SG172315A1 - 5-ht2a and 5-ht2b receptor antagonists for treating stenosis of the spinal canal - Google Patents

5-ht2a and 5-ht2b receptor antagonists for treating stenosis of the spinal canal Download PDF

Info

Publication number
SG172315A1
SG172315A1 SG2011045671A SG2011045671A SG172315A1 SG 172315 A1 SG172315 A1 SG 172315A1 SG 2011045671 A SG2011045671 A SG 2011045671A SG 2011045671 A SG2011045671 A SG 2011045671A SG 172315 A1 SG172315 A1 SG 172315A1
Authority
SG
Singapore
Prior art keywords
patients
group
spinal canal
canal stenosis
compounds
Prior art date
Application number
SG2011045671A
Inventor
Rudolf Reiter
Lothar Pache
Original Assignee
Pfizer
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer filed Critical Pfizer
Publication of SG172315A1 publication Critical patent/SG172315A1/en

Links

Classifications

    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Neurology (AREA)
  • Pain & Pain Management (AREA)
  • Neurosurgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicinal Preparation (AREA)

Abstract

AGENTS FOR TREATING SPINAL CANAL STENOSISThe present invention relates to a new use of compounds for the therapeutic or prophylactic treatment of patients having spinal canal stenosis and of the symptoms caused thereby in these patients.No Figure

