WO2010072774A2 - Agent destiné au traitement de la sténose du canal rachidien - Google Patents

Agent destiné au traitement de la sténose du canal rachidien Download PDF

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WO2010072774A2
WO2010072774A2 PCT/EP2009/067768 EP2009067768W WO2010072774A2 WO 2010072774 A2 WO2010072774 A2 WO 2010072774A2 EP 2009067768 W EP2009067768 W EP 2009067768W WO 2010072774 A2 WO2010072774 A2 WO 2010072774A2
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patients
group
stenosis
spinal
symptoms
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PCT/EP2009/067768
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German (de)
English (en)
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WO2010072774A3 (fr
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Rudolf Reiter
Lothar Pache
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Pfizer Inc.
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Priority to MX2011006852A priority Critical patent/MX2011006852A/es
Priority to CN2009801524590A priority patent/CN102271667A/zh
Priority to SG2011045671A priority patent/SG172315A1/en
Priority to JP2011542819A priority patent/JP2012513446A/ja
Priority to CA2748163A priority patent/CA2748163A1/fr
Priority to EP09795786A priority patent/EP2367543A2/fr
Priority to AU2009331469A priority patent/AU2009331469A1/en
Priority to BRPI0923556A priority patent/BRPI0923556A2/pt
Publication of WO2010072774A2 publication Critical patent/WO2010072774A2/fr
Publication of WO2010072774A3 publication Critical patent/WO2010072774A3/fr
Priority to IL213768A priority patent/IL213768A0/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel use of compounds for the Iherapeulic or prophylactic treatment of patients with
  • 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
  • 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
  • stenosis occurs due to the condition (for example, dysplasia, malformations, subluxations, spina bifida, meningoceles).
  • 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).
  • degenerative diseases ie, physiologically occurring signs of abnuity, which occur secondarily after degenerative disorders
  • Degenerative changes can occur at different points of the spinal canal and thus lead to a constriction and Ir ⁇ talion 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.
  • 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.
  • 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.
  • 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%)
  • spinal stenosis in the area of the cervical spine 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
  • a gait ataxia 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
  • electrophysiological examinations can also contribute to the assessment and estimation of the severity of spinal canal stenosis.
  • EMG electromyography
  • NVG nerve conduction velocity
  • SSEP somatosensory evoked potentials
  • 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.
  • 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
  • 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
  • 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
  • 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
  • serotonin antagonists such as sarpogrelate
  • the treatment of patients with neurogenic claudication Intermittens due to lumbar spinal stenosis by administration of sarpogrelate, as a 5-HT, ⁇ 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.
  • limaprost alfadex a prostaglandin El derivative
  • Opalmon for the treatment of symptoms associated with lumbisthinosis (Spine 2008 June; 33 (13) '1 465-9).
  • 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.
  • 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
  • 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.
  • nicergoline does not affect the serotonergic system such as dopamine agonists such as sarpogrelate or the ergoline derivative Tergu ⁇ d
  • 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 2 ⁇ , 5-HT 28 and 5-HT 7 receptor antagonists,
  • 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.
  • 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 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.
  • 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
  • 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
  • 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.
  • 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- ad ⁇ enoceptor antagonists, can be determined in particular according to the methods described in the dissertation Gornemann, FU Berlin, 2008
  • 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 ⁇ Annual et ⁇ l (2005) N ⁇ uyn-Schmiedebergs Aren Ph ⁇ rm ⁇ col 37 1 89 98)
  • Suitable ⁇ 2 adrenoceptor ⁇ nt ⁇ gonistcn in particular ⁇ 2C - Adrenozeptor ⁇ nt ⁇ gonisten can be identified in particular under selected experimental conditions by characterizing contractile effects on pulmonary veins of Schiachtschweinen (sa Gorneman ⁇ 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 ? -adrenolyt ⁇ sche 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
  • 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
  • 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
  • preferred compounds according to the invention are 5 HT 7 receptor antagonists with a pA 2 of> 7 5
  • 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.
  • 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 p ⁇ 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
  • 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 2 ⁇ - and 5-HT 2 ⁇ - and 5-HT 2 ⁇ - 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.
  • 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).
  • 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
  • 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.
  • 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).
  • 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
  • the use according to the invention involves the treatment of all symptoms possibly associated with spasmal canal stenosis
  • 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
  • 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.
  • 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.
  • this is for the treatment of spasmal canal stenosis, which is a chronic effect of whiplash, other traumatic changes or herniated disc
  • 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
  • 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,
  • 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
  • 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
  • Optionally substituted alkyl may be included within the scope of the entire invention, i. also in connection with the other Substituenfen jury preferred:
  • 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,
  • 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.
  • alkyl radicals m ⁇ 1 1 to 8 carbon atoms include a methyl group, an ethyl group, a n propyl group, a ⁇ -propyl group, a n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, a ⁇ 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
  • 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
  • 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 Elherze such as methoxymethyl, Ethoxymel "hyl, 2-methoxyethylene etc.
  • trfindungsgem ⁇ ß 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
  • 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-D ⁇ chlorethyl distr, a 1, 2-dibromoethyl, a 2,2 , 2-trifluoroethyl group, one
  • hydroxy-substituted alkyl group examples 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.
  • 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
  • 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 ⁇ -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,
  • Dimethylbutyloxy group 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-gl ⁇ edr ⁇ ge aromatic heterocycles such as pyridyl, Py ⁇ dyl N-oxide, pyrimidyl, Py ⁇ dazinyl, furyl and thienyl are preferred
  • Optionally substituted alkylaryl includes throughout the scope of the
  • arylalkyl is benzyl.
  • 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 P ⁇ per ⁇ d ⁇ n- 1 -yl, Morphol ⁇ n-4-yl, Thiomorphol ⁇ n-4-yl, pyrrolidin-1
  • 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-Ethand ⁇ yl, ethane-1, 1 -d ⁇ yl, 1, 3-propylene, propane-1, 1 -diyl, propane-1, 2-diyl, propane-2,2-diyl , 1, 4- Butylene, butane-1, 2-d ⁇ yl, but
  • l, 5-d ⁇ yl, hex-3-enyl, 6-d ⁇ yl and hexa-2,4-diene-l, 6-d ⁇ yl 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
  • 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 ⁇ -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
  • 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
  • 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
  • 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.
  • 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.
  • R 1 and R 4 independently of one another are hydrogen, alkyl, alkenyl,
  • R 2 and R 3 mean:
  • 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-gl ⁇ edr ⁇ gen, which may optionally contain 1 further heteroatom, and / or
  • R 15 and R 16 are each independently
  • R 5 is hydrogen
  • the 8 ⁇ derivatives each represent the bpimers of the 8a derivatives, such as 8a-lisuride or 8a-terguride.
  • 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.
  • 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 Pyridazinontagenen 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 .
  • prostaglandins include for example, a prostaglandins, prostaglandin derivatives, so-called “nonsieroidal anti-inflammatory drugs” (NSAID), vitamins, muscle relaxants, antidepressants, poly-ADP- ⁇ bosepolymerase (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
  • PG prostaglandins
  • 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.
  • NSAIDs examples 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,
  • muscle relaxants include: Tolpe ⁇ son 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.
  • antidepressant agents include t-cyclic antidepressants, such as imipiamine hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, trimipramine maleate, amitriptyline hydrochloride, nortptinyl imine hydrochloride, lofepr ⁇ minhydrochlo ⁇ d, Amox ⁇ pm, Dosulepin hydrochloride ⁇ tc
  • 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
  • the present invention further relates to and preferably 8 ⁇ -L ⁇ su ⁇ d or 8 ⁇ -Tergur ⁇ d, more preferably 8 ⁇ -Tergur ⁇ d for ther ⁇ peulischen or prophylactic treatment of Patienlen with spinal canal stenosis and thereby caused in these patients symptoms.
  • the present invention particularly preferably relates to 8 ⁇ -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
  • 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
  • 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, Netzm ⁇ 11el, 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.
  • a liquid carrier such as water and / or pharmaceutically-contracted organic solvents.
  • such liquid formulations may also contain pH adjusting agents, emulsifiers or dispersing agents, buffering agents, preservatives, Netzm ⁇ 11el, gelling
  • the viscosity of the liquid compositions may be determined using a pharmaceutically acceptable thickening agent such as Methyl cellulose can be adjusted.
  • 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.
  • 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.
  • 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.
  • Cervical spine performed with Magnetic Resonance Imaging (MRI) as an imaging procedure
  • MRI Magnetic Resonance Imaging
  • 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) abandonedme
  • 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).
  • 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.
  • grade 1 there is a partial constriction of anterior or posterior subarachoid space or both.
  • 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 Prufmedik ⁇ fion was over 21 days gradually auflit ⁇ ert of a half tablet to a maximum of ⁇ tablets / day, then was further treated for 9 weeks at a constant dosage. The medication was taken in the morning and in the evening.
  • 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).

