GB2272439A - Benzo-fused lactams that inhibit the release of growth hormone - Google Patents

Benzo-fused lactams that inhibit the release of growth hormone Download PDF

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GB2272439A
GB2272439A GB9323124A GB9323124A GB2272439A GB 2272439 A GB2272439 A GB 2272439A GB 9323124 A GB9323124 A GB 9323124A GB 9323124 A GB9323124 A GB 9323124A GB 2272439 A GB2272439 A GB 2272439A
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methyl
alkyl
independently
phenyl
tetrahydro
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Wanda W-S Chan
Kang Cheng
William R Schoen
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Merck and Co Inc
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Merck and Co Inc
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    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
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    • A61K38/00—Medicinal preparations containing peptides
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
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    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract

Certain novel benzo-fused lactams inhibit the release of growth hormone in humans and animals. This property can be utilized to counteract excess natural growth hormone secretions in acromegaly afflicted patients. Growth hormone inhibiting compositions contain such benzo-fused lactams and optionally other active ingredients.

Description

TITLE OF THE INVENTION NOVEL BENZO-FUSED LACTAMS THAT INHIBIT THE RELEASE OF GROWTH HORMONE 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 process 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.
Excess growth hormone secretions can result in various medical disorders, such as giantism and acromegaly.
Various ways are known to inhibit the release of growth hormone. For example, chemicals such as somatostatin and certain analogs thereof.
Other compounds have been developed which inhibit the release of endogenous growth hormone such as the somatostatin analogs stilamine or sandostatine or the GHRP-6 antagonist His-D-Trp-D-Lys-Trp-D-Phe-Lys-NH2.
SUMMARY OF THE INVENTION The instant invention covers certain benzofused lactam compounds which have the ability to inhibit the release of natural or endogenous growth hormone. The compounds thus have the ability to be used to treat conditions which require the inhibition of growth hormone production or secretion such as in humans with excess secretions of natural growth hormone. Thus, it is an object of the instant invention to describe the benzofused lactam 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 inhibit the secretion of growth hormone in humans and animals.A still further object of this invention is to describe compositions containing the benzo-fused lactam compounds for the use of treating humans and animals so as to decrease the level of growth hormone secretions. Further objects will become apparent from a reading of the following description.
DESCRIPTION OF ThE INVENTION The novel benzo-fused lactams of the instant invention are best described in the following structural formula I:
where L is
n is O or 1; p is O to 3; q is O to 4; w is O or 1; u is O or 1; OH R10 X is C=O, O, S(O)m, -CH-, -N-, -CH=CH; m is O to 2; A is
where x and y are independently 0 to 3.
R1 R, Rla, R2a, Rlb, and R2b, are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, S(O)mR7, cyano, nitro, R7bO(CH2)v-, R7bCOO(CH2)v-, R7bOCO(CH2)v-, R4R4bN(CH2)v-, R7bCON(R4)(CH2)v-, R4R4bNCO(CH2)v-, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;R7a and R7b are independently hydrogen, C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl or substituted phenyl; phenyl or substituted phenyl where the phenyl substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy and v is O to 3; R3 is Rb, R2b independently disubstituted phenyl, Rib, R2b independently disubstituted naphthyl, Rib, R2b independently disubstituted fluorenyl, Rlb R2b independently disubstituted indolyl or Rib, R2b independently disubstituted quinolyl, where Rlb and R2b are as defined above;; R4 and R4b are independently hydrogen, phenyl, substituted phenyl, C1-C10 alkyl, substituted C1-C10 alkyl, C3-C10 alkenyl, substituted C3-C10 alkenyl, C3-C10 alkynyl, or substituted C3-C10 alkynyl where the substituents on the phenyl, alkyl, alkenyl or alkynyl are from 1 to 5 of hydroxy, C1-C6 alkoxy, C3-C7 cycloalkyl, fluoro, R1, R2 independently disubstituted phenyl C1-C3 alkoxy, R1, R2 independently disubstituted phenyl, C1-C20 alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl, or -NR1OR11; where R10 and R11 are independently hydrogen, C1-C6 alkyl, phenyl, phenyl C1-C6 alkyl, C1-C5-alkoxycarbonyl, or C1-C5-alkanoyl-C1-C6 alkyl; R4 and R4b can be taken together to form (CH2)r-B-(CH2)s- where B is O or S(O)m, r and s are independently 1 to 3 and m is as defined; R5 is COR9, COOR9, CONR6bR9, SO2R9 or S02NR6bR9. R6b and R9 can be taken together to form -(CH2)r-B-(CH2)s- where B is 0, or S(O)m; where r and s are independently 1 to 3 and m is as defined;; R9 is hydrogen, C1-C3 perfluoroalkyl, C1-C6 alkyl, R1, R2 independently disubstituted phenyl, R1, R2 independently disubstituted naphthyl, R1, R2 independently disubstituted fluorenyl or substituted C1-C6 alkyl where the substituents are R1, R2 independently disubstituted phenyl, R1, R2 independently disubstituted naphthyl or R1, R2 independently disubstituted fluorenyl, with the proviso that when R5 is COOR9 or S02R9, R9 is other than hydrogen; R6a and R6b are independently hydrogen, C1-C10 alkyl, phenyl or phenyl C1-C10 alkyl;; R8 and R8a are independently hydrogen, C1-C10 alkyl, trifluoromethyl, phenyl, substituted C1-C10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O)mR7, C1-C6 alkoxy, C3-C7 cycloalkyl, R1, R2 independently disubstituted phenyl C1-C3 alkoxy, R1, R2 independently di substituted phenyl, C1-C5-alkanoyloxy, C1-C5-alkoxycarbonyl, carboxy, formyl, or -NR10R11 where R1, R2, R10 and Rll are as defined above; or R8 and R8a can be taken together to form -(CH2)t- where t is 2 to 6; and R8 and R8a can independently be joined to R4 to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms; and pharmaceutically acceptable salts 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. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, 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. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
The term "halogen" is intended to include the halogen atom fluorine, chlorine, bromine and iodine.
