Amido spiropiperidines promote the release of growth hormone

Details Amido spiropiperidines promote the release of growth hormone Amido spiropiperidines promote the release of growth hormone

2000-07-10

2002-07-16

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S017000

Reexamination Certificate

active

06420376

ABSTRACT:

BACKGROUND OF THE INVENTION
Growth hormone, which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic processes of the body: (1) Increased rate of protein synthesis in all cells of the body; (2) Decreased rate of carbohydrate utilization in cells of the body; (3) Increased mobilization of free fatty acids and use of fatty acids for energy. A deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.
Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone releasing hormone or all of these.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering GRF or a peptidal compound which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray. Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, while considerably smaller than growth hormones are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low. Non peptidal growth hormone secretagogues are disclosed in e.g., U.S. Pat. Nos. 5,206,235, 5,283,241, 5,284,841, 5,310,737, 5,317,017, 5,374,721, 5,430,144, 5,434,261, 5,438,136, 5,494,919, 5,494,920, 5,492,916, 5,536,716 and 5,578,593. Other growth hormone secretagogues are disclosed e.g., in PCT Patent Publications WO 94/13696, WO 94/19367, WO 95/03289, WO 95/03290, WO 95/09633, WO 95/11029, WO 95/12598, WO 95/13069, WO 95/14666, WO 95/16675, WO 95/16692, WO 95/17422, WO 95/17423, WO 95/34311, and WO 96/02530. The instant compounds are low molecular weight peptide analogs for promoting the release of growth hormone which have good stability in a variety of physiological environments and which may be administered parenterally, nasally or by the oral route.
SUMMARY OF THE INVENTION
The instant invention is directed to certain spiropiperidines which have the ability to stimulate the release of natural or endogenous growth hormone. The compounds thus have the ability to be used to treat conditions which require the stimulation of growth hormone production or secretion such as in humans with a deficiency of natural growth hormone or in animals used for food or wool production where the stimulation of growth hormone will result in a larger, more productive animal. Thus, it is an object of the instant invention to describe the piperidine compounds. It is a further object of this invention to describe procedures for the preparation of such compounds. A still further object is to describe the use of such compounds to increase the secretion of growth hormone in humans and animals. A still further object of this invention is to describe compositions containing the piperidine compounds for the use of treating humans and animals so as to increase the level of growth hormone secretions. Further objects will become apparent from a reading of the following description.
DESCRIPTION OF THE INVENTION
The novel spiropiperidines of the instant invention are described by structural Formula I:
wherein:
R
1
is selected from the group consisting of:
 or their regioisomers where not specified;
R
2
and R
3
are independently selected from the group consisting of:
hydrogen, —C
1
-C
6
alkyl, —C
3
-C
7
cycloalkyl, and —CH
2
-phenyl, wherein the alkyl, the cycloalkyl and the phenyl are unsubstituted or substituted with —OR
2a
, —C(O)OR
2a
, —C(O)N(R
2a
)(R
2b
), halogen, —C
1
-C
4
alkyl, —S(O)
n
R
2a
, —NHS(O)2(R
2a
), and wherein R
2
and R
2
are optionally joined to form a C
4
-C
5
cyclic ring being selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, and thiomorpholine;
R
2a
and R
2b
are independently selected from: hydrogen and C
1
-C
6
alkyl;
R
3a
and R
3b
are independently selected from: hydrogen, —C
1
-C
6
alkyl, —OR
2
, and halogen;
R
4
is selected from: hydrogen, C
1
-C
6
alkyl, and substituted C
1
-C
6
alkyl where the substituents on alkyl are selected from halo, —OR
2
, phenyl, C
1
-C
6
alkoxycarbonyl, —S(O)
n
R
2a
, and —NHS(O)
n
(R
2a
);
R
5
is selected from:
hydrogen,
C
1
-C
6
alkyl,
substituted C
1
-C
6
alkyl where the substituents on alkyl are selected from halo, —OR
2
, phenyl, —S(O)
n
R
2a
, —NHS(O)
n
(R
2a
),
R
5a
and R
5b
are independently selected from: hydrogen, C
1
-C
6
alkyl, or substituted C
1
-C
6
alkyl where the substituents are selected from: halo, —OR
2
, C
1
-C
6
alkoxy, phenyl, C
1
-C
6
alkoxycarbonyl, —S(O)
n
R
2a
, —NHS(O)
n
(R
2a
);
R
6a
and R
6b
are independently selected from: hydrogen, C
1
-C
6
alkyl, or trifluoromethyl;
X is selected from —CH
2
—, —O— and —S—;
n is independently 0, 1 or 2;
and pharmaceutically acceptable salts and individual diastereomers thereof.
In the above structural formula and throughout the instant specification, the following terms have the indicated meanings:
The alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration and if two carbon atoms or more they may include a double or a triple bond. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, propargyl, and the like.
The alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.
The term “halo” or “halogen” is intended to include any of the halogen atoms fluorine, chlorine, bromine and iodine.
The term “aryl” within the present invention, unless otherwise specified, is intended to include aromatic rings, such as carbocyclic and heterocyclic aromatic rings selected the group consisting of: phenyl, naphthyl, pyridyl, 1-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrrazinyl, or isothiazolyl, which may be optionally substituted by 1 to 3 of C
1
-C
6
alkyl, 1 to 3 of halogen, 1 to 2 of OR
2
, methylenedioxy, —S(O)
m
R
2
, 1 to 2 of —CF
3
, —OCF
3
, nitro, —N(R
2
)C(O)(R
2
), —C(O)OR
2
, —C(O)N(R
2
)(R
2
), −1H-tetrazol-5-yl, —SO
2
N(R
2
)(R
2
), —N(R
2
)SO
2
phenyl, or —N(R
2
)SO
2
R
2
, wherein R
2
is as defined herein.
Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other.
Preferred compounds of the instant invention include those of Formula I wherein:
R
1
is selected from the

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