Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-21
2004-01-06
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S369000, C546S209000, C548S183000
Reexamination Certificate
active
06673816
ABSTRACT:
The present invention is concerned with rhodanine carboxylic acid derivatives for the treatment and prevention of metabolic bone disorders, a process for their manufacture as well as medicaments which contain these compounds.
In healthy persons the synthesis and degradation processes in bones is almost in equilibrium, i.e. the activity of the osteoblasts and osteoclasts is balanced. However, if this equilibrium is disturbed in favour of the osteoclasts and/or to the detriment of the osteoblasts, this leads to a reduction in the bone mass and to a negative change in the bone structure and function.
Hitherto, bone resorption inhibitors such as oestrogens, calcitonin and biphosphonates have primarily been used for the treatment of metabolic bone disorders. The use of these substances is, however, limited and also does not show the desired effect in all cases. Compounds which have a stimulating activity on bone synthesis and in addition contribute to an increase in an already reduced bone mass are accordingly of especial significance for the treatment of metabolic bone disorders.
Compounds having the rhodanine carboxylic acid structural element are known as antidiabetics, cytostatics inflammation inhibitors and for the treatment of cardiovascular illnesses and bacterial infections.
The parathyroid hormone (PTH), a hormone from the parathyroid gland, is the natural ligand of the receptor and an important regulator for the maintenance of the calcium level in the body. PTH can stimulate bone formation or bone resorption. In this, it acts as a regulatory hormone on a series of enzymes, inter alia, on adenylate cyclase (cAMP synthesis) and on ornithine decarboxylase. PTH mobilizes calcium from bones in the case of calcium deficiency, reduces calcium excretion from the kidneys and simultaneously improves the resorption of calcium from the intestine by an increased synthesis of 1,25—(OH)
2
D
3
. A normalization of the calcium level is achieved by the action on these target organs. On the other hand, the incorporation of calcium in bones is stimulated in the case of an elevated calcium level. This osteoanabolic activity of PTH and its fragments has been attributed to the activation of adenylate cyclase and of cAMP-dependent protein kinases (Rixon, R. Whitfield, J. et al JMBR 9 (8) 1179-89 (1994).
Surprisingly, it has now been found that rhodanine carboxylic acid derivatives of the present invention stimulate the PTH receptor-mediated cAMP formation. Compounds of the present invention are accordingly suitable for the broad treatment of metabolic bone disorders. They can be used primarily to good effect where the bone synthesis is disturbed, i.e. they are especially suitable for the treatment of osteopenic disorders of the skeletal system such as e.g. osteoporosis, inter alia, osteogenesis imperfecta as well as for the local assistance in bone regeneration and osteoinduction such as e.g. in orthopedic and maxillary medical indications, in fracture healing, osteosyntheses, pseudoarthroses and for the healing in of bone implants. However, having regard to these properties they also find use in the prophylaxis of osteoporosis.
By their influence on bone metabolism medicaments with the rhodanine carboxylic acid derivatives of the present invention as active substances furthermore form a basis for the local and systemic treatment of rheumatoid arthritis, osteoarthritis and degenerative arthrosis.
The object of the present invention are compounds of general formula (I),
in which
m signifies a number between 0-8,
q signifies a number between 0-8
a signifies a number between 0-4
A signifies a single or double bond
R
1
, R
2
signify hydrogen or lower alkyl, whereby R
1
and R
2
can be the same or different and, when m signifies 2-8, R
1
and R
2
in the group CR
1
═CR
2
can have various significances within the following sequence
R
3
signifies hydrogen or lower alkyl
X signifies hydrogen or —(CH
2
)
b
—COR
4
with b=0-4
Y signifies hydrogen, —COR
4
, phenyl or indolyl residue
R
4
signifies hydroxyl, lower alkoxy or the NR
1
R
2
residue, whereby R
1
and R
2
can be the same or different
W signifies an optionally mono- or polysubstituted saturated or unsaturated mono-, bi- or tricycle which can contain one or more hetero atoms,
As a rule, lower alkyl signifies linear or branched alkyl residues with one to six carbon atoms, preferably methyl, ethyl, propyl, i-propyl, butyl, t-butyl, pentyl, hexyl, particularly methyl.
