagonists,

Antagonists for the purposes of the present invention are generally compounds which bind to the said receptors (5-HT _2A , 5-HT ₂₆ - and 5-HT ₇ - receptor and a ₂ -adrenoceptor, in particular a ^ _c -adrenoceptor) and reduce or eliminate the effect of the body's own messengers serotonin and norepinephrine, or of active ingredients in the stomach

To characterize the antagonistic activity of a compound is often the pA ₂ value,

The pA ₂ value represents the negative decadic logarithm of the molar concentration of an antagonist that makes it necessary to double the agonist concentration, such as serolonin, to achieve the original effect in the absence of the antagonist. The pA ₂ value is thus a measure of the affinity of an antagonist for the receptor, regardless of how the antagonist acts. Preferably, the pA ₂ -Wer1 is prepared according to the method of Arunlakshana and Schild (Arunlakshana O, Schild HO, Some quantitative uses of drug antagonisis, Br J Pharmacol 14: 48-58 (1959))

Suitable 5-HT _2A , 5-HT _2B , 5-HT ₇ receptor antagonists and / or a ₂ -adrenoceptor antagonists, in particular a _2C- adιenoceptor antagonists, can be determined in particular according to the methods described in the dissertation Gornemann, FU Berlin, 2008

Thus, 5-HT _2A receptor antagonists can be identified in particular under certain experimental conditions by characterizing contractile effects on porcine coronary arteries (see a, Cushing DJ, Cohen ML (1 993), J Pharmacol Exp Ther 264: 1 93-200).

Suitable 5-HT _2B receptor antagonists can be identified, in particular under certain experimental conditions, by the characterization of relaxing effects on porcine pulmonary arteries (s, a Glusa E, Pertz HH (2000) Br J Pharmacol 1 30: 692-698).

Suitable 5-HT ₇ receptor antagonists can be identified, in particular under certain experimental conditions, by the characterization of relaxing effects on pulmonary artery of weaner pig (race pig) are (s α Annual et αl (2005) Nαuyn-Schmiedebergs Aren Phαrmαcol 37 1 89 98)

Suitable α ₂ adrenoceptor αntαgonistcn in particular α _2C - Adrenozeptorαntαgonisten can be identified in particular under selected experimental conditions by characterizing contractile effects on pulmonary veins of Schiachtschweinen (sa Gornemanπ et al Br J Pharmacol 2007 May 1 5 1 (2) 1 86 94) As a rule overlapping interaction of active substances with a _2A and a _9C receptors are hereafter the inhibition constants for the a _3C receptor as a measure of the a _? -adrenolytιsche action of a substance defined

Preferred compounds according to the invention have the following pA ₂ values on 5 HT _2A 5 HT ₂₆ 5 HT ₇ receptors and a ₂ adrenoceptors preferentially have a _2C adrenoceptors

The compounds according to the invention are preferably 5 HT, _A receptor antagonists with a pA ₂ of> 7 5

The compounds according to the invention are preferably 5 HT _2B receptor antagonists with a pA ₂ of> 7 5

Particularly preferably, the inventive shaped compounds have both the 5 I IT _{A -} and at the 5-HT _2B receptor a pA ₂ of> 7 5 more preferably a pA ₂ of> 8

In a particularly preferred embodiment, the compounds according to the invention have a pA on both the 5HT _2A and the 5HT _2B receptor _. of> 7 5, more preferably a pA ₂ of> 8

In addition, preferred compounds according to the invention are 5 HT ₇ receptor antagonists with a pA ₂ of> 7 5 Furthermore, and particularly preferably, the compounds according to the invention are, in addition to their properties as 5-HT _2A and 5-HT ₂₈ receptor agonists, also u ₂ -adrenoceptor antagonists, preferably a _2C- adrenoceptor antagonists, preferably with a pA ₂ of> 7.5.

Furthermore, compounds according to the invention are particularly preferred in which the pA _? Value for 5-HT _2A receptors at a maximum of 1 unit from the pΛ ₂ value of the compounds to 5-HT _{? B} receptors unierscheidet. D h. According to the invention, those compounds are particularly preferred in which

PA ₂ (5-HTJ _A) - pA, (5-HT _2B) <1

is. This ensures that under treatment with agents of pathophysioiogische processes that run through one or the other receptor, are significantly inhibited in the same dose range and thus an increase in therapeutic effect and a wider response of spinal stenosis patients with different medical history can be achieved can.

The following table exemplifies compounds which are 5-HT _2A and 5-HT _{2 B} receptor antagonists and their pA ₂ values.

Table - 5-HT _aA and 5-HT _2B receptor antq _. gon _. istιsche properties of selected compounds

The table shows that especially cyproheptadine, mianserin, ritanserin, methiothepln, methysergide, metergoline, lisuride, terguride, trazodone, pizotifen and nicergoline are preferred according to the invention, since their pA ₂ at 5-HT _2A and 5-HT _2B receptors each> Cyproheptadine, ritanserin, methiothepin, methysergide, lisuride, tergurid and pizotifen, since their pA _{2 is linked} to 5-HT _2Λ- and 5-HT _2Λ- and 5-HT _2Λ - and 5 HT _2B receptors is> 8, and differs by less than one unit (absolute). Very particularly preferred among these compounds are the terguride and lisuride.

The compounds used according to the invention serve the treatment of patients with spinal stenosis and the symptoms caused thereby in these patients. The compounds used according to the invention are particularly preferably used for the treatment of patients with cervical spinal canal stenosis and the associated symptoms. As already described in detail in the introduction, the term "spinal canal stenosis" means a narrowing of the vertebral canal, in particular a degenerative change or narrowing of the vertebral canal. In the case of cervical spinal stenosis, which is preferably treated according to the invention, this is in the area of the cervical spine (cervical spine). There is therefore a discrepancy between the size of the spinal cord (myelon) and the spinal canal, which is relatively too small, the consequences are compression on the spinal cord and / or the nerve roots, on the basis of radiological In particular, one speaks of a repressive stenosis with a narrowing of the sagittal diameter of the cervical spine to 1 0-1 2 (1 3/1 4) mm, of an absolute stenosis of less than 1 0 mm. A cervical myelopathy may be clinically very different, There may be diffuse and uncharacteristic pain or discomfort on the arms and / or legs as well as neck (cervicalgias) or ache (brachialgia). Patients often report a slowly increasing weakness in the arms and / or legs, which is mostly lateral Relatively typical is a gait with spastic gait, it may also micturition added

In contrast, as already stated, a herniated disc is characterized by a mechanical displacement of the vertebral bodies or a so-called slippage of the intervertebral discs, thereby exerting a painful pressure on the spinal cord. Such a symptom is in marked contrast to a degenerative change of the vertebral body, as they are characteristic of a spinal stenosis is unlike the case of spinal canal stenosis in a herniated disc also rarely the so-called causa equina affected. In a spinal canal stenosis, the clinical symptoms are not directly caused by the narrowing itself but rather by additional degenerative deformities of the vertebral bodies, which had no symptoms without the spinal canal narrowing (Clin. Biormech, 1 992 (7), 3-1, 7).

