Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-05-03
2001-04-24
Berch, Mark L. (Department: 4263)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S265100, C544S267000, C544S269000, C544S270000, C544S271000, C544S272000
Reexamination Certificate
active
06221874
ABSTRACT:
BACKGROUND OF INVENTION
Calcitonin is a 32 amino acid polypeptide hormone secreted by the parafollicular or C cells of the thyroid gland in response to elevated blood levels of calcium. This hormone decreases blood calcium (hypocalcemic activity) primarily by inhibiting bone resorption through plasma membrane-associated receptors on the osteoclast. High-turnover bone loss, as seen with hypercalcemia of malignancy, estrogen withdrawal as following the onset of the menopause, and certain anti-inflammatory or arthritis therapies, has recently been shown to be preventable by the administration of calcitonin (Bilezikian, J. P.,
J. Fert. Menopausal Studies
. 1996, 41, 148-155). As recently demonstrated for post-menopausal osteoporosis, treatment leads to not only a maintenance of bone mass and total body calcium, but also to decreases in the incidence of hip and vertebral fractures [Rico, H., et al.,
Calcif. Tissue Int
. 1995, 56, 181-185, Gennari, C.,
Aust. Family Physician
. 1994, 48, 196-200. Thus, it is apparent that calcitonin is an appropriate therapeutic for the prevention and treatment of osteoporosis by virtue of its hypocalcemic activity.
Although calcitonin has demonstrated efficacy in the prevention of high-turnover bone loss, a limitation for its wide-spread use is the lack of oral bioavailability, necessitating administration by parental (intra-muscular) or nasal routes. However, stimulation of endogenous calcitonin synthesis and release by inducer compounds would be expected to result in a similar therapeutic effect. This invention describes the ability of a series of xanthine sulfonamides to induce the expression and release of endogenous calcitonin, an activity not previously described for these compound.
Smith et al. disclose a class of 6-aminoxanthine-7-sulfonamides, 6-amino-sulfonylxanthine-7-sulfonamides and 6-aminobis(sulfonyl)xanthine-7-sulfonamides as phosphodiesterase (PDE) inhibitors in U.S. Pat. No. 5,409,934 and
J. Med. Chem
. 1994, 37, 476-85. Ginger et al. disclose of series a xanthine-7-sulfonamides as bronchodilating agents in U.S. Pat. No. 3,900,474.
The synthesis of variously substituted xanthine sulfonamides are described in the following publications: Buckle et al.,
J. Med. Chem
. 1994, 37, 476-85, Primenko et al.,
Ukr. Khim. Zh
. (
Russ. Ed
.) 1985, 51, 660-3, Acatrinei et al,
An. Stint. Univ. “Al. I Cuza” lasi, Sect
. 2
a
, 1974, 20, 247-52.
DESCRIPTION OF THE INVENTION
The present invention relates to xanthine sulfonamides having pharmacological activity, and to their use in the treatment of disorders associated bone loss by increased transcription and elevation of plasma calcitonin levels. Such disorders include, but are not limited to: Paget's Disease, post menopausal osteoporosis, senile osteoporosis, and glucocorticoid-induced osteoporosis.
In accordance with this invention there, is provided a group of compounds represented by the formula (I):
wherein:
R
1
and R
2
are independently, alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, allyl of 3 to 12 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aryl of 4 to 10 carbon atoms, 4 to 10 membered heteroaryl or a moiety of the formula (CH
2
)
m
—A wherein m is an integer from 1 to 9 and A is cycloalkyl of 3 to 7 carbon atoms;
R
3
is H, alkyl of 1 to 12 carbon atoms or cycloalkyl of 3 to 10 carbon atoms; and
R
4
is alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, cycloalkylalkyl of 4 to 10 carbon atoms, aryl of 4 to 10 carbon atoms, aralkyl of 5 to 10 carbon atoms; or 4 to 10 membered heteroaryl having 1 to 3 heteroatoms selected from N, S and O;
or a pharmaceutically acceptable salt thereof.