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 are realized when in the above structural formula: n is O or 1: p is O to 3; q is O to 3; w is O or 1; u is O or 1; R10 X is, O, 5(0)m -N-, -CH=CH; m is O to 2; A is
where x and y are independently 0 to 2; R1 R2 Rla R2a, Rlb, and R2b, are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, -S(O)mR7a, R7bo(CH2)v-, R7bCoo(CH2)v-, R7bOCO(CH2)v-, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;R7a and R7b are independently hydrogen, C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl; phenyl v is O to 2; R3 is as defined above; R4 is hydrogen, phenyl, substituted phenyl. C1-C10 alkyl, substituted C1-C10 alkyl, the substituents are from 1 to 5 of hydroxy, C1-C6 alkoxy, C3-C7 cycloalkyl, fluoro, R1, R2 independently disubstituted phenyl C1-C3 alkoxy, R1, R2 independently disubstituted phenyl, C1-C20 alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl; R5 is COR9, COOR9, CONR6bR9, S02R9. R6b and R9 can be taken together to form -(CE2)r-B-(CH2)S- where 3 is O or S(O)m; r and are independently 1 to 3 and m is as defined; R9 is C1-C3 perfluoroalkyl, C1-C6 alkyl, R1, R2 independently disubstituted phenyl, R1, R2 independently disubstituted naphthyl, R1, R2 independently disubstituted fluorenyl or substituted C1-C6 alkyl where the substituents are R1, R2 independently disubstituted phenyl, R1, R2 independently disubstituted naphthyl or R1, R2 independently disubstituted fluorenyl; R6a and R6b are independently hydrogen, C1-C10 alkyl, or phenyl C1-C10 alkyl;; R8 and R8a are independently hydrogen, C1-C10 alkyl, phenyl, substituted C1-C10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(0)mR7, C1-C6 alkoxy, C3-C7 cycloalkyl, R1, R2 independently disubstituted phenyl C1-C3 alkoxy, R1, R2 independently disubstituted phenyl, C1-C5-alkanoyloxy, C1-C5-alkoxycarbonyl, carboxy, formyl, or -NRlORll where R1, R2, R10 and Rll are as defined above; or R8 and R8a can be taken together to form -(CH2)t- where t is 2 to 4; and R8 and R8a can independently be joined to Ra to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms; and pharmaceutically acceptable salts thereof.
Still further preferred compounds of the instant invention are realized in the above structural formula when; n is O or 1; p is O to 2; q is O to 2; w is O or 1; u is O or 1: X is S(O)m, -CH=CH; m is O or 1; A is
where x and y are independently 0 to 1; R1, R2 Rla R2a, Rlb, and R2b, are independently hydrogen, halogen.C1-C7 alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, -S(o)mR7a, R7bO(CH2)v-, R7bCOO(CH2)v-, R7bOCO(CH2)v-, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy; R7a and R7b are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl and v is O to 2; R3 is as defined above; R4 is hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl, where the substituents are from 1 to 5 of hydroxy, C1-C6 alkoxy, fluoro, R1, R2 independently disubstituted phenyl, C1-C20 alkanoyloxy. C1-C5 alkoxycarbonyl, or carboxy; R5 is COR9, COOR9, or S02R9;; R9 is C1-C6 alkyl, R1, R2 independently disubstituted phenyl, R11 , R2 independently disubstituted naphthyl, R1, R2 independently disubstituted fluorenyl or substituted C1-C6 alkyl where the substituents are R1, R2 independently disubstituted phenyl, R1, R2 independently disubstituted naphthyl or R1, R2 independently di substituted fluorenyl; R6a is hydrogen or C1-C10 alkyl;; R8 and R8a are independently hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, s(o)mR7a, C1-Cs alkoxy, C3-C7 cycloalkyl, R1, R2 independently disubstituted phenyl C1-C3 alkoxy, R1, R2 independently disubstituted phenyl, C1-C5-alkanoyloxy, C1-C5-alkoxycarbonyl, carboxy, formyl, or -NR1OR11 where R1, R2, R10 and R11 are as defined above; or R8 and R8a can be taken together to form -(CH2)t- where t is 2; and R8 and R8a can independently be joined to R4 to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms; and pharmaceutically acceptable salts thereof.