Grade 0 Radical symptomatology, no signs of myelon involvement

Grade Signs of myelon involvement, no gait ϊrad L mild gait, fully functional

Degree Moderate gait, no help, restricted work / active - I i

? rαd IV Only possible with support

Grade V Bedridden, wheelchair dependent

Thoracic spinal stenosis:

The thoracic spine is due to their anatomical relationship to the ribs incorporated into a more compact support apparatus, so that degrees of freedom in the longitudinal and transverse direction are less than in the cervical and lumbar spine and thus less risk / possibility of abrasion and bone remodeling is given, spinal stenosis Thoracic (thoracic) spine dori are much rarer, the diagnostic and treatment options are the same as those of other spinal stenoses

Lumbar spinal stenosis:

Typical complaints: Often "only" pain along the dermatomes of certain lumbar roots (usually L3 to L5), often accompanying paralysis of the hip flexors, the front thigh muscles, more rarely the foot elevation, very rarely the foot drop. In the classical expression so-called "Claudicatio inlermittens" (neurogenic claudication), i. the patient has to sit down after a short time, then relieves pain, then he can walk a few meters again, then sit down again e1c.

For the diagnosis of all spinal stenoses mentioned includes the detailed clinical, neurological examination (possibly also with evoked potentials) by the specialist (neurologist), a detailed medical history, as well as further special examinations (EMG, measurement of nerve conduction velocity, above, evoked potentials, etc), and in particular, the imaging techniques (MRI, CT, possibly, myelography), among which MRI is the most preferred method of diagnosis, by means of which the narrowing of the sagittal diameter of the spinal canal is determined and the presence of a spinal canal stenosis can be clearly clarified, The compounds mentioned are preferably used for the treatment of cervical and / or lumbar, preferably cervical spasmal canal stenosis

The use according to the invention involves the treatment of all symptoms possibly associated with spasmal canal stenosis

In addition to the symptoms already mentioned above, the symptoms include paresis, hypasthesia, parasthesia, pain and / or sensory impairments, such as deafness, which are improved by the administration of the compounds according to the invention

Furthermore, the use according to the invention also serves the improvement of physical impairments, in particular the limited mobility of affected Abschniiten the spine. Accordingly, the use according to the invention also achieves an improvement in the reduction of muscle strength, an improvement in gait disturbances, an improvement in carpal paralysis and / or an improvement in ataxia. In particular, the use of the compounds according to the invention in the treatment of spinal canal stenoses can result in a functional improvement in painless mobility and a reduction in the malposition of the head can be achieved. Such a painful miscarriage of the head usually leads to a deterioration of mobility and an increase in the sensation of pain due to additional muscle stiffness and cramped muscle failure.

In a particularly preferred use according to the invention, this is for the treatment of spasmal canal stenosis, which is a chronic effect of whiplash, other traumatic changes or herniated disc In a further particularly preferred embodiment of the use according to the invention, the latter serves for the prophylactic treatment of patients with a whiplash injury in order to prevent the chronic effects of a spinal canal stenosis in consequence thereof,

In a further particularly preferred embodiment of the use according to the invention, this serves for the prophylactic treatment of patients with spinal canal stenosis and the symptoms caused thereby in these patients for the prevention of the chronification of the symptoms complex

The present invention furthermore relates to those of ergoline derivatives, including preferably the compounds mentioned, which are 5-HT _2A and 5-HT ₂₁₃ receptor antagonists, as already described in detail above, for the therapeutic or prophylactic treatment of patients with spinal stenosis, in particular preferred Treatment of Patients With Cervical Spinal Canal Stenosis and the Symptoms Caused by It in These Patients, Also As Described Above In Detail Ergoline derivatives are, according to the invention, such compounds which are formally derivatized from ergoline,

ie 4, 6, 6a, 7, 8, 9, 1 0, 1 Oa-Octahydro-ιndolo [4,3-fglchιnolιn-Gerust optionally also have in form dehydrogemerter form Among the dehydrogenated forms in particular the Lisuπd underlying skeleton:

which is a 4, ό, 6α, 7,8,9-Hexαhydro-ιndolo [4,3-fg] quinoline skeleton. Ergoline derivatives within the meaning of the invention are therefore all formally resulting by substitution of at least one hydrogen atom in ergoline or dehydro-ergone derivatives.