Description

AGENTS FOR TREATING SPINAL CANAL STENOSIS
Description:
The present invention relates to a new use of compounds for the therapeutic or prophy- lactic treatment of patients having spinal canal stenosis and of the symptoms caused thereby in these patients.
Spinal canal stenosis describes a constriction of the vertebral canal of the spinal col- umn, in most cases due to degenerative, wear-related changes in vertebral joints, ligaments and intervertebral disks. It is characterized by a constriction of the spinal canal which causes pressure on the spinal cord contained therein and the nerve roots. These constrictions of the spinal column now belong to the most frequently diagnosed and operated disorders of the spinal column.
If the constriction exists at the level of the cervical spine, one speaks of cervical spinal canal stenosis. A constriction of the thoracic spine is referred to as thoracic spinal canal stenosis. If the lumbar spine is affected, one speaks of a lumbar spinal canal stenosis.
Numerous anatomical causes can result in a restriction of the vertebral canal. In rare congenital cases an inherent or constitutional stenosis occurs (e.g., displasias, malformations, sublaxations, spina bifida, meningoceles). However, acquired deformations of the thoracic spine are more frequent. These can result traumatically, through instabilities, through in- flammatory or neoplastic processes or through post-operative changes (e.g., scars). Clinically, by far the most relevant cause for spinal canal stenosis of the spinal column are degenerative disorders, that is physiologically occurring wear phenomena which occur secondary to degen- erative disorders.
Various anatomical structures which together form the wall of the vertebral canal are involved in the development of spinal canal stenoses. These comprise the intervertebral disks, intervertebral joints and the ligamentum flavum, a strong ligament extending in the longitu- dinal direction. A direct restriction results when a damaged intervertebral disk protrudes to the back or herniates. Arthrosis of the intervertebral joints, on the contrary, indirectly affect the width of the vertebral canal by forming bony protrusions (spondylophytes) which, in term, constrict both the vertebral canal as well as the nerve openings. A further cause is a thicken- ing of the ligamentum flavum which forms the rear closure of the vertebral canal.
Degenerative changes can occur at various locations of the vertebral canal and thus re- sult in a restriction and irritation of the spinal chord and/or the nerve roots. If spondylotic osteophytes are formed from the rear edge of the vertebral body, this results in a retrospondy- losis, which mainly occurs medially. Degeneratively caused bone protrusions starting from the processus uncinati results in an uncarthrosis involving a rather laterally constricting spacial demand. The arthorisis of the vertebral joints in the sense of a spondylotic arthrosis also causes a lateral constriction of the vertebral canal as well as the neuroforamina. Further- more, all forms of herniated or protruding intervertebral disks can result in a stenosis. A phe- nomenon which is more frequent in the Asian population is the ossification of the posterior longitudinal ligament (OPLL). While the disorders just mentioned constrict the spinal canal from the ventral or lateral side and thus compress the spinal cord from the front or laterally, somewhat rarer causes for a dorsal space occupation also exist. This is then caused by a hy- pertrophy of the ligamentum flavum, i.e. a thickening of the ligamentum flavum or by an os- sification of the same.
According to epidemiological studies, the incidence is estimated to be 2 to 8%, the symptoms characteristically developing, without predominance in any of the sexes, in the fifth or sixth decade of life. In patients aged over 60 years, spinal canal stenosis is actually the most frequent reason for spinal column operations. In special risk groups, comprising persons suffering from whiplash trauma, athletes practicing contact sports or pilots, a higher inci- dence has been described also at younger ages.
The lumbar spine is most frequently affected by spinal canal stenosis. The principle complaints in cases of lumbar stenosis are feelings of heaviness, pain and weakness in the legs, in particular when walking and standing, as well as numbness in the bottom and/or in the legs in about 90% of patients. More than 85% of patients complain of back pain. Neuro- genic claudicatio intermittens (90%), 1.e. pain after walking short distances, occurs in 90% of all patients. The discomfort increases on adoption of an upright posture, while a bent posture, on the contrary, results in an improvement of the symptoms. As further symptoms there are described muscle tension, disrupted coordination of movements (ataxia) as well as bladder and colon disturbances, i.e. problems in defaecation and urination. The most frequent find- ings on examination are impaired flection of the spine (40%), pain when reclining (79%),
Laségue sign (12%), paresthesias (32%), pareses (27%), reflex deficit (64%) and bladder dys- function (6%).
In contrast thereto, a spinal stenosis in the region of the cervical spine, a cervical spinal canal stenosis, can have rather different clinical manifestations. There may occur diffuse and uncharacteristic pain or discomfort in the arms and/or legs as well as neck pain (cervicalgia) or arm pain (brachialgia). Patients frequently report slowly increasing weakness in the arms and/or legs which is usually pronounced on the sides. Insecurity in walking with a spastic gait is relatively typical; furthermore, voiding disorders may additionally occur.
Compared to lumbar and cervical spinal canal stenosis, thoracic spinal canal stenosis is extremely rare.
Diagnosis of spinal canal stenosis:
On examination, distally pronounced pareses and sensitivity disorders may be found.
Frequently, increased reflexes may be detected below the affected part of the spine. A gait ataxia (spastic, with legs apart, stumbling) may also be an indication of the disease. Rather rare and only in patients with cervical spinal canal stenosis, positive pyramidal path symp- toms (Babinski’s sign) or a positive Lhermitte’s sign are found, while an electric sensation along the spine or extremities is caused by flexion of the cervical spine.
However, for specific identification of a spinal canal stenosis as cause of pain and neu- rological symptoms, an examination using imaging methods has to be carried out. Spinal ca- nal stenosis itself cannot be recognized directly in conventional X-ray images. This requires cross-sectional imaging methods such as CT (computed tomography) and MRT (magnetic resonance tomography), which can depict the width of the spinal canal by their transversal cross sectioning. MRT is most valuable since it can not only represent bony structures, but also, and much better than CT, represent soft tissue structures in the affected region of the spine.
Apart from clinical examination and imaging diagnostics, electrophysiclogical exami- nations can contribute to an assessment of the severity of a spinal canal stenosis. By electro- myography (EMG), velocity of nerve conduction (NLG) and somatosensory evoked poten- tials (SSEP) it is possible to assess, in particular, the extent and severity as well as the prog- nosis of a spinal dysfunction.
The natural history of spinal canal stenosis varices greatly from patient to patient. The onset of the disease is hardly perceptible and, in the further course, a changing progress of the symptoms occurs. The progress of the deterioration is rarely linear. Stagnation at various stages of the disease is possible. As the degenerative changes increase, there occurs a pro- gressing constriction of the vertebral canal and the spinal cord is ultimately crushed. Ulti- mately, unbearable pain and symptoms of paralysis may occur.
Conventional therapy:
If, based on anamnesis, clinical symptoms, imaging methods and/or unusual electro- physiological examination results, a confirmed diagnosis has been made and if, in particular, symptoms of spasticity with dysfunction (including partial pareses) and severe sensibility disorders exist, an operation is clinically indicated. The aim of any operation in this context is the removal of the stenosis and thus the relief of the spinal cord. Depending on the results of imaging methods (X-ray, CT, MRT, myelography), various surgical techniques are employed.
The most frequently used methods are ventral decompression with fusion, corporectomy as an extension of ventral decompression by vertebral body substitution and fusion, dorsal de- compression with or without opening and extension of the dura and laminoplasty. Such surgi- cal methods as surgical orthopaedic invasion for removing lumbar spinal canal stenoses and, in particular, neurosurgical invasion in the region of the cervical spine for removing cervical spinal canal stenoses, generally involve a comparatively high risk and, therefore, are used only in advanced stages of the disease, in particular, with impending paralysis and after ex- tensive benefit risk analysis by the treating physician. Furthermore, in the context of such surgical methods, the risk of irreparable damage to the spinal cord due to minor accident has to be taken into consideration.
If the sensory and/or motoric dysfunction is less severe or if surgery is contraindicated, spinal canal stenosis is usually treated conservatively. This involves, on the one hand, the immobilization of the cervical spine by external fixation (neck collar) or by wearing a corsage or corset in the case of lumbar stenoses. On the other hand, physical exercise 1s used to stabi- lize the musculature and for delordosing.
The leading symptom of pain, which is present in most cases, is usually treated symp- tomatically by administration of pain-relieving medicaments such as analgesics (e.g. paracetamol, N-acetyl salicylic acid), opioids, pain-relieving plasters, implanted pain pumps or by infiltration therapy using nerve blockade, periradicular therapy, trigger point infiltra- tions or transcutaneous electrical nerve stimulation (TENS). In cases of muscular spasms, medicaments such as baclofen or tetrazepam are used. Likewise, non-steroidal anti- inflammatory agents or epidurally administered corticosteroids are used.
Although the aforementioned medicaments relieve pain, the pain-relieving effect is usually effective only for a limited time and the other effects of the disease, such as muscular rigidity, impaired painless mobility and impairment of the ability to work are hardly influ- enced.
Pathobiology and molecular targets:
Apart from symptomatic pain therapy and treatment with anti-inflammatory medica- ments, so far, only few drugs have been described whose administration results in an holistic pronounced improvement of the clinical symptoms of spinal canal stenosis by causal action on the pathophysiological process.
Experimental indications suggest a combination of various pathological mechanisms involving inflammatory processes in the multi-facetted symptoms of spinal canal stenosis.
Physiological changes in the epidural pressure and in the diameter of blood vessels supplying the spinal cord and the nerve ganglia, which are caused by the by the posture of patients having spinal canal stenosis, are clinically proven and correlate with the development of neurogenic claudicatio intermittens. A dysfunction of endothelial cells of local blood ves- sels and a changed response to the body’s messenger substances are discussed in this connec- tion. As a further mechanism, the up-regulation of neurotransmitter receptors in the spinal cord and in the dorsal and ventral nerve ganglia is discussed, which result in a changed proc- essing of nerve impulses and in a hypersensitivity and irritation of the spinal cord.
These pathomechanisms form the rationale for the therapeutic effect of calcitonin (Cal- cif Tissue Int 1992 May; 50(5): 400-3) in the treatment of spinal canal stenosis and for a pos- sible use of serotonin antagonists such as sarpogrelate for the treatment of symptoms related to herniated discs in the region of the [umbar spine. In particular, the treatment of patients having neurogenic claudicatio intermittens due to lumbar spinal canal stenosis by administra-
tion of sarpogrelate as 5-HT, receptor antagonist has been described. In this connection, the effective mechanism is assumed to be an improvement in the blood flow in the nerve ends which are chronically constricted due to the stenosis (J Peripher Nerv Syst. 2004 Dec; 9 (4):263-9). EP 1 609 480 Al 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 E1 derivative, is approved under the name of opalmon for the treat- ment of the symptoms associated with lumbar stenosis (Spine 2008 June; 33(13): 1465-9).
Moreover, US 20060058310 Al describes the use of aldose reductase inhibitors for the treatment of spinal canal stenosis and DE 69919191 T2 discloses the use of a pyridazinone compound for treating spinal canal stenosis.
Claviceps purpurea produces alkaloids which can result in the disease known as ergo- tism (Saint Anthony’s Fire) involving symptoms such as intestinal cramps, necrosis of fingers and toes due to circulatory disorder and hallucinations. Ergoline forms the structural skeleton of the ergoline alkaloids. [ I ! “Sh
N
H
The ergoline skeleton contains structural elements which are the basis of interactions with various neurotransmitters and their receptors. The basic skeleton emulates structures of the neurotransmitters dopamine, serotonine, noradrenaline and histamine. Depending on the modification of the basic skeleton of ergoline by chemical modification, there may result compounds which act as agonists or as antagonists at one or more of the aforementioned neu- rotransmitter receptors. Due to their pharmacological effects, some ergoline alkaloids are used in medicine, inter alia for the treatment of migraine, peripheral circulation disorder,
