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
  • 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
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • 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
  • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
• • 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
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
  • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis

Definitions

• the present invention relates to the field of bone biochemistry and is concerned in particular with the provision of medicaments for the treatment of diseases of the bone.
• the present invention is also concerned with novel usage for known materials and compositions and processes for the preparation of the same.
• Vertebrate bone as a tissue providing mechanical support for the body, undergoes constant remodelling through the formation and reso tion of bone mediated, it is widely thought, by the activities of osteoblasts and osteoclasts respectively.
• Bone remodelling comprises a complex and highly organised interaction between cells and the extracellular matrix (ECM).
• ECM extracellular matrix
• the remodelling process is, however, adaptive in response to requirements for growth or environmental stressing.
• the rate of bone formation approximates with the rate of bone resorption, a process known as coupling.
• Bone resorption or formation is not, though, a generalised feature of the skeleton but occurs in discrete sites which may be surrounded by areas of quiescent bone. Where resorption occurs excessively, several clinical problems can occur either at a specific locality or more extensively throughout the skeleton.
• osteoporosis is a disease that is characterised by abnormalities in the amount and architectural arrangement of bone tissue. Osteoporosis results from excessive resorption of bone and is a major clinical condition that can lead to fractures of bone following only minimal trauma. In addition to the distress to sufferers, the direct hospital costs of osteoporosis have been estimated, in the U.S. only, to approach $5.2 billion for women alone (Phillips et al (1988), Bone 9:271-279). The term Osteoporosis' in fact refers to a group of conditions that are associated with loss of bone tissue and an accompanying architectural abnormality that occurs in cancellous bone space.
• post menopausal osteoporosis When the condition develops in post-menopausal women it is referred to as post menopausal osteoporosis. Fractures occur commonly in the hip, spine and distal radius and is considered by many countries to be a major public health problem (Lindasay R (1993), Clinical Rheumatology Osteoporosis; V.7, No.3). While diet and life-style appear to be factors in the pathogenesis of the disease, loss of ovarian function is an important determinant, at least in post menopausal osteoporosis.
• osteoporotic-associated disease states include steroid induced osteoporosis, idiopathic juvenile osteoporosis, post- transplantation osteoporosis where bone resorption is a secondary indication of disorder.
• Paget's disease In a disease of old age known as Paget's disease, there is excessive osteoclastic resorption of bone and reorganisation with loss of structure leading to deformities and liability to fracture.
• osteoclastomas and other primary and secondary tumours often cause resorption and subsequent increased liability to fracture.
• Tumour induced osteolysis may also lead to pathologically raised serum calcium levels which are believed to increase significantly morbidity in cancer patients.
• JP 63-295561 2-quinolone derivatives are disclosed which are described as having potent bone absorption-inhibiting activity.
• N-methyl-D-Aspartate (NMDA) like receptor antagonists have a history of use in the field of medicine in treating disorders, primarily conditions such as neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycaemia and surgery as well as treating neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, Huntingdon's disease, Down's syndrome, chronic pain, opiate tolerance and the like.
• NMDA like receptors principally thought of as present in the central nervous system (CNS) where they are believed to be involved in processes such as learning and development are also present on the surface of at least osteoclasts, the cells mainly responsible for bone resorption and furthermore that the inhibitors of this receptor inhibit osteoclast activity.
• NMDA-receptor antagonist in the manufacture of a medicament for the treatment of diseases or clinical conditions featuring or characterised by undesired bone resorption.
• a method for the treatment of diseases or clinical conditions as hereinbefore described comprising the step of; administering a therapeutically effective amount of a NMDA-receptor antagonist.