Preferred ergoline derivatives are compounds of the formula

wherein

R 'and R ^{4 are} independently. Hydrogen, alkanoyl (preferably -CHO, -COCH ₃ , -COC ₂ H ₅ , -COC ₃ H ₇ , -CO-CyCl-C ₃ H ₅ , -COCH (CH ₃ J ₂ , -COC (CH ₃ J ₃ ) , Carboxyl (-COOH), alkoxycarbonyl (preferably -COOCH ₃ , -COOC ₂ H ₆ , -COOC ₃ H ₇ , -COO-OVCIO-C ₃ H ₅ , -COOCH (CH ₃ J ₂ , -COOC (CH ₃ J ₃ ), alkoxythiocarbonyl, alkylthiothiocarbonyl, carbamoyl (-CONH ₂ ,), mono- or dialkylaminocarbonyl (evokes -CONHCH ₃ , -CONHC ₂ H ₀ , -CONHC ₃ H ₇ , -CONH-CyCl-C ₃ H ₅ , -CONH [ CH (CH ₃ J ₂ ], -CONH [C (CH ₃ I ₃ ], -CON (CH ₃ J ₂ , -CON (C ₂ H ₅ J ₂ , -CON (C ₃ H ₇ J ₂ , -CON ( cyclo ~C ₃ H ₅ ) ₂ , -CON [CH (CH ₃ ) ₂ ] ₂ , -CON [C (CH ₃ ) ₃ ] ₂ ), amino (-NH _? ), mono- or dialkylamino (preferred! -NHCH ₃ , -NHC ₂ H ₆ , -NHC ₃ H ₇ , -NH-CyClO-C ₃ H ₅ , -NHCH (CH ₃ J ₂ , -NHC (CH ₃ J ₃ , -N (CH ₃ J ₂ , -N (C ₂ H ₅ J ₂ , - N (C ₃ H _z ) ₂ , - N (cyclo-C ₃ H ₅ ) ₂ , - N [CH (CH ₃ ) ₂ ] ₂ , -N [C (CH, J ₃ I ₂ ), alkylsulfoxyl (preferably SOCH ₃ , -SOC ₂ H ₅ , -SOC ₁ H ₇ , -SO-CyClo-C ₃ H ,, -SOCH (CH ₃ J ₂ , -SOC (CH,),), alkylsulfonyl (preferably -SO ₂ CH ₃ , -SO ₂ C ₂ H ₅ , SO ₇ C ₁ H ₇ , -SO ₂ -CyClO-C ₃ H ₅ , SO ₂ CH (CH ₃ I ₂ , -SO ₂ C (CH ₁ ) O, sulfo (-SO ₃ H,), Alkylsulfonαt (preferably -SO ₃ CH ₃ , - SO ₃ C ₂ H ₅ , -SO ₃ C ₁ H ₇ , - SO ₃ -CyCIo-C ₃ H ₆ , -SO ₃ CH (CH ₃ ) ₂ , -SO ₃ C (CH ₃ I ₃ ), Hαlogenalkyl (preferably -CH ₂ F, -CHF ₂ , -CF ₃ , CH ₂ Cl, -CH ₂ Br, -CH ₂ I, -CH, CI I ₇ 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 ₁ H ₇ , -CH (CH ₃ J ₂ , -C (CH ₃ J ₁ , C ₄ H ₉ , -CH ₂ -CH (CH ₁ Jj, -CH (CH ₃ JC ₂ H ₅ , -C ₅ H _{1 1} , -C ₆ H ₁₃ , -C ₇ H ₁₅ , -C ₈ H ₁ ,, -cyclo-C ₃ H ₅ , -CVCIO-C ₄ H ₇ , -cyclo-C ₅ H ₉ , -CyClO-C ₆ H _{1 1} ), aryl (preferably phenyl), arylalkyl (preferably -CH ₂ -Ph, - CPh ₃ ), alkenyl (preferably -CH = CH ₂ , -CH ₂ -CH-CH ₂ , C (CH ₃ J - CH ₂ , -CH = CH-CH ₃ , -C ₂ H ₄ -CH = CH ₂ , -CH = C (CH ₃ J ₂ ), alkynyl (preferably -C≡CH, C≡C-CH ₃ , -CH such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted alkylaryl; ₂ -C = CH), R ² and R ^3, independently, ¹ is hydrogen an optionally substituted linear, veizweigten or cyclic, saturated or unsaturated hydrocarbon radical as preferred defined below

Optionally substituted alkyl may be included within the scope of the entire invention, i. also in connection with the other Substituenfengruppen preferred:

Straight-chain or branched alkyl rmif 1 to 8, preferably 1 to 6, carbon atoms, cycloalkyl having 3 to 8, preferably 5 or 6 carbon atoms, or alkyl having 1 to 4 carbon atoms, which is substituted by cycloalkyl, which are each preferably 1 to 3 substituents Irkenes, which are preferably selected from the group consisting of hydroxy, halogen and cyano Halogen here and in the context of the present invention includes fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine, Furthermore, an or a plurality, more preferably 1 to 3, carbon atoms are replaced by heteroalkyl groups which contain nitrogen, acid or sulfur. This means in particular that, for example, one or more methylene groups in the alkyl radicals can be replaced by NH O or S.

Examples of alkyl radicals mι1 1 to 8 carbon atoms include a methyl group, an ethyl group, a n propyl group, a ι-propyl group, a n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, a ι Pentyl group, sec-pentyl group, t-pentyl group, 2-methylbutyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpenyl group, 1-ethylbutyl group, 2-ethylbutyl group, a 3-ethylbutyl group, a 1, 1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1-ethyl-1-methylpropyl group, an n-heptyi group, a 1-methylhexyl group, a 2-methylhexyl group, a 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 4-ethylpentyl, 1, 1-dimethylpentyl, 2,2-dimethyl pentyl group, a 3,3-dimethylpentyl group, a 4, 4-dimethylpentyl group, a 1-propylbutyl group, an n-octyl group, a 1-methylheptyl group, a 2-methylheptyl group, a 3-

Methylheptyl group, a 4-methylheptyl group, a 5-methylheptyl group, a 6-methylheptyl group, a 1-ethylhexyl group, a 2-ethylhexyl group, a 3-ethylhexyl group, a 4-ethylhexyl group, a 5-ethylhexyl group, a 1, 1-dimethylhexyl group, a 2 , 2-

Dimethylhexyl group, a 3,3-dimethylhexyl group, a 4,4 dimethylhexyl group, a 5,5-dimethylhexyl group, a 1-propylpentyl group, a 2-propylpentyl group, etc. Preferred are those having 1 to 6 carbon atoms, especially methyl, ethyl and n-propyl Am most preferred is methyl

Examples of alkyl groups which are formed by exchange with one or more heteroanalogical groups, such as -O-, -S- or -NH - are preferably those in which one or more methylene groups are substituted by ? 4 - - are replaced to form a Elhergruppe such as methoxymethyl, Ethoxymel ^"hyl, 2-methoxyethylene etc. trfindungsgemαß are polyether from the definition of alkyl includes

Cycloalkyl radicals having 3 to 8 carbon atoms preferably include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc. Preference is given to a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. Heterocyclic alkyl radicals which are formed from cycloalkyl by exchange of methylene by heteroanalogical groups are, for example, 5- or 6-glycated heterocyclic radicals, such as tetrahydrofuryl, pyrrohdinyl, pipindinyl or letrahydropyranyl optionally be condensed with aromatic rings, etc