Parkinson’s disease and restless legs syndrome or they were used as agents for uterine involu- tion after birth and for supporting treatment of post-partal bleeding and as antihypertensive agents.
For example, the use of the ergoline derivative nicergoline in the treatment of lumbar spinal canal stenosis in combination with behavioural and physical therapy has been de- scribed (Reumatologia 2004, T. 42(1), 59-63). It is assumed that the medicaments used result in an improvement of the microcirculation in the nerve ends. However, the aforementioned results are only unverified observations which neither confirm the assumed effect of the com-
pounds used nor disclose concrete properties of the used substances belonging to very differ- ent classes.
Nicergoline is known to be an adrenergic antagonist and is used as vasoactive medica- ment for improving blood circulation as well as in the treatment of blood vessel disorders and dementia. In the therapeutically relevant dosage range, nicergoline does not act on the sero- tonergic system as do, for example, dopamine agonists such as sarpogrelate or the ergoline derivative terguride.
The effects of ergoline alkaloids are diverse. They can stimulate the dopamine receptors and inhibit the release of prolactin and somatotropin. The 8-(R)-diastereomer of lisuride has recently been identified as the currently most potent agonist on human H1 receptors (Bakker et al, Mol Pharmacol 65:538-549, 2004). More recent investigations {Dissertation Gorne- mann, FU Berlin, 2008) show that some ergoline derivatives have a high affinity for oy- adrenoreceptors and are 5-HT24, 5-HT>p and SHT receptor antagonists.
WO 07/110047 A2 describes the use of the ergoline derivatives terguride and proter- guride for treating chronic pain, inter alia due to fibromoyalgia. In view of the dopaminergic effect of terguride on the processing of pain, it was assumed that the administration of ter- guride in fibromoyalgia would be therapeutically successful. The leading symptoms of fibro- moyalgia are non-regionalized, unspecific chronic pain and high pressure point stress which are probably due to a malfunction of the central nervous system (CNS). Amongst the large group of fibromoyalgia patients, about 80% report on pain in the region of the cervical spine, but only about 20% of patients actually have cervical spinal canal stenosis.
Holman and Myers (ARTHRITIS & RHEUMATISM, Vol. 52, No. 8, August 2005, pp. 2495-2505) have carried out a double blind study using pramipexole, a dopamine agonist, in patients suffering from fibromoyalgia. In this study, patients having cervical myelopathy were specifically excluded. In a more recent work by Holman, it is indicated in this context that fibromoyalgia patients with cervical stenosis respond poorly to dopamine agonists and that, therefore, other therapeutic options such as pregabalin should be used for such patients (J Pain 2008 Jul; 9(7):613-22).
Furthermore, in Example § of WO 07/110047, there is described the treatment of a pa- tient having chronic pain due to a herniated disk in the lower lumbar region by simultaneous administration of terguride and the analgesic oxycodone. The treatment of spinal canal stenoses, especially of cervical spinal canal stenoses with terguride is not described. A herni- ated disk 1s usually an event of limited duration. Herniated disks usually occur in the lumbar spinal region and much more rarely in the cervical spinal region. The administration of ter- guride for the treatment of lumbar herniated disks has been used for the treatment of the chronic pain associated therewith. An effect on the processing of pain is expected since ter- guride is known to have a dopaminergic effect.
Herniated disks differ from spinal canal stenoses both with respect to the symptoms and the causes of the symptoms. Although a herniated disk may be associated with intermittent constriction of the spinal canal and the pain resulting therefrom or herniated disks can occur in combination with a spinal canal stenosis, this is a mechanical blocking of the vertebral bodies and a painful development of pressure on the spinal cord resulting therefrom. Various studies have shown that spinal canal stenoses comprise symptoms which are untypical of her- niated disks such as specific impairments in functional mobility and sensations in the arms, legs and the back of the neck which are associated with typical gait disorders such as, in par- ticular, the neurogenic claudicatio intermittens (Clin. Biomech. 1992 (7), 3-17). Furthermore, it could be shown that a constriction of the spinal canal alone does not necessarily result in spinal canal stenosis, from which it can be concluded in reverse that a constriction of the spi- nal canal does not constitute the sole cause of a spinal canal stenosis, but that further specific causes, which must be taken into account in the treatment, must play a role (Clin. Biomech. 1992 (7), 3-17). On the contrary, a spinal canal stenosis is always characterized by a growth or ossification of the vertebral body and is thus a degenerative disorder of the vertebra. Such a degeneration of the vertebral bodies is not caused by a herniated disc which, by contrast, as indicated above, is characterized by a mechanical blocking or impairment and a so-called “ship effect”. The fact that a painful change of the spine may be the cause of very diverse symptoms also follows from “Cervical spondylosis and neck pain” (BMJ 2007 (334), 527- 531).
Therefore, it cannot be assumed that the treatment of herniated disks would in general also be successful in the treatment of spinal canal stenoses because, as a matter of principle, different effects must be leveraged.
The clinical study carried out in connection with the present patent application was de- signed to test the effect of terguride as a prototypical dopamine agonist in patients having fibromoyalgia. In view of the aforementioned works by Holman, the patients were addition- ally examined for the presence of a cervical stenosis and a medical history involving chronic neck pain. The working hypothesis was that — in contrast to patients having primary fibro- moyalgia, i.e. without cervical stenosis — patients having cervical stenosis or chronic neck pain would not response to therapy with terguride. For another dopamine agonist, ropinirole, 1t has meanwhile been shown in a clinical study that no therapeutic effect under therapy with this dopamine agonist could be demonstrated in fibromoyalgia patients (http://ctr.gsk.co.uk/summary/ropinirole/Il_rof102100.pdf). In accordance with this, no sig- nificant therapeutic effect of terguride over placebo in patients having primary fibromoyalgia could be demonstrated.
Surprisingly, however, the inventors of the present invention could show that terguride, selectively in patients having spinal canal stenosis, can ameliorate the symptoms caused thereby in these patients, while no significant effect was achieved in neck pain patients with-
out spinal canal stenosis. The combination of 5-HT,4 and 5-HT>p receptor antagonism which is present in terguride and by which both receptor isoforms are simultaneously inhibited in the therapeutically effective dosage range 1s thought to be responsible for this surprising therapeutic effect. At the same time, it describes a therapeutic effective principle for thera- peutic applications.
Thus, the present invention provides a new use of compounds which are 5-HT,4 and 5-HT»g receptor antagonists for the therapeutic or prophylactic treatment of patients having spinal canal stenosis, preferably with cervical spinal canal stenosis and the symptoms caused thereby in these patients. In particular, the invention provides such a use at an early stage of the disease for the preventive and interventive treatment of spinal canal stenosis. At an ad- vanced late stage of the disease at which symptoms of paralysis already occur and paraplegia may be impending, surgical intervention may nonetheless unavoidable. At such a stage, the use according to the invention may still constitute a secondary treatment.
The use of compounds which are both 5-HT,4 and 5-HT»p receptor antagonists for the treatment of patients having spinal canal stenosis, especially cervical spinal canal stenosis, is not described in the prior art. Preferably, the compounds are additionally 5-HT5 receptor an- tagonists and/or op-adrenoceptor antagonists, particularly preferably additionally o;- adrenoceptor antagonists, in particular ozc-adrenoceptor antagonists.
Antagonists within the meaning of the present invention are generally compounds which bind to the aforementioned receptors (5-HT;4, 5-HTp and 5-HT; receptor and o- adrenoceptor, in particular, opc-adrenoceptor) and reduce or abolish the effect of the body’s messenger substances serotonin and noradrenalin or of agonistically acting substances.
The pA, value is frequently used to characterize the antagonistic efficacy of a com- pound.
The pA; value is the negative common logarithm of the molar concentration of an an- tagonist which makes it necessary to double the concentration of the agonist such as sero- tonin, in order to restore the original effect obtained in the absence of the antagonist. Thus, the pA, value is a measure of the affinity of an antagonist to the receptor, which is independ- ent of the way in which the antagonist works. Preferably, the pA, value is determined by the method according to Arunlakshana und Schild (Arunlakshana O, Schild HO, Some quantita- tive uses of drug antagonists, Br J Pharmacol 14: 48-58 (1959)).
Suitable 5-HTa, 5-HT»p and 5-HT7 receptor antagonists and/or ap-adrenoceptor an- tagonists, in particular, ozc-adrenoceptor antagonists, can be determined, in particular, by the methods described in the dissertation of Gérnemann, FU Berlin, 2008.
Thus, 5-HT»a receptor antagonists can be identified, in particular, under certain ex- perimental conditions by characterizing the contractile effects on porcine coronary arteries (s.a. Cushing DJ, Cohen ML (1993), J Pharmacol Exp Ther 264: 193-200).
Suitable 5-HT,p receptor antagonists can be identified, in particular, under certain ex- perimental conditions, by characterizing the relaxing effect on porcine pulmonary arteries (s.a. Glusa E, Pertz HH (2000) Br J Pharmacol 130: 692-698).
Suitable 5-HT; receptor antagonists can be identified, in particular, under certain ex- perimental conditions by characterizing the relaxing effect on pulmonary arteries of weaners (s.a. Jihnichen et al. (2005) Nauyn-Schmiedebergs Arch Pharmacol 371: 89-98).
Suitable op-adrenoceptor antagonists, in particular, aac-adrenoceptor antagonists can be identified, in particular, under selected experimental conditions by characterizing the contrac- tile effect on pulmonary veins of pigs for slaughter (see also Gérnemann et al. Br J Pharma- col 2007 May; 151(2): 186-94). Since, usually, there is an overlapping interaction of active agents with opa- and oac-receptors, the inhibition constants for the ap-receptor are defined hereinafter as a measure of the ap-adrenolytic effect of a substance.
Preferred compounds according to the invention have the following pA, values at 5-HT24, 5-HT3g and 5-HT7 receptors and ap-adrenoceptors, preferably cac-adrenoceptor:
Preferably, the compounds according to the invention are 5-HT»4 receptor antagonists having a pA; value of 27.5.
Preferably, the compounds according to the invention are 5-HT,p receptor antagonists having a pA; value of 27.5.
Particularly preferably, the compounds according to the invention have a pA; both at the 5-HT24 and at the 5-HT3g receptor of =7.5, more preferably, a pA; of 28.
In a particularly preferred embodiment, the compounds according to the invention have a pA; both at the 5-HT;4 and at the 5-HT,p receptor of =7.5, more preferably, a pA; of =8.
Preferred compounds according to the invention are, in addition thereto, 5-HT5 receptor antagonists, preferably having a pA; of =7.5
Furthermore, and particular preferably, the compounds according to the invention are, in addition to their property as 5-HT,s and 5-HT,p receptor antagonists, additionally op-adrenoceptors antagonists, preferably cnc-adrenoceptors antagonists, preferably having a pA; of =7.5.
Furthermore, according to the invention, those compounds are particularly preferred in which the pA; value for 5-HT»4 receptors differs from the pA; value of the compounds at 5-HT3g receptors by at most + 1 unit. That is, according to the invention, those compounds are particularly preferred in which pA (5-HT;4) - pA; (5-HTsp) | <1
This ensures that, by treatment with representatives of active agents, pathophysiological processes mediated by one or the other receptor are significantly inhibited in the same dosage range so that an enhancement of the therapeutic effect and a broad response of spinal stenosis patients with diverse medical histories can be achieved.
The following table shows exemplary compounds which are 5-HT»4 and 5-HTsp recep- tor antagonists as well as their pA; values.
Table — 5-HT,4 and 5-HT»g receptor antagonistic properties of selected compounds omen | 92 | ws wee [aa | a eee | ae | ae ena wa ome | ea |e wie a9 | es pie | as | ww gene | es | as * ergolines
