Proton pump inhibitors

Details Proton pump inhibitors Proton pump inhibitors

2000-12-18

2002-07-16

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S301000, C514S341000, C514S342000, C514S365000, C514S399000, C546S114000, C546S118000, C546S269700, C546S272700, C548S186000, C548S325100

Reexamination Certificate

active

06420384

ABSTRACT:

BACKGROUND OF THE INVENTION
The need to treat debilitating bone disorders, such as osteoporosis, has led to extensive research on the mechanism and regulation of continuous bone formation and resorption. In particular, an appropriate balance of osteoblasts, which function to form bone tissue, and osteoclasts, which function to resorb bone tissue, is required to maintain the structural integrity and proper functioning of the skeleton in spite of continuous metabolism. Any changes in this balance of metabolism, such as an increased bone resorption (either absolute, or an increase via decreased bone formation relative to bone resorption) can lead bone diseases or disorders. One of the most common diseases resulting from this imbalance is osteoporosis, which is characterized by a decrease in bone mass and deterioration in skeletal micro-architecture leading to an increased fragility and susceptibility to fractures. Other diseases which result from alterations in bone resorption include, but are not limited to, Paget's Disease, primary and secondary hyperparathyroidism, humoral hypercalcemia of malignancy, various cancers where resorption is increased, and rheumatoid arthritis.
Because of the serious disorders that may result from a metabolic imbalance, researchers have been interested in studying bone metabolism, specifically the mechanism by which bone resorption and formation occurs, to ultimately develop a strategy for inhibiting resorption, and/or for improving bone mass and/or bone micro-architecture by stimulating osteoblast activity. However, the action of both osteoclasts and osteoblasts is controlled by a number of complex factors, and thus developing selective therapeutics has proven to be a difficult task.
One approach that has been taken for the development of novel therapeutics for bone disorders is inhibition of the osteoclast proton pump. It has been previously demonstrated that this proton pump is a vacuolar H
+
-ATPase (see, Blair et al.,
Science
1989, 245, 855-857; Finbow et al.,
Biochem. J.
1997, 324, 697-712; Forgac,
M. Soc. Gen. Physiol. Ser.
1996, 51, 121-132). It has been shown that osteoclasts, to effect bone resorption, ultimately lower the pH in the sealed microcompartment which underlies their site of attachment to the bone surface (see, Baron et al.,
J. Cell. Biol.
1985, 101, 2210-2222), thus resulting in the acidic envionment required to dissolve the bone mineral and to allow degradation of the bone matrix by proteases. The osteoclast uses a proton pump (an ATP-dependent transport of protons) to achieve this acidification and thus any therapeutic inhibition of the osteoclast proton pump should lead to a decrease in bone loss or turnover. As a result, many novel therapeutics developed to reduce bone resorption have focused on the inhibition of the proton pump to prevent osteoclast activity and excessive bone resorption. For a discussion of the vacuolar H
+
-ATPase and inhibitors of vacuolar H
+
-ATPase see Farina et al.,
Exp. Opin. Ther. Patents
1999, 9, 157-168 and David, P. and Baron, R. “The Vacuolar H
+
-ATPase: A Potential Target for Drug Development in Bone Diseases”
Exp. Opin. Invest. Drugs
1995, 4, 725-740.
A wide variety agents that are capable of inhibiting the action of V-ATPases have been disclosed recently. For example, it has been found that Bafilomycin A
l
, a macrolide antibiotic, can inhibit the V-type H
+
-ATPases at nanomolar concentrations, and thus is the most potent inhibitor of V-ATPases yet described. One major concern relating to the use of this therapeutic, as well as other derivatives representative of this family of compounds, such as concanamicin, (see, U.S. Pat. No. 5, 610, 178 “Macrolides and the Use Thereof”) however, is that it is not capable of specifically inhibiting bone resorption without affecting all other V-ATPases in the body, and thus leads to systemic alteration of cellular physiology and high toxicity. Other therapeutics, such as N-ethylmaleimide, have also proven to be effective inhibitors of V-ATPases, however there is also the concern that these agents may affect other V-type H