Specifically, examples of a halogen-substituted linear or branched alkyl group having 1 to 8 carbon atoms include: a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a chloromethyl group, a bromomethyl group, a dibromomethyl group, a tribromomethyl group, a 1-fluoroethyl group, a 1-chloroethyl, a 1-bromoethyl, a 2-fluoroethyl, a 2-chloroethyl, a 2-bromoethyl, a 1, 2-difluoroethyl, a 1, 2-Dιchlorethylgruppe, a 1, 2-dibromoethyl, a 2,2 , 2-trifluoroethyl group, one

Heptafluoroethyl group, a 1-fluoropropyl group, an I-chloropropyl group, a 1-bromopropyl group, a 2-fluoropropyl group, a 2-chloropropyl group, a 2-bromopropyl group, a 3-fluoropropyl group, a 3-chloropropyl group, a 3-bromopropyl group, a 1, 2-difluoropropyl group, a 1,2-di-chloropropyl group, a 1,2-dibromopropyl group, a 2,3-difluoropropyl group, a 2,3-dichloropropyl group, a 2,3-dibromopropyl group, a 3,3,3-trifluoropropyl group, a 2 , 2,3,3,3-pentafluoropropyl group, a 2-fluorobutyl group, a 2-chlorobutyl group, a 2-bromobutyl group, an A-fluorobutyl group, a 4-chlorobutyl group, a 4-bromobutyl group, a 4,4-trifluoro-butyl group, a 2,2,3,3,4,4,4-heptafluorobutyl group, a perfluorobutyl group, a 2-Huorpentylgruppe, a 2-chlorophenyl, a 2-bromopentyl, a 5-Fluorpeπtylgruppe, a fifth A chloropentyl group, a 5-bromopentyl group, a perfluoropentyl group, a 2-fluorohexyl group, a 2-chlorohexyl group, a 2-bromohexyl group, a 6-fluorohexyl group, a ό-chlorohexyl group, a 6-bromohexyl group, a perfluorohexyl group, a 2-fluoroheptyl group, a 2-chloroheptyl group, 2-bromoheptyl group, 7-fluoroheptyl group, 7-chloroheptyl group, 7-bromo-heptyigroup, perfluoroheptyl group, etc.

Examples of a hydroxy-substituted alkyl group include the above-mentioned alkyl groups having 1 to 3 hydroxyl groups such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, etc

Optionally substituted alkenyl preferably includes throughout the scope of the invention

Straight-chain or branched-chain alkenyl of 2 to 8 carbon atoms and cycloalkenyl of 3 to 8 carbon atoms which may optionally be substituted by preferably 1 to 3 substituents such as hydroxy, halogen or alkoxy examples include vinyl, 1-methylvinyl, ANyl, 1-butenyl , Isopropenyl, Cyclopropenyl, Cyclobutenyl, Cyclopentenyl, Cyclohexenyl Preferred are Vinyi or AlIIyI.

Optionally substituted aryl closes throughout the scope of

Invention prefers a:

Aromatic hydrocarbon radicals having 6 to 1 4 carbon atoms (wherein the carbon atoms of the substituents are not included) and 5- to 10-membered aromalische heierocyclische radicals having up to 3 heteroatoms from the series S, O, N, which may be mono- or bicyciisch and those selected from preferably 1 to 3 substituents selected from hydroxy, halogen, cyano,

Alkyl, acyl and alkoxy can be substituted. It can posted the posted

Definition of alkyl and halogen to the above definitions or

Examples are referenced.

Alkoxy as a substituent of aryl includes here and below, for example an above-mentioned alkyl radical which is bonded to aryl via an oxygen atom, such as a linear or branched alkoxy radical having up to 6 carbon atoms, such as a methoxy group, an ethoxy group, an n-propyloxy group, an i-propyloxy group, emo n-butyloxy group, a ι-butyloxy group, a sec-butyloxy group, a t-butyloxy group, an n-pentyloxy group, an i-pentyloxy group, a sec-pentyloxy group, a t-pentyloxy group, a 2-methylbutoxy group, an n-hexyloxy group, an i-hexyloxy group, a 1-hexyloxy group, a sec-hexyloxy group, a 2-methylpentyloxy group, a 3-methylpentyloxy group, a 1-ethyibutyoxy group, a 2-ethylbutyloxy group, a 1, 1

Dimethylbutyloxy group, a 2,2-dimethylbutyloxy group, a 3,3-dimethylbutyloxy group, a 1-ethyl-1-methylpropyloxy group, etc. Preferred are a methoxy group, an ethoxy group, an n-propyloxy group, an i-propyloxy group, an n-butyloxy group, an i-butyloxy group, a sec-butyloxy group, a t-butyloxy group, etc. Acyl as a substituent of Aryi includes here and hereinafter : aliphatic acyl, aromatic acyl such as C 1 to Co alkanoyl such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc., and Co to C l O aroyl such as benzoyl, toluoyl, xyloyl, etc

Aromatic hydrocarbon radicals having from 6 to 14 carbon atoms include, for example, ^1- phenyl, naphthyl, phenanthrenyl and anthracenyl, which may be optionally substituted. Phenyl is preferred

Heteroaromatic radicals include, for example: pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyi, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl, benzo [b] thienyl, benzo [b] furyl, indazolyl, quinolyl, isoquinolyl, Naphthyridmyl, Chmazolinyl 5- or 6-glιedrιge aromatic heterocycles such as pyridyl, Pyπdyl N-oxide, pyrimidyl, Pyπdazinyl, furyl and thienyl are preferred

Optionally substituted alkylaryl includes throughout the scope of the

Invention prefers a:

Straight-chain or branched alkyl having 1 to 8, preferably 1 to 4 Kohlenstoffαtomen, as described above, which is substituted with Λryl, as described above. Preferred arylalkyl is benzyl.