The table shows that, according to the invention, in particular, cyproheptadine, mianser- ine, ritanserine, methiothepine, methysergide, metergoline, lisuride, terguride, trazodone, pi- zotifene and nicergoline are preferred since their pAz’s at 5-HT24 and 5-HT,p receptors are each =7.5 and differ from each other by less than 1 unit (in absolute terms). According to the invention, cyproheptadine, ritanserine, methiothepine, methysergide, lisuride, terguride and pizotifene are particularly preferred since their pAs’s at 5-HTs4 and 5-HT»p receptors are each =8 and differ from each other by less than one unit (in absolute terms). Among these compounds, terguride and lisuride are particularly preferred.
The compounds used according to the invention serve to treat patients having spinal ca- nal stenosis and the symptoms caused thereby in these patients. Particular preferably, the compounds used according to the invention serve to treat patients having cervical spinal canal stenosis and the symptoms associated therewith. As already described in detail in the intro-
duction, the term spinal canal stenosis refers to a constriction (restriction) of the spinal canal, especially a degenerative change or constriction of the spinal canal. In the case of cervical spinal canal stenosis, which is preferably treated according to he invention, this is located in the region of the cervical spine. Thus, this results in a discrepancy between the size of the spinal cord (myelon) and the spinal canal which, in relative terms, becomes too small. The consequences are compression on the spinal cord and/or the nerve roots. Based on radiologi- cal criteria, one speaks, in particular, of a relative stenosis in the case of a constriction of the sagittal diameter of the cervical spine to 10-12 (13/14) mm, and of an absolute stenosis at less than 10 mm. The clinical manifestation of cervical myelopathy can be very diverse. There may occur diffuse and uncharacteristic pain or discomfort in the arms and/or legs as well as neck pain (cervicalgia) or arm pain (brachialgia). Patients frequently report slowly increasing weekness in the arms and/or legs which is usually laterally pronounced. Insecure gait with spastic characteristics is relatively typical. In addition thereto, there may be voiding disorder.
In contrast thereto, as already explained, a herniated disk is characterized by a mechani- cal shifting of the vertebral body or a so-called slipping of the intervertebral disks resulting in painful pressure being exerted on the spinal cord. Such symptoms are in clear contrast to a degenerative change of the vertebral bodies which are characteristic of a spinal canal stenosis.
In contrast to spinal canal stenosis, in cases of herniated discs, the so-called cauda equina is rarely affected. In spinal canal stenosis, the clinical symptoms are not directly caused by the constriction itself, but rather by the additional degenerative deformation of the vertebral bod- ies which, without the constriction of the vertebral canal would have remained symptom-free (Clin. Biomech. 1992 (7), 3-17). ment of the myelon disorder impaired ability/activity to work
Thoracic spinal stenosis:
Due to its anatomical relationship to the ribs, the thoracic spine is integrated into a compact support structure so that there are fewer degrees of freedom of movement in the lon- gitudinal and transverse direction than with the cervical and lumbar spine and, thus, a lower risk/possibility of wear and bone alteration. Spinal stenoses of the thoracic spine are signifi- cantly rarer; the diagnostic and therapeutic options correspond to those of other spinal stenoses.
Lumbar spinal stenosis:
Typical complaints: “Only” pain along the dermatomes of certain lumbar roots (mostly
L3 to LS). Frequently accompanied by paralysis of the hip flexors, the anterior thigh muscula- ture, more rarely also of pedal lifting, very rarely of pedal lowering. In the classical form, so- called “claudicatio intermittens” (neurogenic claudicatio), i.e. the patient must sit down after a short while, then experiences relief of pain, can then walk again for a few meters, thereafter sitting down again etc.
Diagnosis of all aforementioned spinal stenosis requires a detailed clinical, neurological examination (possibly with evoked potentials) by a specialist (neurologist), a detailed anam- nesis, as well as further special examinations (EMG, measuring the velocity of nerve conduc- tion, the aforementioned evoked potentials etc.), as well as, in particular, imaging methods (MRT, CT, possibly myelography), among which MRT is the most preferred diagnostic method, by which the constriction of the sagittal diameter of the spinal canal and the presence of a spinal canal stenosis can be unambiguously determined.
Preferably, the aforementioned compounds are used for treating cervical and/or lumbar, preferably cervical spinal canal stenosis.
The use according to the invention comprises the treatment of all symptoms that may be associated with spinal canal stenosis.
In addition to the symptoms already mentioned above, these comprise the symptoms of paresis, hypaesthesia, paraesthesia, pain and/or sensation disorders such as numbness which may be ameliorated by administration of the compounds according to the invention.
Furthermore, the use according to the invention also serves to improve physical im- pairments, in particular, the impaired mobility of the affected parts of the spine. Thus, the use according to the invention also achieves an improvement of the reduction in muscular strength, an improvement of gait disorders, an improvement of formications and/or an im- provement of ataxia. In particular, the use of the compounds according to the invention in the treatment of spinal canal stenosis can achieve a functional improvement of pain-free mobility and a reduction of the malposition of the head. Such a malposition of the head due to pain usually results in a deterioration of mobility and an increase in painful sensations due to addi- tional muscular rigidity and cramped muscular abnormal load. Furthermore, the use accord- ing to the invention results in an improvement in urinary and anal incontinence if the cause thereof is a spinal canal stenosis.
In a particularly preferred use according to the invention, this serves to treat a spinal ca- nal stenosis which is the chronic result of a whiplash trauma, other traumatic changes or of a herniated disk.
In a further particularly preferred embodiment of the use according to the invention, this serves to prophylactically treat patients suffering from whiplash trauma to prevent the chronic effects of spinal canal stenosis as a consequence thereof.
In a further particularly preferred embodiment of the use according to the invention, this serves to prophylactically treat patients having spinal canal stenosis and of the symptoms caused thereby in these patients in order to prevent the chronification of the symptom com- plexes.
The present invention further relates to the use of ergoline derivatives, preferably the aforementioned compounds which are 5-HT>a and 5-HT,g receptor antagonists, as described in detail above, for the therapeutic or prophylactic treatment of patients having spinal canal stenosis, in particular, preferably for treating patients having cervical spinal canal stenosis and of the symptoms caused thereby in these patients, as also described in detail above. Ac- cording to the invention, ergoline derivatives are compounds formally derived from ergoline: or
N
H i.e. which have its 4,6,6a,7,8,9,10,10a-octahydro-indolo[4,3-fg]quinoline skeleton, op- tionally in formally dehydrogenated form. The dehydrogenated forms comprise, in particular, the skeleton on which lisuride is based: ; .,
N
H which is a 4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinoline skeleton. Ergoline deriva- tives within the meaning of the invention are, thus, all derivatives resulting formally by sub- stitution of at least one hydrogen atom in ergoline or dehydro ergoline.
Preferred ergoline derivatives are compounds of the formula
Rr R®
RY
RS
Si
R!'/ N | R® wherein .
R! and RY independently of each other, represent: hydrogen, alkanoyl, (preferably -CHO, —-COCHj3, —-COC;Hs, —~COC3H7, —CO-cyclo-CsHs, —COCH(CH,);, —COC(CHas)3),
Carboxyl (-COOH), alkoxycarbonyl (preferably —COOCH;, -COOC;Hs, —COOC;H,, -COO0-cyclo-C3Hs, —-COOCH(CH3),, —COOC(CHs)s), alkoxythiocarbonyl, alkylthiothiocar- bonyl, carbamoyl (-CONH,,), mono- or dialkylaminocarbonyl (preferably —CONHCHj, -CONHC,Hs, -CONHC;H;, ~CONH-cyclo-C3Hs, -CONH[CH(CH3),], -CONH[C(CH3)s], -CON(CH3)2, —CON(C,Hs)s, -~CON(Cs;H7)2, —-CON(cyclo-C3Hs),, —CON[CH(CHs):]2, -CON[C(CH3)3]2), amino (—NHj;), mono- or dialkylamino (preferably -NHCH;, -NHC,Hj, -NHC3;H;, -NH-cyclo-C3Hs, —-NHCH(CH;3);, -NHC(CHj)s, -N(CHj);, —-N(C;Hs),, -N(CsH4)2, —N(cyclo-CsHs)z, —N[CH(CHj)a]2, ~N[C(CHj3)s]2), alkylsulfoxyl (preferably -SOCH3, —SOC,H;s, —SOC3H4, —SO-cyclo-CsHs, -SOCH(CHai)z, —SOC(CHj3)3), alkylsulfonyl (preferably —SO,CH;, -S0,C:Hs, -S0,CsH;, ~SO,-—cyclo-CsHs, —SO,CH(CHjs),, -SO,C(CHs)s), sulfo (—SOsH,), alkylsulfonat (preferably —SO3;CHs, —S0O;C,Hs, —SO3CsH3, -S0s—cyclo-CsHs, —SO3CH(CH3),, —SO3C(CHs)s), halogenalkyl (preferably —CH,F, —~CHF,, ~CF;, -CH,Cl, ~CH,;Br, —-CH,I, -CH,—CH,F, —-CH,-CHF,, —CH,-CF;, —CH,—CH,ClI, -CH,~CH;Br, —-CH,~CH,l), Alkyl (preferably —CHj;, —C;Hs, —C3H7, —CH(CH3),, —C(CHs)s, —C4Hy, ~CH,~CH(CH3z)2, -CH(CH3)-C;Hs, —CsHyi, —CsHi3, —C7H;s, —CslHy4, —cyclo-CsHs, —cyclo-C4Hj, ~cyclo-CsHo, —cyclo-CgHyy), aryl (preferably phenyl), arylalkyl (preferably -CH>~Ph, -CPhs), alkenyl (preferably —-CH=CH,, -CH,—CH=CH,, —C(CH;)=CH,, -CH=CH-CHj3;, —-C,H4—CH=CH,, —CH=C(CH3),), alkynyl (preferably —C=CH, —C=C-CHs, —CH,-C=CH);
R? und R, independently, represent: hydrogen, an optionally substituted linear, branched or cyclic, saturated or unsaturated hydrocar- bon residue; such as, for example, - optionally substituted alkyl, - optionally substituted alkenyl, - optionally substituted aryl
- optionally substituted alkylaryl, as preferably defined below.
In the context of the entire invention, i.e. also in connection with the other substituent groups, optionally substituted alkyl preferably includes: straight or branched alkyl having 1 to 8, preferably 1 to 6 carbon atoms, cycloalkyl hav- ing 3 to 8, preferably 5 or 6 carbon atoms or alkyl having 1 to 4 carbon atoms which 1s substi- tuted with cycloalkyl, each of which may optionally bear preferably 1 to 3 substituents which are preferably selected from the group consisting of: hydroxy, halogen and cyano. Here and in the context of the present invention, halogen includes fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine. Furthermore, one or more, preferably 1 to 3 carbon atoms may be replaced by hetero analogous groups containing nitrogen, oxygen or sulfur. This means, in particular, that, for example, one or more methylene groups in the alkyl residues may be re- placed by NH, O or S.
Examples of alkyl residues having 1 to 8 carbon atoms include: a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec- butyl group, a t-butyl group, an n-pentyl group, an i-pentyl group, a sec-pentyl group, a t-pen- tyl group, a 2-methylbutyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, an 1-ethylbutyl group, an 2-ethylbutyl group, an 3-ethylbutyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3- dimethylbutyl group, an I-ethyl-l-methylpropyl group, an n-heptyl group, a 1-methylhexyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 4-methylhexyl group, a 5-methylhexyl group, an 1-ethylpentyl group, an 2-ethylpentyl group, an 3-ethylpentyl group, an 4-ethylpentyl group, a 1,1-dimethylpenty! group, a 2,2-dimethylpentyl 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 S-methylheptyl group, a G6-methylheptyl group, an l-ethylhexyl group, an 2-ethylhexyl group, an 3-ethylhexyl group, an 4-ethylhexyl group, an 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 I-propylpentyl group, a 2-propylpentyl group, etc. Preferred are groups with 1 to 6 carbon atoms, in particular, methyl, ethyl and n-propyl. Methyl is most preferred.
Examples of alkyl groups resulting from replacement with one or more heteroanalogous groups such as —O—, —S— or —-NH- are preferably those in which one or more methylene are replaced by -O- to form an ether group, such as methoxymethyl, ethoxymethyl, 2-methoxyethylene, etc. According to the invention, the definition of alkyl also comprises polyether groups.
Cycloalkyl residues 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. Preferred are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. Heterocyclic alkyl residues which are formed from cycloalkyl by replace- ment of methylene by heteroanalogous groups are, for example, 5- or 6-membered heterocyc- lic residues such as tetrahydrofuryl, pyrrolidinyl, piperidinyl or tetrahydropyranyl, which may optionally be fused with aromatic rings etc.
In particular, examples of a halogen substituted linear or branched alkyl residue having 1 to 8 carbon atoms include: a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a bromo- methyl group, a dibromomethyl group, a tribromomethyl group, a 1-fluoroethyl group, a 1-chloroethyl group, a 1-bromoethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 1,2-difluoroethyl group, a 1,2-dichloroethyl group, a 1,2-dibromoethyl group, a 2,2 2-trifluoroethyl group, a heptafluoroethyl group, a 1-fluoropropyl group, a 1-chloropropyl group, a I-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-dichloropropyl 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, a 4-fluocrobutyl group, a 4-chlorobutyl group, a 4-bromobutyl group, a 4,4,4-trifluorobutyl group, a 2,2,3,3,4,4,4- heptafluorobutyl group, a perfluorobutyl group, a 2-fluoropentyl group, a 2-chloropentyl group, a 2-bromopentyl group, a S-fluoropentyl group, a S5-chloropentyl group, a 5-bromopentyl group, a perfluoropentyl group, a 2-fluorchexyl group, a 2-chlorohexyl group, a 2-bromohexyl group, a 6-fluorohexyl group, a 6-chlorohexyl group, a 6-bromohexyl group, a perfluorohexyl group, a 2-fluoroheptyl group, a 2-chloroheptyl group, a 2-bromoheptyl group, a 7-fluoroheptyl group, a 7-chloroheptyl group, a 7-bromoheptyl group, a perfluoro- heptyl group, ete.
