US 5,312,816 A · Method of combatting osteoporosis in mammalian subjects, utilizing organic boron compounds

Abstract

A method of combatting, e.g., preventing as well as treating, a disease state such as cystic fibrosis, neonatal hypoxemia, pulmonary hypertension, adult respiratory distress syndrome, psoriasis, spondyloarthritis, rheumatoid arthritis, gout, inflammatory bowel disease, myocardial infarctions, and/or osteoporosis in an animal subject, by administering to the animal subject an amount of an organic boron compound which is effective thereagainst. The organic boron compounds usefully employed in the method of the invention include any suitable organic boron-containing compounds, such as Lewis base-boron adducts; a preferred class of organic boron compounds useful in such method includes boron analogs of .alpha.-amino acids, and the corresponding amides and esters of such amino acids. A method is also disclosed of inhibiting enzyme activity in in vitro or in vivo systems comprising administering to such system an enzyme-inhibiting amount of an organic boron compound. Further disclosed is a method of reducing hydroxyproline, calcium, and/or inorganic phosphorous in serum and/or urine of an animal subject, by administering to the animal subject an effective amount of an organic boron compound.

A method of combatting osteoporosis in an animal subject, comprising administering to the animal subject an amount of an organic boron compound which (i) is effective against osteoporosis, and (ii) does not cause a statistically significant increase in hydroxylated steroids selected from the group consisting of 17-.beta.-estradiol and testosterone, wherein said organic boron compound is selected from the group consisting of:

(1) organic boron compounds of the formula:
R.sub.1 R.sub.2 R.sub.3 XBR.sub.4 R.sub.5 R.sub.6
wherein:
X is N or P;
R.sub.1, R.sub.2, R.sub.3 are independently selected from H, C.sub.1 -C.sub.20 linear or branched alkyl, alkoxy, alkylaryl, aryl, and substituted aryl, or R.sub.1, R.sub.2, and R.sub.3 together with X form a heterocyclic ring structure, with the proviso that when X.dbd.N, R.sub.1, R.sub.2 and R.sub.3 are not alkoxy:
R.sub.4 and R.sub.5 are independently selected from H, C.sub.1 -C.sub.20 linear or branched alkyl, aryl, alkylaryl, and substituted aryl:
R.sub.6 is H, C.sub.1 -C.sub.20 linear or branched alkyl, aryl, alkylaryl, substituted aryl, CN, COOH, COOM, COOR.sub.7, CONHR.sub.7, CONHOH, or COAA, or
R.sub.4, R.sub.5, and R.sub.6 together with B form a heterocyclic ring structure:
where:
M is Li, Na, K, or ammonium ion;
R.sub.7 is H, C.sub.1 -C.sub.10 alkyl, substituted alkyl, aryl, or substituted aryl;
and AA is NHCH(R.sub.8)COOR.sub.9 or NHCH(R.sub.8)CONHR.sub.9
where R.sub.8 is selected from the side chains of common amino acids and R.sub.9 is H, or C.sub.1 -C.sub.5 alkyl.
(2) organic boron compounds of the formula:
R.sub.1 R.sub.2 R.sub.3 XBR.sub.4 (R.sub.5).sub.2
wherein:
R.sub.1, R.sub.2, R.sub.3, R.sub.4 and X are same as above, and R.sub.5 is CN.
(3) organic boron compounds of the formula:
##STR20## wherein:
R.sub.1, R.sub.2 and R.sub.3 are same as in (1):
R.sub.4 is H, C.sub.1 -C.sub.10 linear or branched alkyl, alkylaryl, or aryl;
and R.sub.5 and R.sub.6 are independently selected from H, C.sub.1 -C.sub.10 alkyl, alkylaryl, aryl, or substuted aryl;
(4) organic boron compounds of the formula:
##STR21## wherein:
R.sub.1 is C.sub.1 -C.sub.10 linear or branched alkyl, alkylaryl, or aryl;
R.sub.2, R.sub.3 are independently selected from H, and C.sub.1 -C.sub.10 linear or branched alkyl;
R.sub.4 is H, C.sub.1 -C.sub.10 linear or branched alkyl, alkylaryl, or aryl;
R.sub.5 is CN, COOH, CONHR.sub.6, or COOR.sub.6, wherein R.sub.6 is same as R.sub.7 in (1);
(5) organic boron compounds of the formula;
##STR22## wherein;
X is O or S;
R.sub.1, R.sub.2, R.sub.3 are independently selected from H, C.sub.1 -C.sub.10 alkyl, alkylaryl, and aryl;
R.sub.4 is NMe.sub.2 or R.sub.5, wherein R.sub.5 is C.sub.1 -C.sub.10 linear or branched alkyl, alkylaryl, aryl, or substituted aryl;
(6) organic boron compounds of the formula:
##STR23## wherein:
X is C or O;
R.sub.1 is H or a suitable protecting group;
R.sub.2 is H or OH;
R.sub.3 is H or OH;
b represents a nucleoside base;
R.sub.4 is CN, COOH, COOR.sub.5, or CONHR.sub.5, wherein R.sub.5 is H, C.sub.1 -C.sub.10 alkyl, alkylaryl, aryl, or substituted aryl;
(7) organic boron compounds of the formula:
##STR24## wherein:
n=1-50;
b is a nucleoside base;
X is O, or OR, wherein R is CH.sub.3, CH.sub.2 CH.sub.2 CN, or CH.sub.2 CH.sub.3 ;
and
Y is BH.sub.3, BH.sub.2 CN, BH.sub.2 COOH, BH.sub.2 COOR.sub.1, or BH.sub.2 CONHR,
wherein R.sub.1 is H, or C.sub.1 -C.sub.5 alkyl;
and
(8) metal complexes of amine-cyanoboranes, and metal complexes of aminecarboxyboranes.

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Method of combatting osteoporosis in mammalian subjects, utilizing organic boron compounds

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Method of combatting osteoporosis in mammalian subjects, utilizing organic boron compounds

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Abstract

Claims12