- CO-R ⁸ , wherein R ^{8 is} an optionally substituted linear, branched or cyclic, saturated or unsubstituted hydrocarbon radical which, as mentioned above soin, -NH-CO-R ⁹ , wherein R 'is an optionally substituted linear, branched or cyclic, saturated or unsaturated carbohydrate, which may be as mentioned above, -NH-CO-NR ^{1 1} R ' ² , wherein R ^{1 1} and R ¹² each independently represent hydrogen and / or an optionally substituted linear, branched or R ^{1 1} and R ¹² , together with the nitrogen atom to which they are attached, form a 5- or 6-membered, optionally substituted ring, optionally containing 1 or 2, to form a cyclic, unsaturated or unsaturated hydrocarbon radical which may be as mentioned above may contain other heteroatoms, such as Pιperιdιn- 1 -yl, Morpholιn-4-yl, Thiomorpholιn-4-yl, pyrrolidin-1-yl, Oxazolιdin-3-yl, Thιazolldin-3-yl, 2-carboxyl-pyrrolidιn- l -yl (prolyl), 3- or 4-hydroxy-carboxy-Pyrrolιdin- 1 -y! (3- or 4-hydroxy-prolyl) etc, -R ¹ ^ 0-CO-R ¹ \ wherein R ^{13 is} a divalent, optionally substituted linear, branched or cyclic, saturated or unsaturated hydrocarbon radical, such as optionally substituted alkanediyl or optionally substituted alkenediyl, wherein optionally substituted alkanediyl preferably includes a bivalent straight or branched alkanediyl radical having 1 to 7, preferably 1 to 6, more preferably 1 to 4, carbon atoms which may optionally carry 1 to 3 substituents selected from the group consisting of is hydroxy, halogen and cyano; by way of example and preferably be methylene, 1, 2-Ethandιyl, ethane-1, 1 -dιyl, 1, 3-propylene, propane-1, 1 -diyl, propane-1, 2-diyl, propane-2,2-diyl , 1, 4- Butylene, butane-1, 2-dιyl, butane-1, 3-dιyl, butane-2,3-dιyl, pentane-1, 5-dιyl, pentane-2,4-diyl, 3-methyl pentan-2,4-diyl and hexan-1, 6-dιyl, a preferred, substituted alkanediyl radical represents a hydroxy-substituted alkanediyl radical optionally substituted alkenediyl is preferably a bivalent straight-chain or branched alkenediyl radical having 2 to 7, more preferably 2 to 6, more preferably 2 to 4 carbon atoms which may optionally bear 1 to 3 substituents selected from the group consisting of hydroxy, halogen and cyano. Examples which may be mentioned by way of example and are preferably: ethene-1, 1-diyl, ethene-1, 2-diyl, propene-1, 1-diyl, propene-1, 2-dιyl, propene-1, 3-diyl, but-1-ene 1, 4-dlyl, Bu1-l -ene-1, 3-diyl, but-2-en-l, 4-dιyl, bufa-1, 3-dien-1, 4-dιyl, Pen1-2-ene In the context of the present invention, l, 5-dιyl, hex-3-enyl, 6-dιyl and hexa-2,4-diene-l, 6-dιyl R ¹³ is particularly preferably alkanediyl, more preferably alkanediyl having 1 to 3 carbon atoms even more preferred is 1, 2-ethanediyl (-CH ₃ CH ₂ -) or 1, 3-propanediyl (-CH ₂ CH ₂ CH ₂ -), and R ^{14 is} an optionally substituted linear, branched or cyclic, saturated or unsaturated Hydrocarbon radical which may optionally have one or more heteroatoms, as defined above, and

-CO-NR ¹ ^ R ^16, wherein R ¹⁵ and R ^{1 6} are each independently of one another represent hydrogen and / or an optionally substituted linear, branched or cyclic, saturated or unsaturated hydrocarbon radical as defined above, or R ¹⁵ and R ¹⁶ together form with the nitrogen atom to which they are attached, a 5- or ό-ghedrigen, optionally substituted ring, which may optionally contain 1 or 2 further heteroatoms, also as already defined above,

R ^{5 is} hydrogen, halogen, cyano or nitro;

R ⁶ and R ^; independently of one another represent hydrogen or alkoxy, wherein with respect to the alkyl moiety reference can be made to the above definition of alkyl, or together represent a bond forming a double bond between the carbon atoms (ie have the following structure ¹

and salts thereof, for the therapeutic or prophylactic treatment of patients with spinal canal stenosis, in particular cervical spinal stenosis, and the symptoms thereby caused in these patients

The compounds used according to the invention comprise, in the presence of asymmetric carbon atoms, as in the case of ergoline derivatives, stereoisomeric forms (racemates, enantiomers, diastereomers). The invention therefore encompasses the use of all stereoisomeric forms, such as enantiomers, diastereomers and their respective mixtures, such as racemates, enantiomers Optionally, forms may be obtained by conventional optical resolution techniques, such as by fractional crystallization of diastereomers, therefrom by reaction with optically active compounds. If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses the use of all tautomeric forms

The compounds used in the present invention may be present as salts, and the invention includes all such salts. The compounds may be used in the form of their pharmaceutically acceptable salts. Compounds containing basic groups can be used in particular as salts of pharmaceutically acceptable acids, such as salts with mineral acids, carboxylic acids and sulfonic acids, for example with hydrochloric acid, hydrobromic acid, iodosulfuric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid, hydroxyethanesulfonic acid, aceturic acid ( Acetylglycine), maleic acid, propionic acid, fumaric acid, toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, naphthalene-1-sulfonic acid, l, salicylic acid, benzoic acid, Lactic acid, malic acid, 3-hydroxy-2-naphthoic acid-2, citric acid or acetic acid, etc. Compounds used according to the invention which contain acidic groups can be used in the form of pharmaceutically acceptable salts with pharmaceutically acceptable bases, such as e.g. B, alkali metal hydroxides (sodium salts, etc.), alkaline earth metal hydroxides (calcium salts, magnesium salts, etc.), amines, etc.

Ergohn derivatives are described, for example, in WO 92/2339 A1, WO 08061 8O5 A1, WO 08043601 A1, WO 071 1 0047 A2, WO 0706571 3, A2 WO 05025546 A1, WO 03076439 A2, WO021 5890 A1, WO021 5889 A1 and the documents cited therein. The above-mentioned documents are insofar fully content to revelation content of the present application to be expected.

