Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-16
2003-03-18
Ramsuer, Robert W. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S403000, C544S131000, C546S275700, C548S361100
Reexamination Certificate
active
06534504
ABSTRACT:
BACKGROUND OF THE INVENTION
An important goal in animal husbandry is to develop biologically active agents which can increase the quantity and improve the quality of meat obtained from livestock animals.
“Increasing the quantity” of food obtained from livestock animals refers to, inter alia, promoting the growth of livestock animals, increasing the efficiency of feed utilized in raising livestock animals and/or enhancing the production of lean body mass in livestock animals. Biologically active agents with these attributes are commonly referred to as “anabolic agents”.
“Improving the quality” of food obtained from livestock animals refers to, inter alia, reducing the quantity of subcutaneous fat in meat and, in poultry, the size of the abdominal “fat pad”. Subcutaneous fat can cause elevated cholesterol and triglyceride levels in individuals who consume large quantities of meat, has minimal nutritional value and decreases the overall yield of meat. Therefore, the reduction or elimination of this type of fat from meat is desirable. On the other hand, intramuscular fat, commonly referred to as “marbling”, contributes positively to the flavor of meat and maintains a high Quality Grade. Marbling is therefore considered a desirable quality. Biologically active agents which are lipolytic can reduce subcutaneous fat while retaining the intramuscular fat.
Certain publications have appeared generally disclosing arylpropanolamines such as U.S. Pat. No. 5,013,761 and WO 97/10825. There continues to be a need for the development of agents which are anabolic and lipolytic to improve the economics of meat production by increasing the yield and improving the quality of meat obtained from livestock animals. Further increases in profitability could be achieved by the development of long-lasting anabolic/lipolytic agents which, because they require less frequent dosing, are more convenient and economical to use.
BRIEF SUMMARY OF THE INVENTION
It has now been found that indazolyloxy propanolamimines such as those represented by Structural Formula (I) and (III) below are both anabolic and lipolytic when administered to livestock (Example 7 and Table 1). It has also been found that the anabolic and lipolytic effects of these compounds are longer lasting than other aryloxy propanolamines. Specifically, the percent decrease in serum urea nitrogen level (SUN) after forty-eight hours and the increase in non-esterified fatty acid levels (NEFA) after twenty-four hours in cattle treated with the indazolyloxy propanolamines of the present invention have been found to be significantly greater than for other aryloxy propanolamines (see Example 8 and Table 2). The percent decrease in SUN is indicative of anabolic activity and the increase in NEFA is indicative of lipolytic effects. Based on these results, novel compounds and novel methods of improving meat production from livestock animals are disclosed herein.
One embodiment of the present invention is a compound represented by Structural Formula (I):
and physiologically acceptable salts thereof; where R1 and R2 are independently —H or a C1-C4 straight chained or branched alkyl group;
Ring A, Ring B and Ring C are independently substituted or unsubstituted, provided, however, that Ring C is not substituted in the para position with a group represented by Structural Formula (II):
R3 and R4 are independently —H, a straight or branched C1-C4 alkyl or, taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring, and Ring D is substituted with zero, one, two or three additional substituents.
Another embodiment of the present invention is a compound represented by Structural Formula (III):
and physiologically acceptable salts thereof; where
R1 and R2 are independently —H, a C1-C4 straight chained or a branched alkyl group;
Ring A, Ring B, Ring C and Ring E are independently substituted or unsubstituted, provided, however, that Ring E is not substituted in the position meta to —N— and ortho to the carbon bonded to oxygen with —CONR3R4;
R3 and R4 are independently —H or a straight or branched chain C1-C4 alkyl group or, taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring.
Another embodiment of the present invention is a method of increasing the quantity and improving the quality of meat obtained from a livestock animal. The method comprises administering to the animal an effective amount of one or more compounds represented by Structural Formula (I). Another embodiment of the present invention is a method of increasing the quantity and improving quality of meat obtained from a livestock animal. The method comprises administering to the animal an effective amount of one or more compounds represented by Structural Formula (III).
The indazolyloxy propanolamines of the present invention have both anabolic and lipolytic activity and can therefore be administered to livestock to increase the output of meat and to decrease its fat content. Moreover, the duration of the anabolic and lipolytic activity of these indazolyloxy propanolamines is longer in vivo than other structurally related aryloxy propanolamines. Consequently, indazolyloxy propanolamines are more convenient and economical to use than other aryloxy propanolamines because indazolyloxy propanolamines need to be administered less frequently and/or at lower doses. The compounds of the present invention are intended for the treatment of healthy animals.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a compound represented by Structural Formula (I) and (III). Also included is a method of improving livestock production by administering one or more compounds of the present invention to the livestock.
In a preferred embodiment, the compound is represented by Structural Formula (IV):
Ring A, Ring B, Ring C, R1 and R2 are as described above for Structural Formula (I). Ring E is substituted or unsubstituted.
X is —CH— or —N—.
In Structural Formula (IV), R1 and R2 are preferably methyl and Rings A-C have no further substitution.
In a preferred embodiment, the compound of the present invention is represented by Structural Formula (V):
X is —N— or —CH—.
Ring E is substituted or unsubstituted. Examples of suitable substituents for Ring E include halo, —CN, —OR5, C1-C4 alkyl, C1-C4 haloalkyl, —CO
2
R5, —CONR6R7, —CONH(C1-C4 alkyl), —SR5, —CSNR6R7, —CSNR6R7, —SO
2
R5, —SO
2
NR6R7, —SOR5, —NR6R7. Preferred substituents are —CN, —CONH
2
, —SO
2
CH
3
, —SO
2
NH
2
or are represented by Structural Formulas (VI) or (VII):
—SR
2
CH
3
is a more preferred substituent.
R5 is —H, C1-C4 alkyl or aryl.
R6 and R7 are independently —H, C1-C4 alkyl, aryl, —(CH
2
)
n
aryl, or combine with the nitrogen atom to which each is bound to form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl.
n is 0, 1, 2, or 3.
In another preferred embodiment, the compound of the present invention is represented by Structural Formula (IV) or (V), provided, however, that Ring E is not substituted in the position meta to —X— and ortho to the carbon bonded to oxygen with —CONR3R4. R3 and R4 are independently —H or a straight or branched chain C1-C4 alkyl group or, taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring.
Also included in the present invention are Compounds 1-5, shown in Tables 1 and 2.
Physiologically acceptable salts of the compounds disclosed herein, including the compounds represented by Structural Formulas (I),(III), (IV), (V) and Compounds 1-5, shown in Tables 1 and 2, are included. Salts can be formed from those compounds which comprise acidic functional groups by reacting with a suitable base. Such salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like. Such bases useful in preparing the salts of this invention thus include ammonium
Hancock Deana Lori
Hopkins Randall Bruce
Quimby Michael Eugene
Wuethrich Andrew Jason
Demeter John C.
Eli Lilly and Company
Ramsuer Robert W.
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