Still further preferred compounds of the instant invention are realized in the above structural formula when: n is O or 1; p is O to 2; q is O to 2; w is O or 1; u is O or 1; X is S(0)m or -CH=CH; m is O; A is
where x and y are independently 0 to 1; R1, R2 Rla R2a, Rlb, and R2b, are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, S(O)mR7a, R7bO(CH2)v-, R7bCOO(CH2)v-, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy or hydroxy;R7a and R7b are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl and v is O to 1: R3 is as defined above; R4 is hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl, where the substituents are from 1 to 3 of hydroxy, C1-C3 alkoxy, fluoro, R1, R2 independently disubstituted phenyl, C1-C20 alkanoyloxy, C1-C5 alkoxycarbonyl, or carboxy; R5 is COR9, COOR9 or S02R9; R9 is C1-C6 alkyl, R1, R2 independently disubstituted phenyl, R1, R2 independently disubstituted naphthyl, R1, R2 independently disubstituted fluorenyl or substituted C1-C6 alkyl where the substituents are R1, R2 independently disubstituted phenyl.. R1, R2 independently disubstituted naphthyl or R1, R2 independently disubstituted fluorenyl; R6a is hydrogen; ; R8 and R8a are independently hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O)mR7, C1-C6 alkoxy, R1, R2 independently di substituted phenyl, C1-C5-alkanoyloxy, C1-C5-alkoxycarbonyl or carboxy; or R8 and R8a can be taken together to form -(CH2)t- where t is 2; and R8 and R8a can independently be joined to R4 to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms; and pharmaceutically acceptable salts thereof.
Representative examples of the nomenclature employed are given below:
3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[(1-naphthyl)methyl]-1H-1-benzazepin-3yl]-butanamide
2-Benzylowycarbonylamino-2-methyl-N-t2,3.4,5-tetra- hydro-2-oxo-1-[[[1,1'-biphenyl]-4-yl]methyl]-1H-1 benzazepin-3-yl) -propanamide
3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1-[(1Hindole-3-yl)methyl]-1H-1-benzazepin-2-one
3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-(phenylmethyl)-1,5-benzothiazepin-3yl]-butanamide Representative preferred growth hormone inhibiting compounds of the present invention include the following: 1. 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1- (phenylmethyl)-1H-1-benzazepin-2-one 2. 2-t-Butoxycarbonylamino-2-methyl-N-[2.3,4,5-tetra- hydro-2-oxo-1-(phenylmethyl)-1H-1-benzazepin-3 yl]-propanamide 3. 3-t-Butoxycarbonylamino-3-methyl-N-[2 ? 3,4,5-tetra- hydro-2-oxo-1-(phenylmethyl)-1H-1-benzazepin-3 yl]-butanamide 4. 3-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-1- (phenylmethyl)-1H-1-benzazepin-2-one 5. 2-Benzyloxycarbonylamino-2-methyl-N-[2,3,4,5 tetrahydro-2-oxo-1-(phenylmethyl)-1H-1-benzazepin 3-yl)-propanamide 6. 3-Benzyloxycarbonylamino-3-methyl-N-r2.3,4,5- tetrahydro-2-oxo-1-(phenylmethyl)-1H-1-benzazepin 3-yl]-butanamide 7. 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1-[(1 naphthyl)methyl]-1H-1-benzazepin-2-one 8. 2-t-Butoxycarbonylamino-2-methyl-N-[2,3,4,5-tetra- hydro-2-oxo-1-( (l-naphthyl )methyl)-lH-l- benzazepin-3-yl]-propanamide 9. 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetra hydro-2-oxo-1-[(1-naphtyl)methyl]-1H-1 benzazepin-3-yl]-butanamide 10. 3-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-1 [(1-naphthyl)methyl]-1H-1-benzazepin-2-one 11. 2-Benzyloxycarbonylamino-2-methyl-N-F2,3,4,5- tetrahydro-2-oxo-1-((l-naphthyl)methyl]-lH-l- benzazepin-3-yl]-propanamide 12. 3-Benzyloxycarbonylamino-3-methyl-E-t2,3,4,5- tetrahydro-2-oxo-1-[(1-naphthyl)methyl]-1H-1 benzazepin-3-yl)-butanamide 13. 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1- [[[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin 2-one 14. 2-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetra hydro-2-oxo-1-[[[1,1'-biphenyl)-4-yl]methyl]-1H 1-benzazepin-3-yl]-propanamide 15. 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetra hydro-2-oxo-1-[[[1,1'-biphenyl]-4-yl]methyl]-1H l-benzazepin-3-yl]-butanamide 16. 3-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-1- [[[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin 2-one 17. 2-Benzylexycarbonylamino-2-methyl-N-t2,3,4,5- tetrahydro-2-oxo-1-[[[1,1'-biphenyl]-4-yl]methyl] lH-l-benzazepin-3-yl]-propanamide 18. 