US 6,211,174 B1Granted

Naphtho-fused lactams promote release of growth hormone

AssigneeMerck & Co., Inc.

InventorsRobert J. Devita, Matthew J. Wyvratt

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Abstract

The present invention is directed to certain naphtho-fused lactams of the general structural formula: wherein and R1, R1a, R1b, R2a, R2b, R3a, R4, R5, R6, A, L, X, n, p and w are as defined herein. These compounds promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to treat physiological or medical conditions characterized by a deficiency in growth hormone secretion, such as short stature in growth hormone deficient children, and to treat medical conditions which are improved by the anabolic effects of growth hormone.

Claims10

Dependent claims

A compound which is selected from the group consisting of:

2-Amino-2-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]propanamide;
3-Amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]-methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
2-Amino-2-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[(aminocarbonyl)amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]propanamide;
3-Amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[(aminocarbonyl)amino]methyl][1,1+-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[((aminocarbonyl)amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[(aminocarbonyl)amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
2-Amino-2-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(ethylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]propanamide;
3-Amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(ethylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(ethylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(ethylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
2-Amino-2-methyl-N-[3(R -2,3,4,5-tetrahydro-5-[[2′-[[[[(hydroxyethyl)amino]carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]propanamide;
3-Amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[[(hydroxyethyl)amino]carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[[(hydroxyethyl)amino]carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]-methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[[(hydroxyethyl)amino]carbonyl]amino]-methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
2-Amino-2-methyl-N-[3(S)-2,3,4,5-tetrahydro-1-[[2′-[2-[[(methylamino)carbonyl]amino]prop-2-yl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]propanamide;
2-Amino-2-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[1-[[(methylamino)carbonyl]amino]ethyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]propanamide;
2-Amino-2-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]oxy]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]propanamide;
3-Amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]oxy]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]oxy]methyl][1,1′-biphenyl]-4-yl]-methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]oxy]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
and pharmaceutically acceptable salts thereof.

20 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/159,451Filed 24 Sep 1998 · us provisional application
Priority: 31 Oct 1997
Granted: 3 Apr 2001
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 281/08
Having the hetero atoms in positions 1 and 4: condensed with carbocyclic rings or ring systems
A61K 31/66
Medicinal preparations containing organic active ingredients: phosphorus compounds
C07D 223/14
Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom: condensed with carbocyclic rings or…
C07D 267/10
Having the hetero atoms in positions 1 and 4: not condensed with other rings

Family

Application60/063,948Us provisional application · filed 31 Oct 1997
US 6,211,174 B1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound which is selected from the group consisting of:

2-Amino-2-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]propanamide;
3-Amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]-methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
2-Amino-2-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[(aminocarbonyl)amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]propanamide;
3-Amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[(aminocarbonyl)amino]methyl][1,1+-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[((aminocarbonyl)amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[(aminocarbonyl)amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
2-Amino-2-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(ethylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]propanamide;
3-Amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(ethylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(ethylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(ethylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
2-Amino-2-methyl-N-[3(R -2,3,4,5-tetrahydro-5-[[2′-[[[[(hydroxyethyl)amino]carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]propanamide;
3-Amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[[(hydroxyethyl)amino]carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[[(hydroxyethyl)amino]carbonyl]amino]methyl][1,1′-biphenyl]-4-yl]-methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[[(hydroxyethyl)amino]carbonyl]amino]-methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
2-Amino-2-methyl-N-[3(S)-2,3,4,5-tetrahydro-1-[[2′-[2-[[(methylamino)carbonyl]amino]prop-2-yl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]propanamide;
2-Amino-2-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[1-[[(methylamino)carbonyl]amino]ethyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]propanamide;
2-Amino-2-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]oxy]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]propanamide;
3-Amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]oxy]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]oxy]methyl][1,1′-biphenyl]-4-yl]-methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[3(R)-2,3,4,5-tetrahydro-5-[[2′-[[[(methylamino)carbonyl]oxy]methyl][1,1′-biphenyl]-4-yl]methyl]-4-oxo-1H-naphtho[2,1-b]azepin-3(R)-yl]butanamide;
and pharmaceutically acceptable salts thereof.

20 more elements

Facts

Application

09/159,451Filed 24 Sep 1998 · us provisional application

Priority

31 Oct 1997

Granted

3 Apr 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 281/08
Having the hetero atoms in positions 1 and 4: condensed with carbocyclic rings or ring systems
A61K 31/66
Medicinal preparations containing organic active ingredients: phosphorus compounds
C07D 223/14
Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom: condensed with carbocyclic rings or…
C07D 267/10
Having the hetero atoms in positions 1 and 4: not condensed with other rings