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Abstract

L'invention concerne une nouvelle utilisation de composés destinés au traitement thérapeutique ou prophylactique de patients présentant une sténose du canal rachidien, et des symptômes qui en résultent chez ces patients.
PCT/EP2009/067768 2008-12-23 2009-12-22 Agent destiné au traitement de la sténose du canal rachidien WO2010072774A2 (fr)

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MX2011006852A MX2011006852A (es) 2008-12-23 2009-12-22 Agentes para el tratamiento de la estenosis del conducto vertebral.
CN2009801524590A CN102271667A (zh) 2008-12-23 2009-12-22 用于治疗椎管狭窄的5-ht2a和5-ht2b受体拮抗剂
SG2011045671A SG172315A1 (en) 2008-12-23 2009-12-22 5-ht2a and 5-ht2b receptor antagonists for treating stenosis of the spinal canal
JP2011542819A JP2012513446A (ja) 2008-12-23 2009-12-22 脊椎管狭窄症を処置するための薬剤
CA2748163A CA2748163A1 (fr) 2008-12-23 2009-12-22 Agent destine au traitement de la stenose du canal rachidien
EP09795786A EP2367543A2 (fr) 2008-12-23 2009-12-22 Agent destiné au traitement de la sténose du canal rachidien
AU2009331469A AU2009331469A1 (en) 2008-12-23 2009-12-22 5-HT2A and 5-HT2B receptor antagonists for treating stenosis of the spinal canal
BRPI0923556A BRPI0923556A2 (pt) 2008-12-23 2009-12-22 agente para o tratamento de estenose do canal espinhal
IL213768A IL213768A0 (en) 2008-12-23 2011-06-23 5-ht2a and 5-ht2b receptor antagonists for treating stenosis of the spinal canal

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EP2367543A2 (fr) 2011-09-28
AU2009331469A1 (en) 2011-07-21
KR20110098965A (ko) 2011-09-02
BRPI0923556A2 (pt) 2016-01-26
WO2010072774A3 (fr) 2010-09-23
IL213768A0 (en) 2011-07-31
CA2748163A1 (fr) 2010-07-01
JP2012513446A (ja) 2012-06-14
MX2011006852A (es) 2011-07-20

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