3-Benzyloxycarbonylamino-3-methyl-N-t2,3,4,5- tetrahydro-2-oxo-1-[[[1,1'-biphenyl]-4-yl]methyl] lH-l-benzazepin-3-yl]-butanamide 19. 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1-[(1H indole-3-yl)methyl]-1H-1-benzazepin-2-one 20. 2-t-Butoxycarbonylamino-2-methyl-N-t2,3,4,5-tetra- hydro-2-oxo-1-[1H-indole-3-yl)methyl]-1H-1 benzazepin-3-yl]-propanamide 21. 3-t-Butoxy-carbonylamino-3-methyl-N-t2,3,4,5-tetra- hydro-2-oxo-1-[1H-indole-3-yl)methyl]-1H-1 benzazepin-3-yl]-butanamide 22. 3-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-1 [(1H-indole-3-yl)methyl]-1H-1-benzazepin-2-one 23. 2-Benzyloxycarbonylamino-2-methyl-N-[2,3,4,5 tetrahydro-2-oxo-1-[(1H-indole-3-yl)methyl]-1H-1 benzazepin-3-yl]-propanamide 24. 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5 tetrahydro-2-oxo-1-[(1H-indole-3-yl)methyl]-1H-1 benzazepin-3-yl] -butanamide 25. 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-5- (phenylmethyl)-1,5-benzothiazepin-4-one 26. 2-t-Butoxycarbonylamino-2-methyl-N-[2,3,4,5-tetra hydro-4-oxo-5-(phenylmethyl)-1,5-benzothiazepin-3 yl] -propanamide 27. 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetra hydro-4-oxo-5-(phenylmethyl)-1,5-benzothiazepin-3 yl]-butanamide 28. 3-Benzyloxycarbonylamino-2, 3,4, 5-tetrahydro-5- (phenylmethyl)-1,5-benzothiazepin-4-one 29. 2-Benzyloxycarbonylamino-2-methyl-N-[2,3,4,5 tetrahydro-4-oxo-5-(phenylmethyl)-1,5-benzothi azepin-3-yl3-propanamide 30. 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5 tetrahydro-4-oxo-5-(phenylmethyl)-1,5-benzothi azepin-3-yl]-butanamide 31. 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-5-t(1- naphthyl)methyl]-1,5-benzothiazepin-4-one 32. 2-t-Butoxycarbonylamino-2-methyl-N-[2,3,4,5-tetra hydro-4-oxo-5-t(l-naphthyl)methyl]-1,5-benzothi- azepin-3-yl]-propanamide 33. 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetra hydro-4-oxo-5-[(1-naphthyl)methyl]-1,5-benzothi azepin-3-yl-butanamide 34. 3-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-5-[(1- naphthyl)methyl]-1,5-benzothiazepin-4-one 35. 2-Benzyloxycarbonylamino-2-methyl-N-[2,3,4,5 tetrahydro-4-oxo-5-[(1-naphthyl)methyl]-1,5-benzo thiazepin-3-yl] -propanamide 36. 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5 tetrahydro-4-oxo-5-t(l-naphthyl)methyl3-1,5-benzo- thiazepin-3-yl]-butanamide 37. 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-5- [[[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin 4-one 38. 2-t-Butoxycarbonylamino-2-methyl-N-[2,3,4,5-tetra hydro-4-oxo-5-[[[1,1'-biphenyl]-4-yl]methyl]-1,5 benzothiazepin-3-yl]-propanamide 39. 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetra hydro-4-oxo-5-[[[1,1'-biphenyl]-4-yl]methyl]-1,5 benzothiazepin-3-yl]-butanamide 40. 3-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-5 [[[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin 4-one 41. 2-Benzyloxycarbonylamino-2-methyl-N-[2,3,4,5 tetrahydro-5-[[[1,1'-biphenyl]-4-yl]methyl] 1,5-benzothiazepin-3-yl]-propanamide 42. 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5 tetrahydro-5-[[[1,1'-biphenyl]-4-yl]methyl] 1,5-benzothiazepin-3-yl]-butanamide 43. 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-5-[(1H indole-3-yl)methyl]-1,5-benzothiazepin-4-one 44. 2-t-Butoxycarbonylamino-2-methyl-N-[2,3,4,5-tetra hydro-4-oxo-5-[(1H-indole-3-yl)methyl]-1,5-benzo thiazepin-3-yl]-propanamide 45. 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetra hydro-4-oxo-5-[(1H-indole-3-yl)methyl]-1,5-benzo thiazepin-3-yl]-butanamide 46. 3-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-5 [(1H-indole-3-yl)methyl]-1,5-benzothiazepin-4-one 47. 2-Benzyloxycarbonylamino-2-methyl-B-[2,3,4,5 tetrahydro-4-oxo-5-[(1H-indole-3-yl)methyl]-1,5 benzothiazepin-3-yl)-propanamide 48. 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5- tetrahydro-4-oxo-5-[(1H-indole-3-yl)methyl]-1,5 benzothiazepin-3-yl)-butanamide The compounds of the instant invention all have at least one asymmetric center as noted by the asterisk in the structural Formula I above.
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 optical isomers or racemic mixtures thereof, be included within the ambit of the instant invention.