Examples of a hydroxy substituted alkyl residue include the aforementioned alkyl resi- dues having 1 to 3 hydroxyl residues, such as, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl etc.
In the context of the entire invention, optionally substituted alkenyl preferably includes:
Straight or branched alkenyl having 2 to 8 carbon atoms and cycloalkenyl having 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, allyl, 1-butenyl, isopro- penyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl. Vinyl or allyl are preferred.
In the context of the entire invention, optionally substituted aryl preferably includes:
Aromatic hydrocarbon residues having 6 to 14 carbon atoms (the carbon atoms of the substituents not being counted) and 5- to 10-membered aromatic heterocyclic residues having up to 3 hetero atoms selected from the series S, O, N, which may be mono- or bicyclic and which may be substituted by preferably 1 to 3 substituents selected from hydroxy, halogen, cyano, alkyl, acyl and alkoxy. Regarding the definition of alkyl and halogen, reference may be made to the aforementioned definitions or examples.
Alkoxy as a substituent of aryl includes here and in the following, for example: an aforementioned alkyl residue which is bound to aryl via an oxygen atom such as a linear or branched alkoxy residue having up to 6 carbon atoms, such as 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, 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 t-hexyloxy group, a sec-hexyloxy group, a 2-methylpentyloxy group, a 3-methylpentyloxy group, a l-ethylbutyloxy 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, a ethoxy group, an n-propyloxy group, an i-propyloxy group, an n-butyloxy group, an t-butyloxy group, a sec- butyloxy group, a t-butyloxy group, etc.
Acyl as substituent of aryl includes here and in the following: aliphatic acyl, aromatic acyl, such as C1 to C6 alkanoyl, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc. as well as C6 to C10 aroyl, such as benzoyl, toluoyl, xy- loyl, etc.
Aromatic hydrocarbon residues having 6 to 14 carbon atoms include, for example: phenyl, naphthyl, phenanthrenyl and anthracenyl, which may optionally be substituted.
Phenyl is preferred.
Heteroaromatic residues include, for example: pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl, benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl, isoqui- nolyl, naphthyridinyl, quinazolinyl. 5- or 6-membered aromatic heterocycles such as for ex- ample pyridyl, pyridyl-N-oxide, pyrimidyl, pyridazinyl, furyl and thienyl are preferred.
In the entire context of the invention, optionally substituted alkylaryl preferably in- cludes: straight or branched alkyl having 1 to 8, preferably | to 4 carbon atoms as described above, which is substituted with aryl as described above. Preferred arylalkyl is benzyl. -CO-R?, wherein R® is an optionally substituted linear, branched or cyclic, saturated or unsaturated hydrocarbon residue, which may be as mentioned above; "NH-CO-R®, wherein R’ is an optionally substituted linear, branched or cyclic, satu- rated or unsaturated hydrocarbon residue, which may be as mentioned above; “NH-CO-NR''R'?, wherein R'! and R'* are each independently of each other, hydrogen and/or an optionally substituted linear, branched or cyclic, saturated or unsaturated hydrocar- bon residue, which may be as mentioned above, or R'' and R" together with the nitrogen atom to which they are bound form a 5 or 6-membered, optionally substituted ring, which may optionally contain 1 or 2 further hetero atoms, such as, for example, piperidine-1-yl, morpholine-4-yl, thiomorpholine-4-yl, pyrrolidine-1-yl, oxazolidine-3-yl, thiazolidine-3-yl, 2- carboxyl-pyrrolidine-1-yl (prolyl), 3- or 4-hydoxy-carboxyl-pyrrolidine-1-yl (3- or 4-hydroxy- prolyl) etc. -R"-0-CO-R", wherein R"® is a divalent, optionally substituted linear, branched or cyclic, saturated or unsaturated hydrocarbon residue, such as, for example, optionally substi- tuted alkanediyl or optionally substituted alkenediyl, wherein optionally substituted al- kanediyl preferably includes: a divalent straight or branched alkanediyl residue having 1 to 7, preferably 1 to 6, more preferably 1 to 4 carbon atoms, which may optionally have 1 to 3 sub- stituents selected from the group consisting of hydroxy, halogen and cyano; for example and preferably, the following shall be mentioned: methylene, 1,2-ethandiyl, ethane-1,1-diyl, 1,3- propylene, propane-1,1-diyl, propane-1,2-diyl, propane-2,2-diyl, 1,4-butylene, butane-1,2- diyl, butane-1,3-diyl, butane-2,3-diyl, pentane-1,5-diyl, pentane-2,4-diyl, 3-methyl-pentane- 2,4-diyl und hexane-1,6-diyl; a preferred substituted alkanediyl residue is a hydroxy substi- tuted alkanediyl residue. Optionally substituted alkenediyl is preferably a divalent straight or branched alkenediyl residue having 2 to 7, preferably 2 to 6, more preferably 2 to 4 carbon atoms, which may optionally have 1 to 3 substituents selected from the group consisting of hydroxy, halogen and cyano. For example and preferably, the following shall be mentioned: ethene-1,1-diyl, ethene-1,2-diyl, propene-1,1-diyl, propene-1,2-diyl, propene-1,3-diyl, but-1- ene-1,4-diyl, but-1-ene-1,3-diyl, but-2-ene-1,4-diyl, buta-1,3-diene-1,4-diyl, pent-2-ene-1,5- diyl, hex-3-ene-1,6-diyl und hexa-2,4-diene-1,6-diyl. In the context of the present invention,
R" is particularly preferably alkane diyl, more preferably alkane diyl having 1 to 3 carbon atoms, more preferably is 1,2-ethane diyl (-CH>CH,-) or 1,3-propane diyl (-CH>CH,;CH,-), and R' is an optionally substituted linear, branched or cyclic saturated or unsaturated hydro- carbon residue, which may optionally have one or more hetero atoms, as defined above; and -CO-NR!PR'S, wherein R!® and R'® are independently of each other hydrogen and/or an op- tionally substituted linear, branched or cyclic, saturated or unsaturated hydrocarbon residue as defined above, or R' and RS, to gether with the nitrogen atom to which they are bound, form a 5- or 6-membered optionally substituted ring, which may optionally contain I or 2 further hetero atoms, also as defined above;
R® is hydrogen, halogen, cyano or nitro;
R® and R are, independently of each other, hydrogen or alkoxy, wherein, regarding the alkyl part, reference to the above definition of alkyl may be made, or together represent a bond, forming a double bond between the carbon atoms (i.e. have the following structure:
RZ R°
Soa = R® \ and salts thereof, for the therapeutic or prophylactic treatment of patients having spinal canal stenosis, in par- ticular, cervical spinal canal stenosis, and of the symptoms caused thereby in these patients.
The compounds used according to the invention comprise, if asymmetric carbon atoms are present, as in the case of the ergoline derivatives, stereoisomeric forms (racemates, enan- tiomers, diastercomers). Therefore, the invention comprises the use of all stereoisomeric forms, such as enantiomers, diastereomers and their mixtures such as racemates. The enanti- omerically pure forms can optionally be obtained therefrom by common methods of optical resolution, such as by fractional crystallization of diastereomers, therefrom by reaction with optically active compounds. Insofar as the compounds according to the invention may exist in tautomeric forms, the present invention comprises the use of all tautomeric forms.
The compounds used according to the invention may be present as salts and the inven- tion comprises all such salts. The compounds may be used in the form of their pharmaceuti- cally acceptable salts. Compounds containing basic groups may be used, in particular, as salts of pharmaceutically acceptable acids, such as, for example, salts with mineral acids, carbox- ylic acids and sulfonic acids, such as, for example, with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, tartaric acid, methane sulfonic acid, hydroxy ethane sulfonic acid, aceturic acid (acetyl glycine), maleic acid, propionic acid, fumaric acid, toluene sulfonic acid, benzene sulfonic acid, trifluoroacetic acid, naphthalene-1,5-disulfonic acid, salicylic acid, benzoic acid, lactic acid, malic acid, 3-hydroxy-2-naphthoic acid, citric acid or acetic acid etc. Compounds used according to the invention which contain acidic groups may be used in the form of pharmaceutically acceptable salts with pharmaceutically acceptable bases, such as, for example, alkali metal hydroxides (sodium salts etc.), alkali earth metal hydroxides (calcium salts, magnesium salts etc.), amines etc.
Ergoline derivatives are described, for example, in WO_9220339 Al,
WO 08061805 Al, WO 08043601 A2, WO _07110047_A2, WO_07065713_A2,
WO _05025546_A1, WO _03076439 A2, WO 0215890 Al, WO_0215889_Al and the documents cited therein. The aforementioned documents are thus to be regarded, in their en- tirety, as part of the disclosure of the present application.
In particular, compounds of the following formula are preferred:
RA. R°
RY
RE
Rr e N R’ wherein
R! and R* are independently of each other: hydrogen, alkyl, alkenyl,
R? and R? mean: hydrogen, “NH-CO-NR!'R"?, wherein R!! and R'? are each independently of each other, hydrogen and/or alkyl, or R'! and R'? form together with the nitrogen atom to which they are bound a 5- or 6-membered ring, which may optionally contain 1 further hetero atom; and/or —CO-
NRPR'®, wherein R'® and R'® are each independently of each other hydrogen and/or an op- tionally substituted linear, branched or cyclic, saturated or unsaturated hydrocarbon residue, or R" and R'® form together with the nitrogen atom to which they are bound a 5- or 6- membered, optionally substituted ring, which may optionally contain 1 or 2 further hetero atoms;
R’ is hydrogen;
R® and R” are independently of each other hydrogen, or together represent a bond form- ing a double bond between the carbon atoms, wherein the preferred substituents are as described above.
The use of the compounds according to the following formula is particularly preferred:
R%, ,R
RZ “,
RS
N< ge
H . rR" rR? which are preferably selected from:
XA
. . i on, —CH 8B-lisuride H H a |H bond
A, 1-allyl-6-ethyl H, i —o— 1suride A
Jig
H,
A gro
AE
J didehydro- A Lon a. ) H | weg |H 3 |H bond diperguride &, didehydro- 1
H ary H —CH, |H bond meterguride CH, ag didehydro- Jn piperguride didehydro- fn
A H wr H —CH; |r bond pyrroguride
QO morpholino- Jad . ° H "1H —CH; IH bond isuride
Nmone- H 15 —CH, |g bond
N 3 on desethyl-lisuride rT
Ha
H,C j -
Ae :
GOH
9
A A cten | _ 1-allyl-6- H, J ,CH, . ~Cgacn, A Len H —§ BH H H ethylterguride H A, 2 1-allyl-6-propyl H, Be Hy, CH, terguride gon, il don, H 4 “ H H H
H, 1-allyl-10c- o
H, A on, —CH —0— methoxy- - “e=cn, “| Lon H 3 |H O—CH; |H terguride 1-allylme- H, I Pe, . - sce, "f oi H —CH; 1H H H terguride H Ho 1-methyl- 1 en —CH, [ay ws CH terguride aE ¢ cra i : | H H 1,6-diallyl- H, ire, H, . ~Ce=ch, my H ~Cczcn, H H H terguride H go H 1 he H ,CH, 6-ethylterguride H —GC H H H gC H,
A
H a H, an terguride A 0
TE
_C—CH, én oO
CH,
EE CC CA CA I CN
Sea i SO piperguride Hl H —CH,; |H H H o
N’’-mono- H desethyl- H Ee H —CH, |H H H terguride xe 7 nicergoline —CH, H —CH; |H —O0—CH,; | H 0” 0 we
The 8B3-derivatives are each the epimer of the 8a-derivative, such as 8a-lisuride or 8a- terguride.
Among these compounds, the use of 8o-lisuride or 8o-terguride is particularly pre- ferred and the use of terguride or 8a-terguride is most preferred.
The present invention further provides the use of the compounds described above in combination with one or more further active agents. Preferred such further active agents in- clude, in particular, further active agents which are known for the treatment of spinal canal stenosis, such as, in particular, the aldose reductase inhibitors, known from
US 20060058310_A1, the pyridazinone compounds known from DE 69919191 T2 as well as, in particular, and preferably the EP2 agonists and EP3 agonists or their combinations known from EP 1609480 Al such as the prostaglandin El derivative approved under the trade name of opalmon.
Further active agents which may be used in combination with the compounds used ac- cording to the invention include, for example, prostaglandin, prostaglandin derivatives, so- called “nonsteroidal anti-inflammatory drugs” (NSAID), vitamins, muscle relaxants, anti- depressive agents, poly-ADP-ribosepolymerase (PARP)-inhibitors, exitatory amino acid re- ceptor antagonists (such as NMDA receptor antagonists and AMPA receptor antagonists), radical scavengers, astrocyte-modulators, IL-8-receptor antagonists, immunosuppressants (such as cyclosporine and FK506), and aldose reductase inhibitors. Examples of prostagland- ins, abbreviated as PG) include PG-receptor agonists, PG-receptor antagonists etc. Examples of PG-receptors include PGE-receptors (EP1, EP2, EP3 and EP4), PGD-receptors (DP,
CRTH2), PGF-receptors (FP), PGl-receptors (IP), TX-receptors (TP) etc. Examples of pros- taglandin derivatives include additionally limaprost, iloprost and beraprost.