In some preferred aspects of the invention are provided compounds of formula (I):
wherein:
R
1
and R
2
are independently alkyl of 1 to 6 carbon atoms or allyl of 3 to 6 carbon atoms;
R
3
is hydrogen, alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 10 carbon atoms;
R
4
is aryl of 4 to 10 carbon atoms substituted with halogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or NR
5
R
6
; substituted or unsubstituted aralkyl of 7 to 10 carbon atoms; substituted or unsubstituted 4 to 10 membered heteroaryl having 1 to 3 heteroatoms selected from N, S and O; substituted or unsubstituted cycloalkyl of 3 to 10 carbon atoms; or substituted or unsubstituted cycloalkylalkyl of 4 to 10 carbon atoms; provided that aryl is substituted with NR
5
R
6
when R
1
and R
2
are alkyl;
R
5
and R
6
are independently selected from H, —OH, —COR
7
, —OCOR
7
; provided that R
5
and R
6
are not both H; and
R
7
is alkyl of 1 to 6 carbon atoms; or a pharmaceutical salt thereof.
In still other preferred aspects of the invention:
R
1
and R
2
are independently alkyl of 1 to 6 carbon atoms;
R
3
is H; and
R
4
is 4 to 6 membered heteroaryl.
In yet other preferred aspects of the invention:
R
1
and R
2
are independently alkyl of 1 to 6 carbon atoms;
R
3
is H;
R
4
is aryl substituted with NR
5
R
6
.
In other preferred aspects of the invention R
1
or R
2
is allyl.
In still other preferred aspects of the invention, R
4
is cycloalkylalkyl of 6 to 10 carbon atoms or aralkyl of 5 to 10 carbon atoms.
Alkyl, whether used alone or as part of another group (i.e. alkoxy) refers to an aliphatic hydrocarbon group. Alkyl includes straight and branched chain alkyl groups containing from 1 to 12 carbon atoms, and more preferably 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl and t-butyl are encompassed by the term alkyl. In some embodiments of the present invention alkyl may refer to substituted or unsubstituted alkyl.
Alkenyl as used herein refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond. Alkenyl includes straight and branched chain alkenyl groups containing from 2 to 12 carbon atoms, and more preferably from 2 to 6 carbon atoms. For example, ethenyl, n-butenyl, i-butenyl and n-pentenyl are encompassed by the term.
Allyl, as used herein refers to a conjugated hydrocarbon group containing from 3 to 12 carbon atoms, and more preferably from 3 to 6 carbon atoms. Allyl groups may be substituted or unsubstituted.
Halogen, as used herein means chlorine, bromine, iodine and fluorine.
Aryl, as used herein refers to single or multiple 4 to 10 membered aromatic ring radicals including but not limited to phenyl, naphthalene, anthracene, phenanthrene, indene and indacene. Preferred are phenyl and napthalene. In some embodiments of the present invention the aryl group may be substituted.
Aralkyl, as used herein refers to an aryl-alkyl group in which the aryl and alkyl are as previously described. Exemplary aralkyl groups include benzyl and phenethyl.
Heteroaryl as used herein refers to single or multiple 4 to 10 membered aromatic ring radicals having from 1 to 3 heteroatoms selected from S, O, or N including, but not limited to, furan, thiophene, pyrrole, imidazole, oxazole, thiazole, isoxazole, pyrazole, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, napthyridine, pteridine, pyridine, pyrazine, pyrimidine, pyridazine, pyran, triazine, indole, isoindole, indazole, indolizine and isobenzofuran. Preferred hetroaryls include furan, thiophene, pyrrole, imidazole, oxazole, thiazole, isoxazole, pyrazole, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, quinolizine, quinoline, and isoquinoline. More preferred heteroaryls include furan, thiophene, imidazole, isoxazole, quinoline and pyrazole. In some embodiments of the present invention the heteroacryl group is substituted.
Throughout, carbon number refers to carbon backbone and does not include carbon atoms of substitutions such as alkoxy substitutions and the like.
Preferably, the substituted aryl group is substituted with from 1 to 4 groups and more preferable with 1 to 3 groups. The substituted heteroaryl group is preferably substituted with from 1 or 2 groups. Alkyl, alkenyl and cycloalkyl groups may also be substituted. Suitable substitutions include, but are not li
Asselin Magda
Francisco Gerardo
Gilbert Adam Matthew
American Home Products Corporation
Barrett Rebecca R.
Berch Mark L.
LandOfFree
Method of treating bone loss by stimulation of calcitonin does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method of treating bone loss by stimulation of calcitonin, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of treating bone loss by stimulation of calcitonin will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2462729