The instant compounds may be isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic and the like. In addition, certain compounds containing an acidic function such as a carboxy, can be isolated in the form of their inorganic salt in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
The compounds (I) of the present invention are prepared from aminolactam intermediates such as those of formula II. The preparation of these intermediates is described in the following reaction Schemes.
Benzo-fused lactams 3 wherein the lactam is a seven-membered ring are conveniently prepared from substituted tetralones 2 using known procedures The substituted tetralones are, in some cases, commercially available or are prepared from a suitably substituted derivative of 4-phenylbutyric acid l. Cyclization of 1 can be achieved by a number of methods well known in the literature including treatment with polyphosphoric acid at elevated temperatures as shown in Scheme 1.
SCHEME 1
Conversion of substituted tetralones 2 to benzolactams a can be achieved by a number of methods familiar to those skilled in the art. A suitable method involves the use of hydrazoic acid (Schmidt reaction) to form the substituted benzolactam 3.
Benzo-fused lactams wherein the lactam is an eight-membered ring (6) are prepared as described by D. H. Jones, et al, J. Chem. Soc. C, 2176-2181 (1969) by an analogous series of transformations starting from a substituted derivative of 5-phenylpentanoic acid 4 as shown in Scheme 2.
SCHEME 2
As shown in Scheme 3, 3-aminobenzolactam analogs wherein the lactam is a six-membered ring (11) are prepared from a substituted derivative of 2-nitrobenzyl chloride (or bromide) 7 by the method of A. L. Davis, et al, Arch. Biochem. Biophys, 102, 48-51 (1963) and references cited therein.
SCHEME 3
Conversion of substituted benzo-fused lactams to the requisite 3-amino derivatives can be achieved by a number of methods familiar to those skilled in the art, including those described by Watthey, et al, J. Med. Chem., 28, 1511-1516 (1985) and references cited therein. One common route proceeds via the intermediacy of a 3-halo (chloro, bromo or iodo) intermediate which is subsequently displaced by a nitrogen nucleophile, typically azide. A useful method of forming the 3-iodobenzolactam intermediate 12 involves treating the benzolactam with two equivalents each of iodotrimethylsilane and iodine at low temperature, as illustrated in Scheme 4 for the seven-membered ring analog 3.
SCHEMEM 4
R1 R CH3),SiI, I, (CHF)3N, -1 50C \NA ( C2His ) 3 N, -1 5 C R H O 3 R1 NaN3, DMF, 50-1 50our1 00C R Tetramethyl guanidinium azide, CH2C12 12 p H2, Pt/C p2HN or PPh3, H20 13 pi I NH2 2HO H 'O 14 Elaboration of the iodo-benzolactams to the desired aminolactam intermediates II is achieved by a two-step procedure illustrated in Scheme 4.
Typically, iodo-benzolactams 12 are treated with sodium azide in N,N-dimethylformamide at 50-1000C to give the 3-azido derivatives 13. Alternatively, tetramethylguanidinium azide in a solvent such as methylene chloride can be employed to achieve similar results. Bydrogenation with a metal catalyst, such as platinum on carbon, or alternatively, treatment with triphenylphosphine in wet toluene, results in formation of the amine derivative 14. Formation of the analogous derivatives of the eight-membered benzolactams is also achieved by the routes shown in Scheme 4.
Chiral aminobenzolactams are obtained by resolution of the racemates by classical methods familiar to those skilled in the art. For example, resolution can be achieved by formation of diastereomeric salts of the racemic amines with optically active acids such as D- and L-tartaric acid. Determination of absolute stereochemistry can be achieved in a number of ways including X-ray analysis of a suitable crystalline derivative.
A useful preparation of the chiral intermediate 19 is shown in Scheme 5.
SCHEME 5
Conversion of l-tetralone to the sevenmembered benzolactam 16 is achieved by Beckman rearrangement of the intermediate oxime 15.
Treatment of 16 with iodine and hexamethyldisilazane gives the 3-iodo derivative 17 which is sequentially treated with ammonia and D-tartaric acid to give the diastereomeric D-tartrate salt 18 after recrystallization. Liberation of the free amine 19 is achieved by neutralization of the D-tartrate salt with potassium carbonate followed by extractive isolation.
Intermediates of Formula II wherein X is a sulfur atom are prepared by methods described in the literature and known to those skilled in the art. As illustrated in Scheme 6, the seven-membered ring analog 27 is prepared from a protected derivative of cysteine 21 by the method of Slade, et al, J. Med.
Chem., 28, 1517-1521 (1985) and references cited therein (CBz = benzyloxycarbonyl).
SCHEME 6
SCHEME 6 (CONT'D)
24 m= 0, 25 m= 1, 26 m= 2
27 rn = 0, 28 m = 1, 29 m = 2 Sulfoxide and sulfone intermediates 28 and 29 are prepared by oxidation of 24 with various oxidants such as sodium periodate or meta-chloroperbenzoic acid. Eight-membered ring intermediates of Formula II wherein X is sulfur can be prepared by an analogous route starting from derivatives of homo-cysteine.
Intermediates of Formula II wherein X is an oxygen atom are prepared by methods described in the literature and known to those skilled in the art.