Particular preference is given to compounds of the formula

wherein

R ¹ and R ⁴ independently of one another are hydrogen, alkyl, alkenyl,

R ² and R ³ mean:

Hydrogen,

-NH CO-NR ^{1 1} R ¹² , wherein R ^{1 1} and R ^{12 are} each independently

Hydrogen and / or alkyl, or R "and R ¹² form together with the nitrogen atom to which they are attached, a 5- or 6-glιedrιgen, which may optionally contain 1 further heteroatom, and / or

-CO-NR ¹⁵ R ¹⁶ , wherein R ¹⁵ and R ^{16 are} each independently

Hydrogen and / or an optionally substituted linear, branched or cychschen, saturated or unsaturated Kohlenπwαsserstoffrest stand, or R ^{1 5} and R ¹⁶ form together with the

Nitrogen atom to which they are attached, a 5 ~ or 6 membered, optionally substituted ring, which optionally 1 or 2 more

May contain heteroatoms,

R ^{5 is} hydrogen;

K 'una R' unaonangig voneiπanaer for vVubbeibtuff stentin, or zusammer a bond forming a double bond between the

Represent carbon atoms, wherein the preferred substituents are described above

Particularly preferred is the use of compounds according to the following formula:

which are preferably selected from

Therein, the 8β derivatives each represent the bpimers of the 8a derivatives, such as 8a-lisuride or 8a-terguride.

Among these compounds, the use of 8a-lisuride or 8a-terguride is particularly preferred, and the most preferred is the use of terguride or 8a-terguride.

The present invention further provides the use of the compounds described above in combination with one or more other active ingredients. Preferred such other active ingredients include, in particular, other active ingredients which are known for the treatment of spinal canal stenosis, such as, in particular, the aldose reductase known from US 2 006 005 581 A1 Inhibitors which are known from DE 6991 91 91 T2 known Pyridazinonverbindungen and in particular and preferably from EP 1 609480 Al known EP2 agonists and EP3 agonists or combinations thereof, such as the prostaglandin E l derivative, which is approved under the trade name Opalmon .

Other active ingredients that can be used in combination with the compounds used in the invention include for example, a prostaglandins, prostaglandin derivatives, so-called "nonsieroidal anti-inflammatory drugs" (NSAID), vitamins, muscle relaxants, antidepressants, poly-ADP-πbosepolymerase (PARP) inhibitors, exitatory amino acid Rezeplorantagonisten (such as NMDA receptor antagonists and AMPA receptor antagonists), radical scavengers, Astrocytic modulators, IL-8 receptor antagonists, immunosuppressive agents (such as cyclosporin and FK506), and aldose reductase inhibitors Examples of prostaglandins (abbreviated as PG) include PG receptor chorates, PG receptor antagonists, etc. Examples of PG receptors include PGE reagents. Receptors (tPl, EP2, FP3 and EP4), PGD receptors (DP, CR1 H2), PGF receptors (FP), PGI receptors (IP), TX receptors (TP) etc. Examples of prostaglandin derivatives additionally include Limaprost, lloprosi and beraprost.

Examples of NSAIDs include sasapyrins, sodium salicylaf, aspirin, aspirin dialuminate, diflunisal, indomethacin, suprofen, ufenamate, dimethylisopropylazulen, bufexamac, felbinac, diclofenac, tolmetinin, clinoril, fenbufen, nabumetone, proglumetacin, indomethacin-farnesyl, acemetacin, proglumetacin maleate, amfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofen-piconol, naproxen, flurbiprofen, flurbiprofenaxetil, ketoprofen, fenoprofen-calcium, tiaprofenic acid, oxaprozin, pranoprofen, loxoprofen-natrium, alminoprofen, zaltoprofen, mefenamic acid, mefenamic acid aluminum, tolfenic acid, floctafenine, ketophenylbutazone , Oxyphenbutazone, piroxicam, tenoxicam, ampiroxicam, felbinac, epiπzol, tiararnide hydrochloride, tinoridine hydrochloride, emorfazone, sulpvrme, migrenm, saridone, sedes G, amipylo N, solvone, acetammophen, phenacetin, dimetotiazmium silicate, etc. Examples of muscle relaxants include: Tolpeπson hydrochloride, chlorzoxazone, chlormezanone, methocarbamol, phenpr obamate, pyridinol mesilate, chlorphenesine carbamate, baclofen, eperisone hydrochloride, afloqualone, tizaindm hydrochloride, alcuronium chloride, suxamethonium chloride, tubocurarine chloride, dantrolenenafranium, pancuronium bromide, vecuronium bromide, etc. Examples of antidepressant agents include t-cyclic antidepressants, such as imipiamine hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, trimipramine maleate, amitriptyline hydrochloride, nortptinyl imine hydrochloride, lofeprαminhydrochloπd, Amoxαpm, Dosulepin hydrochloride θtc Examples of tetralocytic antidepressants include maprotiline, mianserin, etc.

Said combination includes various modes of administration, such as the simultaneous or sequential administration of separate active ingredients, or the simultaneous administration of a combination of active ingredients. The said combination also includes an associated presentation in a random combination, such as a so-called "kit of parts". one.

The present invention further relates to the compounds which are 5-HT _2A and 5-HT, _B receptor antagonists and wherein the pA ₂ value of the compounds at 5-HT _2A and 5-HT _5B receptors is> 7.5 therapeutic or prophylactic treatment of patients with spinal stenosis and the symptoms caused thereby in this patient

The present invention further relates to the Ergohn-Derlvate for the therapeutic or prophylactic treatment of patients with spinal stenosis, in particular cervical spinal canal stenosis, and the symptoms thereby caused in this patient, wherein the Ergol-Derlvate are as described above

The present invention further relates to the compounds of the formula

as described above, their salts for the therapeutic or prophylactic treatment of patients with Spinalkanalsienose and thereby caused in these patients symptoms. The present invention further relates to and preferably 8α-Lιsuπd or 8α-Tergurιd, more preferably 8α-Tergurιd for therαpeulischen or prophylactic treatment of Patienlen with spinal canal stenosis and thereby caused in these patients symptoms.

The present invention particularly preferably relates to 8α-mercuride for the therapeutic or prophylactic treatment of patients with cervical spinal canal enema and the symptoms thereby caused in these patients.

The present invention further relates to a combination preparation containing one or more compounds as defined in any one of the preceding claims in association with one or more more potent drugs for the therapeutic or prophylactic treatment of patients with spinal canal stenosis and the symptoms thereby caused in that patient.

