Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-12
2002-04-30
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S217000, C540S586000, C540S593000
Reexamination Certificate
active
06380184
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel benzoazepines and analogs thereof which are growth hormone secretagogues, that is they stimulate endogenous production and/or release of growth hormone, and to methods for treating obesity and diabetes, improving bone density (to treat osteoporosis) and stimulating increase in muscle mass and muscle strength employing such compounds.
BACKGROUND OF THE INVENTION
The pituitary gland secretes growth hormone which stimulates growth in body tissue capable of growing and affects metabolic processes by increasing rate of protein synthesis and decreasing rate of carbohydrate synthesis in cells. Growth hormone also increases mobilization of free fatty acids and use of free fatty acids for energy.
The prior art is replete with patents/applications which disclose compounds which are useful as growth hormone secretagogues.
The following patents/applications, disclose benzofused lactams which are disclosed as being useful in promoting release of growth hormone:
U.S. Pat. Nos. 5,206,235; 5,283,741; 5,284,841; 5,310,737; 5,317,017; 5,374,721; 5,430,144; 5,434,261; 5,438,136; 5,545,735; 5,583,130; 5,606,054; 5,672,596 and 5,726,307; WO 96-05195 and WO 95-16675.
SUMMARY OF THE INVENTION
In accordance with the present invention, novel benzoazepines and analogs thereof are provided which are growth hormone secretagogues and have the structure
including pharmaceutically acceptable salts thereof and all stereoisomers thereof, wherein
X is (CH
2
)
m
where m is an integer from 0 to 4, CO, SO or SO
2
;
T is N—R
6
, O or S;
provided that (1) where Y is
X is CO, SO or SO
2
, or (CH
2
)
m
where m is 2, 3 or 4, and (2) where Z is
then n=o and X is CO, SO or SO
2
or (CH
2
)
m
where m is 2, 3 or 4;
L is —R
7
—(CH
2
)
q
-aryl-(CH
2
)
q′
— or
Q is —NR
10
R
11
,
n is 0 to 1; p is 1 to 3; q is 0 to 3; q′ is 0 to 3;
the benzene ring depicted by broken lines may or may not be fused to the benzo ring of the benzoazepine.
R
1
, R
1a
, R
2
, R
3
and R
4
are independently selected from hydrogen, hydroxy, halogen, cyano, nitro, amino, CF
3
, OCF
3
, S(O)
r
R
9b
, SO
2
NR
9b
R
9c
, COOR
9b
, CONR
9b
R
9c
, NR
9b
COR
9c
, alkyl, cycloalkyl, alkoxyl, alkylaryl, acyl, aryl and heteroaryl where the alkyl, cycloalkyl, alkoxyl, alkylaryl, acyl, aryl and heteroaryl groups in R
1
, R
1a
, R
2
, R
3
and R
4
are optionally substituted with hydroxy, halogen, cyano, nitro, amino, CF
3
, OCF
3
, S(O)
r
R
9b
, SO
2
NR
9b
R
9c
, CO
2
R
9b
or CONR
9b
R
9c
;
r is 0, 1 or 2;
R
3a
, R
4a
and R
5
are independently selected from hydrogen, hydroxy, halogen, cyano, nitro, amino, CF
3
, OCF
3
, CO
2
H, CONH
2
, SO
2
NH
2
, SO
2
Me, NHCON(CH
3
)
2
, NHSO
2
CH
3
, NHSO
2
N(CH
3
)
2
, tetrazole, R
12
alkyl, acyl, alkoxyl, alkylaryl, aryl or heteroaryl; R
12
is independently selected from a bond, oxygen, CONR
9d
, S(O)
t
, SO
2
NR
9d
, NR
9d
, NR
9d
CO, NR
9d
CONR
9e
, or NR
9d
SO
2
. The alkyl, acyl, alkoxyl, alkylaryl, aryl and heteroaryl groups in R
3a
, R
4a
and R
5
can be optionally substituted with 1, 2 or 3 of halogen, cyano, CF
3
, OCF
3
, OR
9f
, NR
9f
R
9g
, COOR
9f
, COR
9f
, CONR
9f
R
9g
, S(O)
t′
R
9f
, SO
2
NR
9f
R
9g
or tetrazole; t and t′ are independently from 0, 1 or 2.
