Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-09-30
2001-07-03
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S237800, C514S255060, C514S256000, C514S419000, C514S586000, C544S162000, C544S335000, C544S406000, C548S516000, C564S027000, C564S047000, C564S048000
Reexamination Certificate
active
06255351
ABSTRACT:
BACKGROUND OF THE INVENTION
Bone is a dynamic tissue, and homeostasis in the adult skeleton requires a balance between bone resorption and bone formation. Osteoclasts and osteoblasts play a key role in this balance, with osteoclasts initiating bone resorption and osteoblasts synthesizing and depositing new bone matrix. Imbalances in bone homeostasis are associated with such conditions as osteoporosis, Paget's disease, and hyperparathyroidism.
The activities of osteoclasts and osteoblasts are regulated by complex interactions between systemic hormones and the local production of growth factors and cytokines. Calcitonin, a peptide hormone secreted by the thyroid and thymus of mammals, plays an important role in maintaining bone homeostasis. Calcitonin inhibits bone resorption through binding and activation of a specific calcitonin receptor on osteoclasts (The Calcitonins-Physiology and Pharmacology Azria (ed.), Karger, Basel, Su., 1989), with a resultant decrease in the amount of calcium released by bone into the serum. This inhibition of bone resorption has been exploited, for instance, by using calcitonin as a treatment for osteoporosis, a disease characterized by a decrease in the skeletal mass often resulting in debilitating and painful fractures. Calcitonin is also used in the treatment of Paget's disease where it provides rapid relief from bone pain, which is frequently the primary symptom associated with this disease. This analgesic effect has also been demonstrated in patients with osteoporosis or metastatic bone disease and has been reported to relieve pain associated with diabetic neuropathy, cancer, migraine and post-hysterectomy. Reduction in bone pain occurs before the reduction of bone resorption.
Salmon calcitonin has been shown to be considerably more effective in arresting bone resorption than human forms of calcitonin. Several hypotheses have been offered to explain this observation: 1) salmon calcitonin is more resistant to degradation; 2) salmon calcitonin has a lower metabolic clearance rate (MCR); and 3) salmon calcitonin may have a slightly different conformation, resulting in a higher affinity for bone receptor sites.
Despite the advantages associated with the use of salmon calcitonin in humans, there are also disadvantages. For treatment of osteoporosis, for instance, the average cost can exceed $75 a week and involve daily prophylactic administration for 5 or more years. In the United States, calcitonin must be administered by injection, and since the disease indications for this drug are not usually life threatening, patient compliance can be low. Resistance to calcitonin therapy may occur with long-term use. What triggers this resistance or “escape phenomenon” is unknown (see page 1093,
Principles of Bone Biology
, Bilezikian et al., (eds.) Academic Press, NY; Raisz et al.,
Am. J. Med.
43:684-90, 1967; McLeod and Raisz,
Endocrine Res. Comm.
8:49-59, 1981; Wener et al.,
Endocrinology.
90:752-9, 1972 and Tashjian et al.,
Recent Prog. Horm. Res.
34:285-303, 1978). Use of calcitonin mimetics, either in place of native calcitonins or in rotation with native calcitonins, would help avoid resistance to such treatment during long-term use. In addition, some patients develop antibodies to non-human calcitonin, calcitonin mimetics would be useful for such patients.
What is needed in the art are alternative methods of inhibiting bone resorption. The present invention fulfills these and other needs.
SUMMARY OF THE INVENTION
The present invention provides isolated compounds that are useful as calcitonin mimetics. As used herein, the term “calcitonin mimetic” refers to a compound with the ability to mimic the effects generated by calcitonin's interaction with its receptor and its signal transduction pathway and, by such interaction, stimulate G-protein-mediated activation by adenyl cyclase.