• a prophylactic method for the prevention of diseases or clinical conditions as hereinbefore described comprising the steps of repeated administration of a therapeutically effective amount of a NMDA-receptor antagonist.
• NMDA-receptor antagonist in the manufacture of a medicament for the treatment of diseases of bone mass deficiency.
• NMDA-receptor antagonist as used herein is meant a medicinal composition that inhibits the biological action triggered by the binding of glutamate or other natural ligand to a NMDA receptor or subtype thereof present on the surface of osteoclasts or other bone cell type.
• This may include, for example, reversible and irreversible competitive binding-site receptor inhibitors or other inhibitors (for example non-competitive inhibitor) that bind to a portion of the NMDA receptor and inhibits its activation for example glycine NMDA associated antagonists, glutamate site NMDA receptor antagonists and polyamine site antagonists.
• Other inhibitors include e.g. an NMDA receptor antibody or Fab fragment thereof or other protein moiety. Those skilled in the art will also recognise that this may include anti-sense mRNA capable of inhibiting translation of NMDA-receptor mRNA within osteoclasts.
• the present invention is aimed at the treatment of undesired bone resorption which may often involve excessive resorption.
• the disease or clinical condition may feature bone resorption i.e. bone resorption is a secondary indication of the disorder.
• bone resorption may characterise, i.e. be the primary indication of the disorder.
• Multi-nucleated osteoclasts are characterised by a high degree of expression of the enzyme Tartrate Resistant Acid Phosphatase (TRAP), an assay for which is disclosed in Barka et al: (1962) J Histochem Cytochem; 10,p741-753 and incorporated herein by reference.
• TRIP Tartrate Resistant Acid Phosphatase
• the receptor-antagonist of the present invention is preferably one which by virtue of its form (e.g. association with a carrier) and/or route of administration, does not cross to a significant extent the blood-brain barrier.
• osteoporosis including osteoporosis of disuse, Sch ⁇ ller's disease, post menopausal osteoporosis, post- traumatic osteoporosis, senile osteoporosis
• Paget's disease undesired bone resorption featured in cancer, renal disease, fracture healing, rheumatoid arthritis and other arthritic conditions.
• a receptor-antagonist previously used with respect to the CNS may be modified for use in the manufacture of medicament according to the present invention by for example modifying lipid solubility or increasing the charge on the receptor-antagonist such as known to those skilled in the art.
• Other possibilities include labile coupling of the receptor-antagonist to a 'bone-seeking' substance such as Tetracyclines, Bisphosphonates or antibody.
• NMDA-receptor antagonists previously thought of as having minimum therapeutic use because of their inability to penetrate the blood/brain barrier effectively to treat CNS disorders may be useful in the present invention.
• NMDA associated antagonists such as 5,7 dichlorokynurenic acid and indole-2- carboxylic acid have been regarded as ineffectual as therapeutic agents for treating disorders associated with the NMDA receptor because of their inability to cross this barrier (McNarmara, D et al; Neurosci.Lett; 120;17-20 (1990) and Gray N.M et al, J.Med. Chem; 34 1283 to 1292 (1991).
• the NMDA receptor-antagonist for use in the present invention may be selected from a group consisting of, but not limited to;
• Preferred tartrates include (7)-2-(4-benzyl piperidino-1)-p- hydroxyphenyl propanol tartrate (Cas No. 23210-58-4, Validex®, Hoechst Marion Roussel).
• Preferred maleate include hydrogen maleates such as MK-801 hydrogen maleate (Merck, Sharpe and Dohme Inc)
• Preferred phosphonopentanoic acids include D(-)-2-amino-5- phosphonopentanoic acid, (Research Biochemicals International RBI) and D,L-2-amino-5-phosphonovaleric acid (RBI)
• Glycine NMDA associated antagonists include various heterocyclic compounds and especially aromatic heterocyclic compounds.
• Glycine NMDA associated inhibitors of the invention can be selected from the group quinolones, quinoxalinediones, indole-2-carboxylates and 6-phenyl pyrazinones.
• the aromatic aryl ring preferably comprises a halo, e.g. chloro, substituted aryl ring.
• quinolones are 7-chloro-2-quinolones, for example; 7-chloro-4-hydroxy-3-(3-phenoxyphenyl)-2(1 H)- quinolinone; 7-chloro-4-hydroxy-3-methoxycarbonyl-2-quinolone; or 7-chloro-4-hydroxy-2-(4-methoxy-2-methylphenyl) pyridazino[4,5-b] quinoline-1 ,10(2H,5H)-dione monosodium salt.