Alkoxy groups signify a combination of a C
1
-C
10
-alkyl group in accordance with the above definition with an oxygen atom, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentoxy groups.
Under monocycle there are to be understood optionally mono- or polysubstituted, saturated or unsaturated ring systems with 3-8, preferably 3-7 carbon atoms, which optionally can be interrupted by one or more hetero atoms, such as nitrogen, oxygen or sulphur, especially the phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, morpholinyl, thiamorpholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, furyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl residue, as well as residues such as e.g. phenyl phenyl ether, diphenylmethane and biphenyl. Substituents are preferably lower alkyl, alkoxy, alkoxycarbonylalkyl, alkoxycarbonyl, acetylamino, alkoxydialkylamino, amino, dialkylamino, benzyl, benzyloxy, benzyloxybenzyloxy, carboxyl, chlorophenylsulphanyl, dioxymethylene, mercaptoalkyl, nitro, phenoxy, styryl and halogen.
In the case of the bicycle set forth under W, this is preferably a residue such as the naphthyl, tetrahydronaphthyl, decalinyl, quinolinyl, chromane, chromene, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, indazolyl, oxindolyl, benzofuranyl, benzothiophenyl, benzochiazolyl, benzoxazolyl or purinyl residue, especially the indolyl, naphthyl, benzimidazolyl, quinolinyl, tetrahydroquinolinyl benzothiophenyl and benzofuranyl residue, which optionally can be mono- or polysubstituted. Substituents are preferably lower alkyl, alkoxy, alkoxycarbonylalkyl, alkoxycarbonyl, acetylamino, alkoxydialkylamino, amino, dialkylamino, benzyl, benzyloxy, benzyloxybenzyloxy, carboxyl, chlorophenylsulphanyl, dioxymethylene, mercaptoalkyl, nitro, phenoxy, styryl and halogen.
In the case of the tricycle set forth under W, this is preferably a residue such as the anthracene, fluorene, dibenzofuran or carbazole.
Compounds of formula I wherein W is phenyl or indolyl, m and g are both 0, R
3
is hydrogen and A is a double bond are disclosed e.g. in EP-A-0677 and EP-A-0587377, however for the treatment of Alzheimer's disease or as hypoglycemic agents.
Therefore subject of the present invention are also new compounds of formula I
in which
m signifies a number between 0-8,
q signifies a number between 0-8
a signifies a number between 0-4
A signifies a single or double bond
R
1
, R
2
signify hydrogen or lower alkyl, whereby R
1
and R
2
can be the same or different and, when m signifies 2-8, R
1
and R
2
in the group CR
1
═CR
2
can have various significances within the following sequence
R
3
signifies hydrogen or lower alkyl
X signifies hydrogen or —(CH
2
)
b
—COR
4
with b=0-4
Y signifies hydrogen, —COR
4
, phenyl or indolyl residue
R
4
signifies hydroxyl, lower alkoxy or the NR
1
R
2
residue, whereby R
1
and R
2
can be the same or different
W signifies an optionally mono- or polysubstituted saturated or unsaturated mono-, bi- or tricycle which can contain one or more hetero atoms,
whereas W is not phenyl or indolyl, if m and g are both 0, R
3
is hydrogen and A is a double bond, as well as their physiologically compatible salts, esters, optically active forms, racemates, tautomers, as well as derivatives which can be metabolized in vivo to compounds of general formula (I), as well as the use of these compounds for the production of medicaments.
Preferred are compounds of general formula I in which m
Esswein Angelika
Honold Konrad
Kaluza Klaus
Schaefer Wolfgang
Tsaklakidis Christos
Esswein Angelika
Rothwell Figg Ernst & Manbeck
Stockton Laura L.
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