The compounds defined above are preferably administered in the present invention in the form of pharmaceutical compositions together with one or more conventional pharmaceutical excipients. The present invention therefore further relates to pharmaceutical compositions comprising the compounds defined above and one or more conventional pharmaceutical excipients for therapeutic or prophylactic Treatment of patients with spinal stenosis and the symptoms caused by it in these patients

The abovementioned pharmaceutical compositions are suitable, for example, for inhalation or for intravenous, intraperitoneal, intramuscular, intravaginal, intrabuccal, percutaneous, subcutaneous, mucocutaneous, oral, rectal, transdermal, topical, intradermal, intragastric or intracutaneous administration and are in the form of pills, for example. Tablets, enteric-coated tablets, film-coated tablets, shift tablets, sustained-release formulations for oral, subcutaneous or cutaneous Administration (in particular as plaster), depot formulation, dragées, suppositories, gels, ointments, syrups, inhalable powders, granules, suppositories, emulsions, dispersions, microcapsules, microformulations, nano-formulations, liposomal formulations, capsules, enteric-coated capsules, powders, inhalable powders, microcrystalline formulations, Inhalation sprays, powders, drops, nose drops, nasal sprays, aerosols, ampoules, solutions, safes, suspensions, emulsions, infusion solutions or injection solutions are preferred. Oral and cutaneous transdermal administration forms are preferred

The compounds of the present invention may be administered in pharmaceutical composition which may contain various organic or inorganic carriers and / or auxiliary materials commonly used for pharmaceutical purposes, in particular solid drug formulations, such as excipients (such as sucrose, starch, mannitol, sorbitol, Lactose, glucoso, cellulose, talc, calcium phosphate, calcium carbonate), binders (such as cellulose, methylcellulose, hydroxypropylcellulose, polypropyipyrrohdone, gelatin, gum arabic, polyethylene glycol, sucrose, starch), disintegrants (such as starchy, hydrolyzed starch, carboxymethylcellulose, calcium salt of carboxymethylcellulose, hydroxypropyl starch , Sodium glycol starch, sodium bicarbonate, calcium phosphate, calcium citrate), lubricants (such as magnesium stearate, talc, sodium lauryl sulfate), a flavoring agent (such as citric acid, menthol, glycine, orange powder), preservatives (such as sodium benzoate, sodium bisulfite, methylparaben, propylparaben), stabilizers (such as citric acid, sodium citrate, acetic acid, and Titπplex series multicarboxylic acids such as, B diethylenetriaminepentaacetic acid (DTPA), suspending agents (such as methylcellulose, polyvinylpyrrolidone, aluminum stearate), dispersants, diluents (such as water, organic solvents), beeswax, cocoa butter, polyethylene glycol, white petrolatum, etc.

Liquid drug formulations such as solutions, suspensions and gels usually contain a liquid carrier such as water and / or pharmaceutically-contracted organic solvents. Furthermore, such liquid formulations may also contain pH adjusting agents, emulsifiers or dispersing agents, buffering agents, preservatives, Netzmι11el, gelling agents (for example methylcellulose), colorants and / or flavorings, the compositions may be isotonic, that is, these may have the same osmotic pressure Have blood. Isolonie of the composition may be adjusted by the use of sodium chloride or other pharmaceutically acceptable agonists such as dextrose, maltose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic soluble substances. The viscosity of the liquid compositions may be determined using a pharmaceutically acceptable thickening agent such as Methyl cellulose can be adjusted. Other suitable thickening agents include, for example, xanthan, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer and the like. The preferred concentration of thickening agent will depend on the agent chosen. Pharmaceutically acceptable preservatives may be used to increase the shelf life of the liquid composition. Benzyl alcohol may be suitable, although a variety of preservatives including, for example, paraben, thimerosal, chlorobutanol or benzene chloride may also be used

The active ingredient may be administered, for example, at a unit dose of 0.25 mg to 50 mg, preferably 0.25 mg to 5.0 mg 1 up to 4 times a day. However, the dosage may vary depending on the age, condition of the patient, severity of the disease or mode of administration increased or decreased.

The present invention furthermore particularly preferably relates to the compounds and compositions as mentioned above for the therapeutic or prophylactic treatment of patients with cervical spinal canal stenosis and the symptoms caused thereby in this patient The invention is further illustrated by the following example. The example is only an illustration of the invention and one skilled in the art will be able to extend this specific example to other claimed compounds.

BJ≡iSP] FL_

The clinical trial included patients with chronic generalized pain. A subgroup of patients met the definition of primary hbromyalgia. Another group of patients was diagnosed with chronic neck pain. Most patients participating in the study underwent an investigation during the course of the study Cervical spine performed with Magnetic Resonance Imaging (MRI) as an imaging procedure Conditions were selected that generally allow the cross section of the spinal canal to be visualized in the cervical spine without the use of contrast elements and normal head position in the resting state Teslar magnetic resonance scanners performed By a bland evaluator who acted as a reviewer, were in all evaluable recordings of the diameter of the spinal canal and the thickness of the nerve cord (the so-called myelon) ausgeme Furthermore, an evaluation of the findings regarding the prevalence of a 7ervinal spinal stenosis was carried out according to an internationally recognized evaluation catalog (NJNR Am J Neuroradiol 1 998 Oct 1 9 (9) 1 763 7 1). This includes a 5-degree scale. 0 here describes a spinal cord canal of normal width with no evidence of narrowing of the anterior or posterior subarachoid space within the spinal canal. At grade 1 there is a partial constriction of anterior or posterior subarachoid space or both. At grade 2 the spinal cord completely fills the subarachoid space of the spinal canal cervical compression or torsion of the spinal cord, and grade 4 a type of myelotype hypersensitivity as evidence of myelopathy Based on this evaluation, approximately 20% of all evaluated patients of the study Grade 2 4 experienced changes that this group of patients described as patients with cervical stenosis ben

The treatment of the patients was carried out with 1 erguπd (1 tablet = 0 5 mg) a Crgohn compound which, as stated above, was both a partial dopamine agonist and also a 5 I IT, _A and a 5-HT _{2 B} - Rθzeptorαntαgonisi is, or Plαcebo. The Prufmedikαfion was over 21 days gradually auflitπert of a half tablet to a maximum of ό tablets / day, then was further treated for 9 weeks at a constant dosage. The medication was taken in the morning and in the evening. The course of therapy after 3, 7 and 1 2 weeks was assessed using patient-oriented scales to determine pain intensity, fatigue, sleeplessness, muscle rigidity, anxiety, nervousness and depression, well-being and work ability, as well as a questionnaire on life-style activities A reduction of the scale values or a lower score in the evaluation of the questionnaire indicates an improvement of the respective characteristic and thus a therapeutic success.