R
12
is selected from a bond, oxygen, CONR
9d
, S(O)
t
, SO
2
NR
9d
, NR
9d
, NR
9d
CO, NR
9d
CONR
9e
, and NR
9d
SO
2
, and where alkyl, acyl, alkoxyl, alkylaryl, aryl and heteroaryl groups in R
3a
, R
4a
and R
5
are optionally substituted with 1, 2 or 3 of halogen, cyano, CF
3
, OCF
3
, OR
9f
, NR
9f
R
9g
, COOR
9f
, COR
9f
, CONR
9f
R
9g
, S(O)
t′
R
9f
, SO
2
NR
9f
R
9g
or tetrazole;
t and t′ are independently 0, 1 or 2;
R
6
is independently selected from hydrogen, SO
2
R
9h
, SO
2
NR
9h
R
9i
, CONR
9h
R
9i
, alkyl, cycloalkyl, acyl or aryl where the alkyl, cycloalkyl, acyl or aryl groups in R
6
is optionally substituted with hydroxy, halogen, cyano, nitro, amino, CF
3
, OCF
3
, CO
2
H, CONH
2
, SO
2
NH
2
, SO
2
CH
3
, NHCON (CH
3
)
2
, NHSO
2
CH
3
, or tetrazole;
R
7
is independently selected from a bond, oxygen or NR
9j
;
R
9
and R
9a
are independently selected from hydrogen, CF
3
, alkyl or alkylaryl, or R
9
and R
9a
can be joined together to form a 4 to 7 membered carbocyclic or heterocyclic ring, or either R
9
or R
9a
, or both, can be joined with R
10
or R
11
to form a 4 to 7 membered heterocyclic ring; and R
9
and R
9a
can be optionally substituted with any of the substituents for R
6
;
R
9b
, R
9c
, R
9d
, R
9e
, R
9f
, R
9g
, R
9h
, R
9i
, R
9j
and R
9k
are independently selected from hydrogen, C
1
-C
6
alkyl or aryl;
R
10
and R
11
are independently selected from hydrogen, alkyl or alkylaryl where the alkyl and alkylaryl groups in R
10
and R
11
can be optionally substituted with 1, 2 or 3 of hydroxy, amino, alkoxyl, aryloxyl, acyl and imidazole; R
10
and R
11
can also be joined together to form a 4 to 7 membered heterocyclic ring.
Thus, the compounds of formula I of the invention preferably include compounds of the structure
Most preferred are compounds of the structure VII
The compounds of the instant invention all have at least one asymmetric center as noted by the asterisk in structural formula I. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof, be included within the ambit of the instant invention. In the case of the asymmetric center represented by the asterisk in formula I, it has been found that the compound in which the 3-amino substituent is above the plane of the structure, as seen in formula I, is more active and thus more preferred over the compound in which the 3-amino substituent is below the plane of the structure. This center will be designated according to the R/S rules as R where the 3-amino substituent is above the plane.
The pharmaceutically acceptable salts of the compounds of formulae I of the invention include alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium, as well as zinc or aluminum and other cations such as ammonium, choline, diethanolamine, ethylenediamine, t-butylamine, t-octylamine, dehydroabietylamine, as well as pharmaceutically acceptable anions such as chloride, bromide, iodide, tartrate, acetate, methanesulfonate, maleate, succinate, glutarate, and salts of naturally occurring amino acids such as arginine, lysine, alanine and the like, and prodrug esters thereof.
In addition, in accordance with the present invention, a method for increasing levels of endogenous growth hormone or increasing the endogenous production or release of growth hormone is provided wherein a compound of formula I as defined hereinbefore is administered in a therapeutically effective amount.
Furthermore, in accordance with the present invention, a method is provided for treating osteoporosis (improving bone density), or treating obesity, or treating diabetes, or increasing muscle mass and/or muscle strength, or renal disease, cardiac myopathy, cachexia, HIV wasting syndrome, long term critical illness (such as cancer), sarcopenia, and/or stimulating wound healing, immune system stimulation, and/or treating Syndrome X and/or Metabolic Syndrome, wherein a compound of formula I as defined hereinbefore is administered in a therapeutically effective amount.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
Unless otherwise indicated, the term “lower alkyl”, “alkyl” or “alk” as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons, more preferably 1 to 6 carbons, in the normal chain,such as methyl, ethyl, propyl, isopropyl, butyl, t-buty
Bristol-Myers Squibb Co.
Coleman Brenda
Hermenau Ronald S.
Rodney Burton
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