• Preferred quinoxalinediones are 7-chloro-quinoxaline-2,3- diiones for example; 7-chloro-6-methyl-5-nitro,14- dihydroquinoxaline; 6,7-dichloro-5-nitro-1 ,4-dihydroquinoxaline-2-3- dione;or (S)-9-chloro-5-[p-aminomethyl-o-(carboxy-methoxy)phenyl- carbamoylmethyl]-6,7-dihydro-1H,5H-pyridol[1 ,2,3-de]quinoxaline- 2,3-dione,e.g. the hydrochloride trihydrate.
• Preferred indole-2-carboxylates for example, the Glaxo Welcome compound known as GV-150526A.
• 6-phenyl pyrazinones are 6-(4-chlorophenyl) pyrazinones, for example 6-(4-chlorophenyl)imidazo[1 ,2- ajpyrazinone.
• receptor antagonists of the present invention are either known per se or may be manufactured according to the teaching of the art, e.g. the manufacture of MK801 is disclosed in US patent 4,399,141.
• the medicament may be administered orally, subcutaneously, intra-muscularly, intravenously, either systematically but preferably locally, intraperitonealy or transdermally (e.g. skin patches) and may be in a composition form such as tablets, capsules, powders, granules, elixirs for oral administration or in sterile solutions or suspensions for parenteral administration.
• a composition form such as tablets, capsules, powders, granules, elixirs for oral administration or in sterile solutions or suspensions for parenteral administration.
• Further composition forms includes pills and suppositories.
• a therapeutically effective amount of the receptor-antagonist can be determined by routine observation and experimentation and will be dependent on factors such as the clinical condition or disease under treatment, age of the patient, severity and locality of the disease. For example, we have demonstrated that MK801 displays a dose-response relationship with concentrations of 10 ⁇ M showing minimal effect and concentrations of 100 ⁇ M having a maximal effect in vitro.
• the therapeutically effective amount of the prophylactic prevention of a disease before clinical manifestation does not necessarily correspond to the effective amount for treatment of the clinical condition following manifestation.
• a therapeutically effective amount of the receptor-antagonist may be combined with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabiliser, flavour etc in a unit dosage form as called by accepted pharmaceutical practice.
• Pharmaceutical compositions of the present invention may comprise the antagonist together with an adjuvant.
• a binder such as gum tragacanth, acacis, corn starch or gelatin
• an excipient such as dicalcium phosphate
• a disintegrating agent such as corn starch, potato starch, alginic acid
• a lubricant such as magnesium stearate
• a sweetening agent such as sucrose.
• a syrup or elixir may contain the receptor-antagonist, sucrose as a sweetening agent, methyl and propyl paralens as preservation, a dye and a flavouring.
• the present invention is aimed primarily at humans, other animals e.g. mammals such as racehorses or dogs who suffer similar or related disorders of the bone may also benefit from the present invention.
• osteoclast/osteoblast co-culture was prepared as follows; calvaria from 12-20 new-born mice was dissected (2 to 3 days old Bb/CBA) and osteoblasts were isolated by digestion of the bones in collagenase followed by incubation in EDTA and a second collagenase digestion according to Takahashi U et al, (1988);
• the long bones were dissected from 2 to 3 adult mice, and the marrow was flushed out with 2 to 4ml Hanks balanced salt solution supplemented with 10% FCS (Gibco/BRL, Paisley, UK) and using a 2SG needle. Pooled marrow sample were then passed through needles of increasing gauge (19G to 25G). Red cells were removed by centrifugation on a cushion of Ficoll-Paque (Pharmacist) at 600 x g for 25 mins. The marrow cells were harvested from the interface, washed once and resuspended in ⁇ -Minimum Essential Medium (MEM) supplemented with 10% FCS and antibiotics (Gibco).
• MEM ⁇ -Minimum Essential Medium
• Adherent osteoblasts were resuspended by gentle trypsin treatment and co-cultures of 4 x 10 4 osteoblasts together with 9 x 10 5 bone marrow cells were prepared in wells of a 24 well plate, containing ⁇ -MEM with 10% FCS and 1,25(OH) 2 D 3 (IO nM).
• test amount of known NMDA-receptor antagonist MK-801 (Merck) and Phencyclidine (PCP) were added for the times described to give the concentrations indicated.

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Citations (5)

• 1997
  • 1997-02-14 GB GBGB9703109.0A patent/GB9703109D0/en active Pending
• 1998
  • 1998-02-12 WO PCT/GB1998/000443 patent/WO1998035674A1/en not_active Application Discontinuation
  • 1998-02-12 CA CA002280722A patent/CA2280722A1/en not_active Abandoned
  • 1998-02-12 EP EP98903203A patent/EP0971712A1/en not_active Withdrawn
  • 1998-02-12 AU AU60017/98A patent/AU6001798A/en not_active Abandoned
  • 1998-02-12 JP JP53547798A patent/JP2001513757A/ja active Pending
  • 1998-02-13 ZA ZA981206A patent/ZA981206B/xx unknown

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