Within one aspect the invention provides a compound of formula I:
wherein R1 and R2 are each members independently selected from the group consisting of hydrogen, alkyls having from 1 to 6 carbon atoms, alkenyls having from 1 to 6 carbon atoms, aryl, substituted aryl, alkylaryl, substituted alkylaryl, carbocyclic ring, substituted carbocyclic ring, heterocyclic ring, substituted heterocyclic ring, and combinations thereof, the combinations are fused or covalently linked and the substituents are selected from the group consisting of halogen, haloalkyl, hydroxy, aryloxy, benzyloxy, alkoxy, haloalkoxy, amino, monoalkylamino, dialkylamino, acyloxy, acyl, alkyl and aryl; R3 is a 2,5 disubstituted aryl; R4 and R5 are each independently selected from the group consisting of hydrogen and alkyls having from 1 to 6 carbon atoms, or taken together from a ring selected from the group consisting of saturated or unsaturated five-member rings, saturated or unsaturated six-member rings and saturated or unsaturated seven-member rings; Z and X are each independently selected from the group NH, O, S, or NR, wherein R is a lower alkyl group of from 1 to 6 carbon atoms; n and m are each independently an integer from 0 to 6. Within one embodiment R1 is selected from the group consisting of phenyl, substituted phenyl, benzyl, substituted benzyl, naphthylmethyl, substituted naphthylmethyl, indolymethyl, and substituted indolymethyl; R2 is selected from the group consisting of alkyls of from 1 to 6 carbon atoms, alkenyls of from 1 to 6 carbon atoms, benzyl, substituted benzyl, naphthylmethyl, and substituted naphthylmethyl; wherein substituents are selected from the group consisting of halogen, haloalkyl, hydroxy, aryloxy, benzyloxy, alkoxy, haloalkoxy, amino, monoalkylamino, dialkylamino, acyloxy, acyl, alkyl and aryl; and R4 and R5 are hydrogen; Z is 0; and X is NH. Within a related embodiment R1 is 4-ethoxybenzyl, 1-ethyl-indolylmethyl, benzyl, 4-alloxybenzyl, 1-allyl-indolylmethyl, 4-chlorobenzyl,. 4-flurobenzyl, 4-iodobenzyl, 2-naphthylmethyl or phenyl; and R2 is ethyl, allyl, benzyl or 2-naphthylmethyl. Within another embodiment the compound has the formula:
wherein, R1 and R2 are each independently selected from the group consisting of hydrogen, alkyls having from 1 to 6 carbon atoms, alkenyls having from 1 to 6 carbon atoms, aryl, substituted aryl, alkylaryl, substituted alkylaryl, carbocyclic ring, substituted carbocyclic ring, heterocyclic ring, substituted heterocyclic ring, and combinations thereof, the combinations are fused or covalently linked and the substituents are selected from the group consisting of halogen, haloalkyl, hydroxy, aryloxy, benzyloxy, alkoxy, haloalkoxy, amino, monoalkylamino, dialkylamino, acyloxy, acyl, alkyl and aryl; and S1, S3 and S4 are each independently selected from the group consisting of hydrogen, halogen, haloalkyl, hydroxy, aryloxy, benzyloxy, alkoxy, haloalkoxy, amino, monoalkylamino, dialkylamino, acyloxy, acyl, alkyl and aryl. S2 and S5 are each independently alkyl or aryl. Within one embodiment R1 is selected from the group consisting of phenyl, substituted phenyl, benzyl, substituted benzyl, naphthylmethyl, substituted naphthylmethyl, indolymethyl, and substituted indolymethyl; R2 is selected from the group consisting of alkyls having from 1 to 6 carbon atoms, alkenyls having from 1 to 6 carbon atoms, benzyl, substituted benzyl, naphthylmethyl, and substituted naphthylmethyl; wherein the substituents are selected from the group consisting of halogen, haloalkyl, hydroxy, aryloxy, benzyloxy, alkoxy, haloalkoxy, amino, monoalkylamino, dialkylamino, acyloxy, acyl, alkyl and aryl and S2 and S5 are t-butyl. Within a related embodiment R1 is 4-ethoxybenzyl, 1-ethyl-indolylmethyl, benzyl, 4-alloxybenzyl, 1-allyl-indolylmethyl, 4-chlorobenzyl, 4-flurobenzyl, 4-iodobenzyl, 2-naphthylmethyl or phenyl; R2 is ethyl, allyl, benzyl or 2-naphthylmethyl; and S2 and S5 are t-butyl.
Within another aspect, the invention provides a pharmaceutical composition comprising an effective amount of a compound as described above in a pharmaceutically acceptable carrier.
Within another aspect the invention provides a method for treating a bone-related diso
Houghten Richard A.
McKernan Patricia A.
Meyer Jean-Philippe
Moore Emma E.
Ostresh John M.
Lingenfelter Susan
O'Sullivan Peter
ZymoGenetics Inc.
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