Examples of NSAID include: sasapyrine, sodium salicylate, aspirin, aspirin dialumi- nate, diflunisal, indomethacin, suprofen, ufenamate, dimethyl isopropylazulene, bufexamac, felbinac, diclofenac, tolmetin sodium, clinoril, fenbufen, nabumetone, proglumetacin, indo- methacin-farnesyl, acemetacin, proglumetacin maleate, amfenac sodium, mofezolac, eto- dolac, ibuprofen, ibuprofen-piconol, naproxen, flurbiprofen, flurbiprofenaxetil, ketoprofen, fenoprofen calcium, tiaprofenic acid, oxaprozin, pranoprofen, loxoprofen sodium, alminopro- fen, zaltoprofen, mefenamic acid, mefenamic acid aluminum, tolfenamic acid, floctafenin, ketophenylbutazon, oxiphenbutazon, piroxicam, tenoxicam, ampiroxicam, felbinac, epirizol, tiaramid hydrochloride, tinoridin hydrochloride, emorfazon, sulpvrine, migrenin, saridon, sedes G, amipylo-N, solvon, acetaminophen, phenacetin, dimetotiazine mesilate, etc. Exam- ples of muscle relaxants include: tolperison hydrochloride, chlorozoxazone, chloromezanone, methocarbamol, phenprobamate, pridinol mesylate, chlorophenesincarbamate, baclofen, eperison hydrochloride, afloqualon, tizaindine hydrochloride, alcuronium chloride, sux- amethonium chloride, tubocurarin chloride, dantrolen sodium, pancuronium bromide, vecuronium bromide ctc. Examples of antidepressants include tricyclic antidepressants, such as imipramine hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, trimipramine maleate, amitriptyline hydrochloride, nortriptyline hydrochloride, iofepramine hydrochloride, amoxapine, dosulepin hydrochloride etc. Examples of tetracyclic antidepres- sants include maprotiline, mianserine etc.
The aforementioned combination includes various kinds of administration, such as si- multaneous or subsequent administration of separate active agents or the simultaneous ad- ministration of a combined preparation of active agents. The aforementioned combination also includes an associated presentation in an arbitrarily arranged combination, such as a so- called kit of parts.
The present invention further relates to the compounds which are 5-HT24 and 5-HTzp- receptor antagonists and wherein the pA, value of the compounds on 5-HT24 and 5-HT2s- receptors is 2 7.5, for the therapeutic or prophylactic treatment of patients having spinal canal stenosis and of the symptoms caused thereby in these patients.
The present invention further relates to the ergoline derivatives for the therapeutic or prophylactic treatment of patients having spinal canal stenosis, in particular, cervical spinal canal stenosis and of the symptoms caused thereby in these patients, wherein the ergoline derivatives are as described above.
Furthermore, the present invention relates to compounds of the formula
RA. R
RY
RE
& RY
Rr 7 N RS as described above, their salts for therapeutic or prophylactic treatment of patients having spinal canal stenosis and of the symptoms caused thereby in these patients.
The present invention further and preferably relates to 8a-lisuride or 8a-terguride, even more preferably 8a-terguride for the therapeutic or prophylactic treatment of patients having spinal canal stenosis and of the symptoms caused thereby in these patients.
Particularly preferably, the present invention relates to 8a-terguride for the therapeutic or prophylactic treatment of patients having cervical spinal canal stenosis and of the symp- toms caused thereby in these patients.
Furthermore, the present invention relates to a combined preparation containing one or more compounds as defined in one of the preceding claims in association with one or more further active agents for the therapeutic or prophylactic treatment of patients having spinal canal stenosis and of the symptoms caused thereby in these patients.
The compounds defined above are administered according to the present invention preferably in the form of pharmaceutical compositions together with one or more conven- tional pharmaceutical excipients. Therefore, the present invention further relates to pharma- ceutical compositions containing the compounds defined above as well as one or more con- ventional pharmaceutical excipients for the therapeutic or prophylactic treatment of patients having spinal canal stenosis and of the symptoms caused thereby in these patients.
The aforementioned pharmaceutical compositions are suitable, for example, for inhala- tion or for intravenous, intraperitoneal, intramuscular, intravaginal, intrabuccal, percutaneous, subcutaneous, mucocutaneous, oral, rectal, transdermal, topical, intradermal, intragastric or intracutaneous application and they are present, for example, in the form of pills, tablets, en- terically coated tablets, film tablets, layered tablets, retard formulations for oral, subcutaneous or cutaneous administration (in particular, as patch), depot formulations, sugar-coated tablets, suppositories, gels, creams, syrups, inhalation powders, granulates, suppositories, emulsions, dispersions, microcapsules, microformulations, nanoformulations, liposomal formulations, capsules, enterically coated capsules, powders, inhalation powders, microcrystalline formula- tions, inhalation sprays, powders, drops, nasal drops, nasal sprays, aerosols, ampules, solu-
tions, juices, suspensions, emulsions, infusion solutions or solutions for injection etc. Oral and cutaneous, transdermal forms of administration are preferred.
The compounds according to the invention can be administered in pharmaceutical com- positions which may contain various organic or inorganic carrier and/or auxiliary materials which are commonly used for pharmaceutically purposes, in particular for solid medical for- mulations, such as, for example, excipients (such as saccharose, starch, mannitol, sorbitol, lactose, glucose, cellulose, tale, calcium phosphate, calcium carbonate), binding agents (such as cellulose, methyl cellulose, hydroxypropyl cellulose, polypropyl pyrrolidone, gelatine, gum arabic, polyethyleneglycol, saccharose, starch), disintegrants (such as starch, hydrolyzed starch, carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropyl starch, sodium glycol starch, sodium bicarbonate, calcium phosphate, calcium citrate), gli- dants and lubricants (such as magnesium stearate, talc, sodium laurylsulfate), a flavoring agent (such as citric acid, menthol, glycine, orange powder), preservatives (such as sodium benzoate, sodium bisulfite, methylparabene, propylparabene), stabilizers (such as citric acid, sodium citrate, acetic acid, and multicarboxylic acid of the titriplex series, such as diethylene triaminepentaacetic acid (DTPA)), suspending agents (such as methyl cellulose, polyvinyl pyrrolidone, aluminium stearate), dispersing agents, diluting agents (such as water, organic solvents), bees wax, cocoa butter, polyethylene glycol, white petrolatum etc.
Liquid medicinal formulations, such as solutions, suspensions and gels usually contain a liquid carrier, such as water and/or pharmaceutically acceptable organic solvents. Further- more, such liquid formulations may also contain pH-adjusting agents, emulsifying or dispers- ing agents, buffering agents, preservatives, wetting agents, gelling agents (for example methyl cellulose), coloring agents and/or flavoring agents. The compositions may be isotonic, i.e. they may have same osmotic pressure as blood. The isotonicity of the composition may be adjusted by using sodium chloride or other pharmaceutically acceptable agents such as, for example, dextrose, maltose, boric acid, sodium tartrate, propylene glycol and other inorganic or organic soluble substances. The viscosity of the liquid compositions may be adjusted by using a pharmaceutically acceptable thickening agent, such as methyl cellulose. Other suit- able thickening agents comprise, for example, xanthan, carboxymethyl cellulose, hy- droxypropyl cellulose, carbomer and the like. The preferred concentration of the thickening agent will depend on the selected agent. Pharmaceutically acceptable preservatives may be used in order to increase the shelf life of the liquid composition. Benzyl alcohol may be suit- able, although a multitude of preservatives including, for example, paraben, thimerosal, chlorobutanol or benzalkoniumchloride may equally be used.
The active agent may be administered, for example, at a unit dose of 0.25 mg to 50 mg, preferably 0.25 to 5,0 mg, 1 to 4 times a day. However, the dosage may be increased or re- duced depending on the age, state of the patient, severity of the disease or the mode of ad- ministration.
Furthermore, particularly preferably, the present invention relates to the compounds and compositions as mentioned above for the therapeutic or prophylactic treatment of patients having cervical spinal canal stenosis and of the symptoms caused thereby.
The invention is illustrated by the following example. The example only constitutes an illustration of the invention and the skilled person is able to extend this specific example to other claimed compounds.
Example:
Patients having chronic general pain were included in the clinical study. One sub-group of patients corresponds to the definition of primary fibromyalgia. A further patient group is characterized by the diagnosis of chronic pain in the back of the neck. In most patients that participated in the study, an examination of the cervical spine by magnetic resonance imaging (MRI) as an imaging method was carried out in the course of the study. This was done under conditions which generally allow the imaging of a cross-section of the spinal canal in the re- gion of the cervical spine without use of contrasting agents and with the head in a normal position. The measurement was carried out on 1.5 Tesla magnetic resonance scanners. In all analyzable images, the diameter of the spinal canal and the thickness of the nerve strand (the so-called myelon) were measured by a blind evaluator acting as independent expert. Further- more, the results were assessed with respect to the presence of a cervical spinal stenosis ac- cording to an internationally recognized catalog of criteria (NJNR Am J Neuroradiol 1998
Oct; 19(9): 1763-71). This comprises a scale of 5 degrees. Degree 0 describes a spinal canal of normal width without signs of a constriction of the anterior or posterior subarachoidal space within the spinal canal. At degree 1, there is a partial restriction of the anterior or poste- rior subarachoidal space or of both spaces. At degree 2, the spinal cord completely fills the subarachoidal space of the spinal canal. Degree 3 describes a cervical cervical compression or torsion of the spinal cord and degree 4 describes a hyperintensity of the myelon as a sign of myelopathy. Based on this evaluation, in about 20% of all patients assessed in the study, at normalities of degrees 2 to 4 were observed which describe this patient group as patients with cervical stenosis.
The patients were treated with terguride (1 tablet = 0.5 mg), an ergoline compound which, as explained above, is both a partial dopamine agonist and, additionally, a 5-HT»a and a 5-HTyp receptor antagonist, or with placebo. The trial medication was stepwise titrated up over a period of 21 days from half a tablet to a maximum of 6 tablets per day; treatment was then continued for 9 weeks at constant dosage. The medicament was taken in the morning and in the evening. The course of therapy after 3, 7 and 12 weeks was checked by means of patient orientated scales for determining intensity of pain, tiredness, well restedness, muscu- lar rigidity, anxiety, nervousness and depression, well being and ability to work and by means of a questionnaire regarding activities of daily life. A reduction in the scale values or a lower point count in the evaluation of the questionnaire showed and improvement in the criterion concerned and, thus, a success of the therapy. It was surprisingly found that, among the pa- tients having chronic generalized pain, only the patient group having cervical spinal canal stenosis (degrees 2 to 4) showed a significant therapeutic success after 3 months (Figure 1).
With respect to the sum of all questions asked (total score), the majority of the patient group responded with a more or less pronounced improvement of the general condition. A reduction in the intensity of pain, an improvement of anxiety and nervousness, and, in particular, an improvement of the subjective physical impairment and of the ability to cope with work- related stress are particularly noteworthy. In contrast thereto, the state of the patient group with chronic generalized pain, but normal unaffected spinal canal in the region of the cervical spine, remained largely unchanged (Figure 2) despite the therapy with terguride. Only muscu- lar rigidity and depressive behavior showed a trend of improvement while the pain was judged to be unchanged. In summary, for patients without cervical spinal canal stenosis, the comparison of patients treated with terguride with those treated with placebo showed no sig- nificant improvement. Similarly, the analysis of the patient group suffering, in particular, from chronic pain in the back of the neck, but showing no signs of cervical spinal stenosis, showed no therapeutic success upon therapy with terguride (Figure 3). On the contrary, for several parameters of the success of treatment, a worsening in the patients was described, in particular, with respect to physical impairment, well being, perception of pain, muscular ri- gidity and anxiety/nervousness.
In summary, it is to be noted that terguride provided a therapeutic success only in pa- tients with cervical spinal canal stenosis.
Explanation of the Figures:
Figure 1 shows the effect of terguride on selected patient-oriented scales and question- naires regarding the general condition in patients having chronic generalized pain and cervi- cal spinal stenosis (degrees 2 to 4).
Figure 2 shows the effect of terguride on selected patient-oriented scales and question- naires regarding the general condition in patients having chronic generalized pain but no cer- vical spinal stenosis (degrees 0 to 1).
Figure 3 shows the effect of terguride on selected patient-oriented scales and question- naires regarding the general condition in patients having chronic generalized pain and chronic pain in the back of the neck, but no sign of spinal stenosis (degrees 0 to 1).