+
-ATPases in vivo. Additionally, gallium and group III metals, nitrate, vanadate, omeprazole and related compounds, WY 47766, S238, and bisphopshonates have also demonstrated inhibition of the osteoclast proton pump, although less effectively or with adverse side effects (see, Baron et al.
Exp. Opin. Invest. Drugs
1995, 4, 725 and Farina et al.
Exp. Opin. Ther. Patents
1999, 9, 157-168).
Clearly, although progress has been made towards developing therapeutic agents for osteoporosis and other bone disorders, there remains a need to develop potent and selective agents having minimal side effects. In particular, there remains a need to develop selective inhibitors of the osteoclast proton pump.
SUMMARY OF THE INVENTION
The present invention provides compounds comprising a bone targeting moiety and a payload and methods for the prevention and/or treatment of bone disorders and/or other related conditions using these compounds or pharmaceutical compositions thereof. In general, the compounds of the present invention comprise a bone targeting moiety and a payload capable of effecting inhibition of the osteoclast proton pump.
Thus, in one aspect, the present invention provides compounds of Formula (I):
wherein X
1
is CH or N;
wherein R
1
, R
2
, R
3
, and R
4
are each independently hydrogen, lower alkyl, halogen, hydroxy, alkyloxy, aryl, aryloxy, heteroaryl, trifluoromethoxy, cyano, nitro, thio, alkylthio or a bone targeting moiety, wherein said bone targeting moiety is selected from any one of i-xx:
wherein each occurrence of M is independently CV
2
, —NV—, —O—or —S—, wherein each occurence of V is independently hydrogen, OH, halogen, or aliphatic; each occurrence of Y is independently a covalent bond, —O—, —S—or N(R
j
)
2
, wherein R
j
, for each occurrence, is is independently hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; each occurrence of x is independently 0-6, and for compounds i-vi, xi, and xvii, x may preferably be 1-6; wherein L is —(Ch
2
)
p
—He—(CH
2
)
n
—, wherein He is absent or is NR', O or S, wherein R' is hydrogen or lower alkyl, n is 0-5, and p is 0-5, except when He is absent, the sum of n and p is
1-5; wherein L
2
is N or CR
K
, wherein R
K
is hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl; and wherein each occurrence of R
5
is independently hydrogen or lower alkyl, with the proviso that if either of R
2
or R
4
are bone targeting moieties, He, for the bone targeting moiety at R
2
or R
4
, is NR', O, or S, wherein R' is hydrogen or lower alkyl; wherein R
13
represents 0-3 substituents selected from hydrogen, halogen, lower alkyl, lower alkenyl, aryl, heteroaryl, carbonyl, thiocarbonyl, ketone, aldehyde, amino, acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphorothioate, phosphonate, phosphinate, —(CH
2
)
t
-alkyl-, —(CH
2
)
t
-alkenyl-, (CH
2
)
t
alkynyl-, —(CH
2
)
t
aryl-, —(CH
2
)
t
aralkyl-, —(CH
2
)
t
OH—, —(CH
2
)
t
O-lower alkyl-, (CH
2
)
t
)-lower alkenyl, —O(CH
2
)
t
R, —(CH
2
)
t
S-lower alkyl, —(CH
2
)
t
S-lower alkenyl, —S(CH
2
)
t
R, —(CH
2
)
t
NR
2
, (CH
2
)
t
NR-lower alkyl, —(CH
2
)
t
NR-lower alkenyl, —NR(CH
2
)
t
R, or protected forms of the above, and wherein t is 1-10;
wherein Hc is:
wherein R
6
, R
7
, R
9
, R
10
, R
11
, and R
12
are each independently selected from the group consisting of bone targeting moiety as described above, hydrogen, lower alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or wherein R
6
and R
7
taken together, or any one of R
11
and R
12
, R
10
and R
11
, and R
9
and R
10
taken together, comprise a substituted or unsubstituted aryl, heteroaryl, or cycloalkyl moiety, wherein said substituted or unsubstituted aryl, heteroaryl, or cycloalkyl moiety is a single ring or is polycyclic; and wherei

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