Oxindole derivative

Details Oxindole derivative Oxindole derivative

2001-03-22

2003-06-10

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S235200, C514S314000, C514S339000, C514S367000, C514S397000, C514S414000, C544S144000, C546S152000, C546S167000, C546S227000, C548S159000, C548S314700, C548S454000, C548S465000, C548S466000, C548S467000, C548S486000, C548S488000, C548S491000

Reexamination Certificate

active

06576656

ABSTRACT:

TECHNICAL FIELD
The present invention relates to an oxindole derivative useful for growth hormone releaser etc.
BACKGROUND ART
Various factors are related to growth in individuals. However, growth hormone should apparently be the most important factor for growing, since surplus secretion of growth hormone may result in gigantism or acromegaly, and deficiency in growth hormone may result in dwarfism. Growth hormone is known to have basic effects on the metabolic processees of the body: to increase rate of protein synthesis, to decrease rate of carbohydrate utilization, and to increase mobilization of free fatty acids and use of fatty acids for energy.
Various compounds such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia are known to cause a release of growth hormone. Activities such as sleep and exercise are also known to release growth hormone. These compounds and activities indirectly cause growth hormone to be released from the pituitary by acting on the hypothalamus in various ways such as to decrease somatostatin secretion and to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone-releasing hormone.
Providing exogenous growth hormone is used as one way to increase levels of growth hormone. The sources of growth hormone used are either from extractions of pituitary glands of cadavers or recombinant growth hormone. However, the resulting growth hormone is very expensive and the extracted products from pituitary glands have risks that diseases associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Growth hormone should be given by injection or by a nasal spray, because its oral administration is difficult.
Another way to increase levels of growth hormone is to administer compounds which stimulate the release of endogenous growth hormone such as GRF or its derivatives (Schoen W. R. et. al., “Growth hormone secretagogues” in Annual Reports in Medicinal Chemistry: Academic Press, Vol. 28, Chapter 19, 1993) and peptidyl compounds (U.S. Pat. No. 4,411,890). These peptides are considerably smaller than growth hormones, but are still susceptible to various proteases. Therefore, their potential for oral bioavailability is low.
WO 94/01369 discloses non-peptide compounds useful as growth hormone releasers. Though these compounds are stable under various physiological environments and applicable parenterally, intranasally or orally, these compounds have not been approaved as a drug.
J. Chem. Soc. Perkin Trans. 1, 1975-1979(1991) describes that benzodiazocine derivatives were formed by heating oxindole derivatives in the presence of acid catalyst.
Chem. Pharm. Bull., 21, 960-971(1973) describes that oxindole derivatives without any substituents on its benzene ring have analgesic and anti-inflammatory effects.
DETAILED DESCRIPTION OF THE INVENTION
The inventors of the present invention have intensively carried out research on growth hormone releasers, and found that oxindole derivatives or prodrugs thereof, and pharmaceutically acceptable salts thereof are growth hormone releasers which are applicable as a medicine. Thus, the present invention has been accomplished.
That is, the present invention is as follows:
[1] An oxindole derivative of Formula 1 or a prodrug thereof, or a pharmaceutically acceptable salt thereof:
 wherein
R
1
, R
2
, R
3
and R
4
are the same or different and each is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, halogen, cyano, nitro, hydroxy, optionally substituted amino, alkoxy, alkanoyl, alkoxycarbonyl, optionally substituted sulfamoyl, optionally substituted carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino or alkanoylamino, provided that all of R
1
, R
2
, R
3
and R
4
are not simultaneously hydrogen;
R
5
is optionally substituted aryl or optionally substituted heteroaryl;
Z is —O— or —NH—;
one of W
1
and W
2
is hydrogen, alkyl or —Y—CON(R
10
)R
11
;
the other of W
1
and W
2
is
n is 1, 2 or 3; m is 0, 1, 2 or 3;
Y is single bond or C
1
-C
3
alkylene;
R
6
and R
7
are the same or different and each is independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; or R
6
and R
7
are taken together with the adjacent nitrogen atom to form optionally substituted saturated heterocyclic ring;
R
8
and R
9
are the same or different and each is independently hydrogen or optionally substituted alkyl; or R
8
and R
9
are taken together with the adjacent carbon atom to form optionally substituted cycloalkane or optionally substituted saturated heterocyclic ring;
R
8
and R
6
may be taken together to form C
1
-C
5
alkylene in which case R
7
is hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl, and R
9
is hydrogen or optionally substituted alkyl;
R
10
and R
11
are the same or different and each is independently hydrogen or alkyl; or R
10
and R
11
are taken together with the adjacent nitrogen atom to form optionally substituted saturated heterocyclic ring.
[2] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to [1] wherein R
1
, R
2
, R
3
and R
4
are independently hydrogen, alkyl optionally substituted by halogen, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbamoyl, halogen, cyano, nitro, alkanoyl, alkoxycarbonyl, alkylsulfinyl or alkylsulfonyl, provided that all of R
1
, R
2
, R
3
and R
4
are not simultaneously hydrogen.
[3] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to [1] wherein R
1
, R
2
, R
3
and R
4
are independently hydrogen, trifluoromethyl, carbamoyl, halogen, 4-carbamoyl-1-butynyl, 4-alkylcarbamoyl-1-butynyl, 4-dialkylcarbamoyl-1-butynyl, 4-morpholinocarbonyl-1-butynyl, —C≡C—(CH
2
)
k
—Q, wherein k is 1 or 2; Q is hydroxy, alkylsulfonyl, alkanoylamino, alkylureido, 2-oxo-1-imidazolidinyl or 2-oxo-1,3-oxazolin-3-yl, provided that all of R
1
, R
2
, R
3
and R
4
are not simultaneously hydrogen.
[4] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to [3] wherein both of R
2
and R
4
are hydrogen.
[5] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to [1] wherein both of R
2
and R
4
are hydrogen; R
1
is trifluoromethyl, chlorine or bromine; and R
3
is carbamoyl, halogen, 4-carbamoyl-1-butynyl, 4-alkylcarbamoyl-1-butynyl, 4-dialkylcarbamoyl-1-butynyl, 4-morpholinocarbonyl-1-butynyl, —C≡C—(CH
2
)
k
—Q, wherein k and Q are as defined above.
[6] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to [1] wherein both of R
2
and R
4
are hydrogen; R
1
is trifluoromethyl, chlorine or bromine; and R
3
is carbamoyl.
[7] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of [1] to [6] wherein R
5
is optionally substituted phenyl or optionally substituted 2-naphthyl.
[8] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of [1] to [6] wherein R
5
is phenyl optionally substituted by halogen(s) and/or trifluoromethyl(s) or 2-naphthyl optionally substituted by halogen(s) and/or trifluoromethyl(s).
[9] An oxindole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to any one of [1] to [8] wherein R
6
and R
7
are independently optionally substituted alkyl or optionally substituted cycloalkyl; or R
6
and R
7
are taken together with the adjacent nitrogen atom to form optiona

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