Claims (21)

1. Use of compounds which are 5-HT»4 and 5-HT»g receptor antagonists and wherein the p42 value of the compounds at 5-HT24 and 5-HT»g receptors 1s = 7.5 for the manufacture of a medicament for the therapeutic or prophylactic treatment of patients having spinal canal stenosis and of the symptoms caused thereby in these patients.
2. Use according to the preceding claim, wherein the pA, value for 5-HT,4 receptors dif- fers from the pA, value of the compounds at 5-HTg receptors by at most + 1 unit.
3. Use according to the preceding claims, wherein the compound is selected from the group comprising cyproheptadine, mianserine, ritanserine, methiothepine, methysergide, me- tergoline, lisuride, terguride, trazodone, pizotifene and nicergoline.
4. Use according to the preceding claims, wherein the compound is terguide and/or lisuride.
5. Use according to the preceding claims, wherein the compounds are selected from 8a- lisuride or 8a-terguride.
6. Use according to one of the preceding claims, wherein the spinal canal stenosis is a cervical spinal canal stenosis.
7. Use according to one of the preceding claims, which serves to ameliorate the symptoms paresis, hypaesthesia, paraesthesia, pain and/or sensation disorders such as numbness.
8. Use according to one of the preceding claims for improving physical impairments, es- pecially the impaired painless mobility and the reduction of the malposition of the head as well as for improving the reduction in muscular strength, for improving gait disorders, for improving formication and/or for improving ataxia as well as for improving urinary and/or anal incontinence.
9. Use according to one of the preceding claims, wherein the spinal canal stenosis is a chronic consequence of a whiplash trauma, other traumatic changes or of a herniated disk.
10. Use according to one of the preceding claims, which comprises the prophylactic treat- ment of patients having spinal canal stenosis and of the symptoms caused thereby in these patients for preventing the chronification of the symptom complexes as well as the prophylac- tic treatment of patients having a whiplash trauma for preventing the chronic consequences of a spinal canal stenosis as a consequence thereof.
11. Use according to one of the preceding claims, wherein said compounds are adminis- tered to the patients in combination with one or more further active agents.
12. Compounds which are 5-HT,4 and 5-HT»g receptor antagonists and wherein the pA» value of the compounds at 5-HT,4 and 5-HTp receptors is = 7.5 for the therapeutic or pro- phylactic treatment of patients having spinal canal stenosis and of the symptoms caused thereby in these patients.
13. 8c-lisuride and 8a-terguride for the therapeutic or prophylactic treatment of patients having spinal canal stenosis and of the symptoms caused thereby in these patients.
14. 8a-terguride for the therapeutic or prophylactic treatment of patients having spinal ca- nal stenosis and of the symptoms caused thereby in these patients.
15. 8a-terguride for the therapeutic or prophylactic treatment of patients having cervical spinal canal stenosis and of the symptoms caused thereby in these patients.
16. Combined preparation containing one or more compound as defined in one of the pre- ceding claims in association with one or more further active agent for the therapeutic or pro- phylactic treatment of patients having spinal canal stenosis and of the symptoms caused thereby in these patients.
17. Use according to one of the preceding claims, wherein the compounds defined in the claims are administered in the form of pharmaceutical compositions together with one or more conventional pharmaceutical excipients.
18. Pharmaceutical compositions containing the compounds defined in the preceding claims as well as one or more conventional pharmaceutical excipients for the therapeutic or prophylactic treatment of patients having spinal canal stenosis and of the symptoms caused thereby in these patients.
19. Pharmaceutical compositions according to the preceding claim, wherein the composi- tion is suitable for oral, sublingual, parenterial, cutaneous, buccal, percutaneous, subcutane- ous, inhalative or nasal administration.
20. Pharmaceutical composition according to the preceding claims which is present in the form of tablets, layered tablets, capsules, retard oralia, transdermal systems, suppositories, microformulations, nanoformulations, liposomal formulations, drops, nasal drops, nasal sprays, aerosols, ampules, solultions, emulsions, dispersions, powders, inhalation powders, microcrystalline formulations, inhalation sprays, transdermal systems or subcutaneous formu- lations.
21. Pharmaceutical composition according to one of the preceding claims for the therapeu- tic or prophylactic treatment of patients having cervical spinal canal stenosis and of the symp- toms caused thereby in these patients.
SG2011045671A 2008-12-23 2009-12-22 5-ht2a and 5-ht2b receptor antagonists for treating stenosis of the spinal canal SG172315A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP08172859 2008-12-23
PCT/EP2009/067768 WO2010072774A2 (en) 2008-12-23 2009-12-22 Agent for treating stenosis of the spinal canal