For example, the seven-membered ring analog 31 can be prepared from a substituted derivative of 3-(2-nitrophenoxy)propanoic acid 30 by the method of J. Ott, Arch. Pharm. (Weinheim, Ger.), 323(9), 601-603 (1990).
SCHEME 7
Six-membered ring analogs wherein X is oxygen (33) may be prepared by reaction of a substituted derivative of 2-aminophenol 32 with chloroacetyl chloride by the method of U.uang and Chan, Synthesis, 10, 851 (1984) and references cited therein. Subsequent incorporation of an amino group at the 3 position of either 31 or 33 is achieved by the methods described in Scheme 4.
SCHEME 8
Seven-membered ring analogs of Formula II wherein X is C=O can be prepared from derivatives of tryptophan as described in the Australian Journal of Chemistry, 33, 633-640 (1980). Seven-membered ring analogs of Formula II wherein X is CH=CH can be prepared from the aforementioned analogs wherein X is C=O. Treatment of 34 with chemical reducing agents such as sodium borohydride in a polar solvent such as methanol or ethanol results in reduction to give the secondary alcohol derivative 35 (X=CHOH).
Dehydration of 35 can be achieved by several methods decribed in the literature and familiar to those skilled in the art. For example, treatment of 35 in an inert solvent, such as benzene, with a strong acid such as p-toluenesulfonic acid, will result in dehydration to the unsatured analog 36.
Intermediates of formula II can be further elaborated to new intermediates (formula III) which are substituted on the amino group (Scheme 9).
Reductive alkylation of II with an aldehyde is carried out under conditions known in the art; for example, by catalytic hydrogenation with hydrogen in the presence of platinum, palladium or nickel catalysts or with chemical reducing agents such as sodium cyanoborohydride in an inert solvent such as methanol or ethanol.
SCHEME 9
Intermediates of formula III are converted to new compounds IV as described in the following schemes:
Compounds of formula IV wherein u is 0 are prepared directly from intermediates of formula III by the following procedures. As shown in Scheme 10, amide compounds 37 are prepared by the reaction of III with a carboxylic acid R9COOH in the presence of a coupling reagent such as benzotriazol-l-yloxytris (dimethylamino)phosphonium hexafluorophosphate ("BOP") in an inert solvent such as methylene chloride.
Separation of unwanted side products and purification of intermediates is achieved by chromatography on silica gel, employing flash chromatography (w.C.
Still, M. Kahn and A. Mitra, J. Org. Chem., 43, 2923, 1978.) or by medium pressure liquid chromatography.
SCHEME 10
R ) O II N-C p NNO p6a 37 R9COOH triethylamne BOP ethylene chloride R1 (X)n < CH2)p RfH O 1l ( III O R9O- C-C1 or :=R90-i \t rie t hylamLne nethylene chloride p CX)n&num;Cfl)p 0 II Run -op9 p 11N0p 38 Reaction of compounds of formula III with the appropriate chloroformate or di carbonate reagents affords carbamate derivatives 38. For example, N-tbutoxycarbonyl (BOC) derivatives can be achieved by a number of methods known in the art, such as treatment with di-t-butyl dicarbonate.Benzyloxycarbonyl (CBz) derivatives are obtained by treatment with benzyl chloroformate.
As shown in Scheme 11, compound III can be treated with N,N'-carbonyldiimidazole to form an intermediate which when treated with an amine gives the urea derivative 39. Alternatively, reaction with the isocyanate R9-N=C=O affords a similar product wherein R6b is hydrogen. Reaction of III with sulfonyl chlorides gives sulfonamide products 40.
SCHEME 11
0 P p1 )n&num;CH2)p II 9 i) N--C N R2 H o R6 a R6b 27 3 9 1. N, N -carbonyldiirddazole 2. R9R6bNH /or: R9-N=C=O R1 - 6a H X XNH R6a o 9 S-C1 p2H 0P9- S-Cl III O III rivet t riet hylarrine nethylene chloride p CX)nCH2)p 0 II I N-S pg p2NH0p6a0I 40 Sulfamide derivatives 42 are prepared.from the appropriate amine by initial formation of a sulfamoyl chloride reagent 41 as shown in Scheme 12.
Reaction of 41 with compounds of formula III gives the desired sulfamide products.
SCHEME 12
0 II R6bR9NH + ClSO3H r R6bR9N-S-Cl II 0 41 0 -Il III + R6bR9N-S-cl II O t riet hylarrLne 41 ethylene chloride pi CX)n&num;CH2)p R6b WN < Ct6e 11 \ 9 Nag 42 Compounds of formula I wherein u is one are prepared from reaction of compounds of formula III with the appropriately protected amino acid derivative V. As illustrated in Scheme 13, the reaction is conveniently carried out in an inert solvent such as methylene chloride in the presence of triethylamine using the previously described coupling reagent BOP.
SCHEME 13 G is t-butoxycarbonyl or benzyloxycarbonyl
R1 ,( x) n cH2) P 8 Re i) NHPa + HO-C-( CH2)x-C-(CH, > , NH-G N P H P6a III BOP t riet hylanine methylene chloride CH2)p P8 H I cH2) x)jca cH2) yNH VI The protected amino acid derivatives V are, in many cases, commercially available in t-butoxycarbonyl (BOC) or benzyloxycarbonyl (CBz) forms. A useful method to prepare the preferred sidechain 47 is shown in Scheme 14.