Fs showed surprisingly that among patients with chronic generalized pain conditions, only the patient group with cervical spinal canal stenosis (grade 2-4) had a significant treatment success after 3 months (Figure 1). In the sum of the questions asked (total score) Majority of patients with a greater or lesser improvement in general condition. A decrease in the intensity of pain, an improvement in anxiety and nervousness, and especially an improvement in the subjectively perceived physical impairments and workload are particularly noteworthy. In contrast, the condition of the patient group with chronic generalized pain, but normal, unimpaired spinal canal remained in the range the cervical spine, despite therapy with Terguπd, remained largely unchanged (Fig. 2), only muscle stiffness, and depressive behavior showed a trend towards improvement, while pain behavior was assessed as unchanged. Overall, significant improvements in Terguπd-treated patients were undetectable in patients treated with cervical spinal canal stenosis compared to placebo-treated patients

Similarly, the analysis of the group of patients suffering from chronic neck pain, in particular, showed no signs of any On the contrary, several of the success parameters of treatment in the patient have been described as worsening, in particular physical impairment, well-being, pain perception, muscle rigidity and anxiety states / nervousness.

In summary, Terguπd has only been successful in treating patients with cervical spasmal stenosis

EXPLANATORY NOTES OF DEPARTMENTS:

Figure 1 shows the effect of terguride on selected patient-oriented scales and general care questionnaires in patients with chronic generalized pain and cervical spinaistenosis (grade 2 4).

Figure 2 shows the effect of terguride on selected patient-oriented scales and general care questionnaire in patients with chronic generalized pain in the absence of cervical spinal stenosis (grade 0-1).

Figure 3 shows the effect of terguride on selected patient orientated scales and general health questionnaires in patients with chronic generalized pain and chronic neck pain, but without spinal fenestration (grade 0-1).

Claims

PALENTANSPRÜCHEi

I use of compounds that 5-H1 _2Λ ^{ur |} d 5-HT _2B

Receptor αntαgonisten are and wherein the pA ₂ value of the compounds at 5-HI _2A and 5-HT _2B receptors> 7.5, for the preparation of a medicament for the therapeutic or prophylactic treatment of patients rnι1 spinal stenosis and thereby caused in these patients symptoms .

2. Use according to the preceding claim, wherein the pA _? Value for 5-HT _2A receptors at a maximum of + 1 unit from the pΛ _? Value of compounds at 5-HT _2B receptors

3. Use according to the preceding claims, wherein the compound is selected from the group comprising cyprohepiadine, mianserin, Ritanseπn, methiothepin, methysergide, metergohn, Lisuπd, terguride, trazodone, pizotifen and nicergoline.

Use according to the preceding claims, wherein the compound is terguride and / or Lisuπd

Use according to the preceding claims, wherein the compounds are selected from 8a-Lιsurιd or 8a Tergurid,

Use according to any one of the preceding claims, wherein the spinal canal stenosis is a cervical spinal canal stenosis.

7, Use according to any one of the preceding claims, which serves to alleviate the symptoms of paresis, hypershesia, parasthesia, pain and / or sensory disorders, such as numbness

8, Use according to one of the preceding claims for the improvement of physical impairments, in particular the limited pain-free mobility and the reduction the malformation of the head and to improve the reduction of muscle strength, to improve gait disturbances, to improve tingling and / or to improve ataxia and zui improvement of grove and / or Stuhlmkonfinenz

Use according to any one of the preceding claims, wherein the spinal stenosis is a chronic effect of whiplash, other traumatic changes or herniated disc. Use according to any one of the preceding claims, comprising the prophylactic treatment of palpates with spinal canal stenosis and the symptoms thereby caused in that patient for prevention of the chronicity of the symptom complexes as well as the prophylactic treatment of patients with a whiplash injury in order to prevent the chronic effects of a spinal stenosis in consequence

A use according to any one of the preceding claims, wherein said compounds are administered to the patient in combination with one or more other active agents. 2. Compounds which are 5-HT _2A and 5-HT _2B receptor antagonists and wherein the p / \ ₂ - Value of compounds at 5-HT _{? A} and 5-HI _2B receptors> 7.5 for the therapeutic or prophylactic treatment of patients with spinal canal stenosis and the symptoms thereby caused in these patients

3 8a-Lisuride or 8a-Tergurιd for the therapeutic or prophylactic treatment of patients with spinal canal stenosis and the symptoms caused thereby in this patient, 4. 8a-Terguπd for the therapeutic or prophylactic treatment of patients with spinal stenosis and thereby caused in these patients symptoms. 1 5, 8α-rergurιd for the therapeutic or prophylactic treatment of patients with cervical spasmal stenosis and the symptoms caused thereby in these patients

A combination preparation, comprising one or more compounds as defined in any one of the preceding claims, in association with one or more other active agents for the therapeutic or prophylactic treatment of patients with sputal canal stenosis and the symptoms thereby caused in that patient

Use according to any one of the preceding claims, wherein the precursors defined in the claims are administered in the form of pharmaceutical compositions together with one or more conventional pharmaceutical excipients,

1 8. Pharmaceutical compositions containing the compounds defined in the preceding claims and one or more conventional pharmaceutical excipients for the therapeutic or prophylactic treatment of patients with spinal stenosis and thereby caused in these patients symptoms.

Pharmaceutical compositions according to the preceding claim, wherein the pharmaceutical composition is suitable for oral, sublingual, parenteral, cutaneous, buccal, percutaneous, subcutaneous, inhalative or nasal administration,

A pharmaceutical composition according to the preceding claims, which is in the form of tablets, coated tablets, capsules, sustained-release, transdermal, suppository, microformulations, nano-formulations, liposomal formulations, drops, nose drops, nasal sprays, aerosols, ampoules, solutions, emulsions , Dispersions, powders, Inhalation powders, microcrystalline formulations, inhalation sprays, transdermal systems or subcutaneous formulations are present

A pharmaceutical composition according to any one of the preceding claims for the therapeutic or prophylactic treatment of patients with cervical spinal canal stenosis and the symptoms thereby caused in said patient,