Publications (1)

Publication Number Publication Date
SG172315A1 true SG172315A1 (en) 2011-07-28

Family

ID=40527906

Family Applications (1)

Application Number Title Priority Date Filing Date
SG2011045671A SG172315A1 (en) 2008-12-23 2009-12-22 5-ht2a and 5-ht2b receptor antagonists for treating stenosis of the spinal canal

Country Status (11)

Country Link
EP (1) EP2367543A2 (en)
JP (1) JP2012513446A (en)
KR (1) KR20110098965A (en)
CN (1) CN102271667A (en)
AU (1) AU2009331469A1 (en)
BR (1) BRPI0923556A2 (en)
CA (1) CA2748163A1 (en)
IL (1) IL213768A0 (en)
MX (1) MX2011006852A (en)
SG (1) SG172315A1 (en)
WO (1) WO2010072774A2 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2016209492B2 (en) 2015-01-20 2020-10-22 Xoc Pharmaceuticals, Inc Ergoline compounds and uses thereof
AU2018275873A1 (en) 2017-06-01 2019-12-19 Xoc Pharmaceuticals, Inc. Ergoline derivatives for use in medicine

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK1123704T3 (en) 1998-09-01 2004-11-01 Nissan Chemical Ind Ltd Remedies for spinal stenosis
WO2004043491A1 (en) 2002-11-14 2004-05-27 Ono Pharmaceutical Co., Ltd. Remedies for vertebral canal stenosis
WO2004089411A1 (en) 2003-04-03 2004-10-21 Ono Pharmaceutical Co., Ltd. Remedy for spinal canal stenosis
DE102006013307B3 (en) 2006-03-21 2007-10-04 Ergonex Pharma Gmbh Terguride / proterguride for the treatment of chronic pain

Also Published As

Publication number Publication date
CN102271667A (en) 2011-12-07
EP2367543A2 (en) 2011-09-28
AU2009331469A1 (en) 2011-07-21
KR20110098965A (en) 2011-09-02
BRPI0923556A2 (en) 2016-01-26
WO2010072774A3 (en) 2010-09-23
IL213768A0 (en) 2011-07-31
WO2010072774A2 (en) 2010-07-01
CA2748163A1 (en) 2010-07-01
JP2012513446A (en) 2012-06-14
MX2011006852A (en) 2011-07-20

Similar Documents

Publication Publication Date Title
JP6445637B2 (en) Tapentadol for preventing and treating depression and anxiety
TWI353835B (en) Novel methods for identifying improved, non-sedati
US9700548B2 (en) Antihistamines combined with dietary supplements for improved health
TW202308601A (en) Formulation for inhibiting formation of 5-ht2bagonists and methods of using same
RU2340333C2 (en) Agonism of 5нт2a-receptor for treatment of disturbance of thermoregulation function
KR20190142364A (en) How to Treat Duz Syndrome Using Fenfluramine
TW201028143A (en) Dosage regimen for a S1P receptor agonist
JP5731094B2 (en) Treatment of microvascular diseases with acetylcholinesterase inhibitors
TW201136916A (en) New uses
JP2019089825A (en) Combination of canagliflozin and probenecid for treatment of hyperuricemia
TW201026684A (en) Phosphodiesterase type III (PDE III) inhibitors or Ca2+ -sensitizing agents for the treatment of hypertrophic cardiomyopathy
ES2625142T3 (en) Therapeutic uses of 1- [2- (2,4-dimethyl-phenylsulfanyl) phenyl] -piperacin
US20210177830A1 (en) Compositions for treating or preventing vasomotor symptoms
KR20230106644A (en) How to Treat Conditions Associated with the S1P1 Receptor
JP2015509931A (en) Pharmaceutical combination
SG172315A1 (en) 5-ht2a and 5-ht2b receptor antagonists for treating stenosis of the spinal canal
JP2002265356A (en) Agent for treating and/or preventing pain of lumbar vertebra herniated intervertebral disk
BG107810A (en) Selective dopamine d4 receptor agonists for treating sexual dysfunction
TWI334780B (en) Method of treating movement disorders using barbituric acid derivatives
US20230355618A1 (en) Raf inhibitor for treating low grade glioma
JP2004523559A (en) Methods for treating irritable bowel syndrome and functional gastroenteropathy
Smyth et al. A Method for Measuring Swelling of Hands and Feet Part II: Influence of New Anti-Inflammatory Drug, Indomethacin, in Acute Gout
TWI835716B (en) Tetrahydrocyclopenta[b]indole compounds and phosphodiesterase inhibitors for the treatment of the signs and symptoms of bph
MX2010006520A (en) Method and composition for treating an alpha adrenoceptor-mediate d condition.
JP2005314347A (en) Sharp pain inhibitor