SCHEME 14
Reaction of isobutylene with N-chlorosulfonylisocyanate 43 in diethyl ether gives the azetidinone derivative 44. Removal of the chlorosulfonyl group with aqueous sodium sulfite followed by reaction with di-t-butyl-dicarbonate gives the BOC-protected intermediate 46. Alkaline hydrolysis gives the protected amino acid derivative 47 in good overall yield.
Intermediate VI is converted to a new.
intermediate VIII by the route shown in Scheme 15.
Removal of the protecting group is achieved by a variety of methods depending on the nature of the group G. For example, t-butoxycarbonyl (BOC) groups can be cleaved by treatment with strong acid such as trifluoroacetic acid or hydrochloric acid, in solvents such as methylene chloride or methanol.
Benzyloxycarbonyl (CBz) groups are liberated by hydrogenolysis in the presence of a metal catalyst, such as palladium on charcoal, in a polar solvent such as methanol or ethanol. It may be appreciated by one skilled in the art that the conditions chosen for removal of the protecting group G must be compatible with other functional groups present. A detailed description of protecting groups may be found in: Protective Groups in Organic Synthesis, T.W. Greene, John Wiley and Sons, New York, 1981.
Reductive alkylation of VII with an aldehyde is then carried out using the aforementioned conditions to give intermediate VIII.
SCHEME 15
VI rensve | group prot ect ing G P1 CX) n CH2) p | p B $ NXNCtCH2)x c CH2) yNH2 N I I H ,6a RBa VII sodium aldehyde, , cyanoborohydride R1 CX)n&num;CH2) Rl 8 R4 ss N-C-C 1 CH2) XCI HzCH2) y NH N 6a Ba R2 H O p VIII G is t-butoxycarbonyl or benzyloxycarbonyl As shown in Scheme 16, amide compounds 48 are prepared by the reaction of VIII with a carboxylic acid R9COOH by the procedure described in Scheme 10.Reaction of compounds of formula VIII with the appropriate chloroformate or dicarbonate reagents affords carbamate derivatives 49.
SCHEMEM 16
R1 (X)ntCH2)p p B R40 0 x-CM o R RB a OH2) R2 I?, OH2) 8a P2 H0Pa p 48 R9COOH triethylaniLne BOP methylene chloride p1 ( X) n( CH2) p O pB p4 N--C OH2) x OH2) RBa VIII O / O\ 0 9 R90-C-Cl or t riet hylanine rrethylene chloride R1 ( X) p C2) p o R 8 l 4 p40 fl2p 0 III 1N N4M CH2) xM OH2) yNC p2 H0pa pSa 49 As shown in Scheme 17, compound VIII can be treated with N,N'-carbonyldiimidazole to form an intermediate which when treated with an amine gives the urea derivative 50. Alternatively, reaction with the isocyanate R9-N=C=O affords a similar product wherein R6b is hydrogen. Reaction of VIII with sulfonyl chlorides gives sulfonamide products 51.
SCHEME 17
R1 CX)nCOH)p o P8 8 P40 N II I I IlN/P --0 MC H2) -NC N T-C HzC, 2 x C HzC2) y p 0R16a pBa p6b SO 1. N, Nl -carbonyldiinidazole 2. R9R6bNH or: R9-N=C=O R1 ( X) n( CH ) p O 1 8 R 4 y NX | x | P CH2gY M0:i;MCH) xD OH2) 1 VIII 0 p9 R9-S-Cl II 0 triet hylaniine nst hylene chloride R' Cj()n 0 PO R8 II I I II OH2) x-CM OH2) -p p2N0pIa l(CH2)y N 1I 51 Sulfamide derivatives 52 are prepared.from the appropriate amine by initial formation of a sulfamoyl chloride reagent 41 as shown in Scheme 18.
Reaction of 41 with compounds of formula VIII gives the desired sulfamide products 52.
SCHEME 18
0 II R6bRNH + ClSO3H > R6bR95-s-cl II o 41 o II VIII + R6bR9N-S-Cl Ii triethylanine 0 41 rTet hylene chloride CX)n&num;OE)p 0 pB P 0 6b iNNL{ I OH2) -,CH,) yNS -N NIa Sa g pH0P 0 52 Compounds of formula I are prepared as shown in Scheme 19 by treatment of the desired lactam intermediate IV with an alkylating agent IX, wherein Y is a good leaving group such as C1, Br, I, O-methanesulfonyl or O-(p-toluenesulfonyl).
Alkylation is conveniently carried out in anhydrous dimethylformamide (DMF) in the presence of strong bases such as sodium hydride or potassium t-butoxide for a period of 0.5 to 24 hours at temperatures of 0C to 100"C. Substituents on the alkylating agent IX may need to be protected during alkylation; a full description of available protecting groups is found in Protective Groups in Organic Svnthesis.
SCHEME 19
R1 C X)nZC CH2) p u y < > N-(A)u R5 ,6a 1. sodium hydride dinethylfornanLde 2. R3CL)wCO2)qY IX p C X) nY CH2) p I)N&num; N-(A)u R p2Nj ( CH2) ( I p Alkylating agents IX are, in most cases, commercially available compounds or can easily be synthesized from readily available intermediates by one skilled in the art. Compounds of formula I containing the (lH-indol-3-yl)methyl substituent (22), are prepared by alkylation of intermediate IV with 3-(dimethylaminomethyl)indole, as illustrated in Scheme 20.
SCHEME 20
R1 (X)n ( CH2)p ss N&num;A)uP5 P H IV 1. sodium hydride dinet hylf orrzrrn de 2. N(CH3)2 NINTH H s R1 x > X)n&num;CH2)p f ci' 1N N&num; A) -5 R2 | O R NH ANH 53 It is noted that the order of carrying.out the foregoing reaction schemes is not significant and it is within the skill of one skilled in the art to vary the order of reactions to facilitate the reaction or to avoid unwanted reaction products.
The growth hormone inhibiting compounds of Formula I are useful in vitro as unique tools for understanding how growth hormone secretion is regulated at the pituitary level. This includes use in the evaluation of many factors thought or known to influence growth hormone secretion such as age, sex, nutritional factors, glucose, amino acids, fatty acids, as well as fasting and non-fasting states. In addition, the compounds of this invention can be used in the evaluation of how other hormones modify growth hormone releasing activity. For example, it has already been established that somatostatin inhibits growth hormone release.Other hormones that are important and in need of study as to their effect on growth hormone release include the gonadal hormones, e.g., testosterone, estradiol, and progesterone; the adrenal hormones, e.g., cortisol and other corticoids, epinephrine and norepinephrine; the pancreatic and gastrointestinal hormones, e.g., insulin, glucagon, gastrin, secretin; the vasoactive intestinal peptides, e.g., bombesin; and the thyroid hormones, e.g., thyroxine and triiodothyronine. The compounds of Formula I can also be employed to investigate the possible negative or positive feedback effects of some of the pituitary hormones, e.g., growth hormone and endorphin peptides, on the pituitary to modify growth hormone release. Of particular scientific importance is the use of these compounds to elucidate the subcellular mechanisms mediating the release of growth hormone.
The compounds of Formula I can be administered to animals, including man, to inhibit the release of growth hormone in vivo. The compounds of Formula I can be administered in combination with the GHRP-6 antagonist His-D-Trp-D-Lys-Trp-D-Phe-Lys-NE2 or somatostatin analogs to inhibit the release of growth hormone in vivo. Examples of such somatostatin analogs include stilamine and sandostatin&commat;.
Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of Formula I in association with a pharmaceutical carrier or diluent. Optionally, the active ingredient of the pharmaceutical compositions can comprise a growth hormone inhibiting agent such as somatostatin or an analog thereof, in addition to at least one of the compounds of Formula I or another composition which exhibits a different activity, e.g., an antibiotic or other pharmaceutically active material.
The compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated in dosage forms appropriate for each route of administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.
Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.
Generally, dosage levels of between 0.0001 to 100 mg/kg. of body weight daily are administered to patients and animals, e.g., mammals, to obtain effective inhibition of growth hormone.
The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.
EXAMPLE 1 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1-(phenyl- methvl)-lH-l-benzazepin-2-one Step A: 3-Amino-2,3,4,5-tetrahydro-lH-l-benzazepin- 2-one A solution of 9.22 g (45.6 mol) of 3-azido2,3,4.5-tetrahydro-1H-1-benzazepin-2-one (prepared by the method of Watthey, et al., J. Med. Chem., 28, 1511-1516 (1985)) in 30 mL methanol was hydrogenated at 40psi in the presence of 1.0 g of 5% Pt/C for 4.5 hours. Celite was added and the mixture filtered through a pad of Celite. The filtrate was concentrated and allowed to stand for 16 hours at room temperature which resulted in formation of crystals. The material was isolated by filtration and dried under vacuum to afford 4.18 g (23.7 mmol, 52%) of the product.The mother liquors were diluted to 100 mL with methanol, treated with 2 g of charcoal, filtered through Celite and the filtrate concentrated under vacuum to approximately 15 mL. A second crop formed yielding 2.02 g of product (11.5 mmol, 25%). Another recycling of the mother liquors afforded a third crop of 0.88 g (5.0, 11%). A total of 7.08 g (40.2 mmol, 88%) of the product was thus obtained. 1H NMR (200MHz, CDC13): 1.6 (br s, 2H), 1.80 (m, 1H), 2.55 (m, 2H), 2.88 (m, 1H), 3.42 (dd; 7Hz, 11Hz; 1H), 6.98 (d, 8Hz, 1H), 7.2 (m, 3H), 8.3 (br s, 1H). FAB-MS: calculated for C10H12N20 176; found 177 (M+H, 100%).
Step 3: 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro- lH-l-benzazepin-2-one To a solution of 755 mg (4.28 mmol) of 3-amion-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one in 5 mL of methylene chloride at room temperature was added 1.3 mL (1.24 g, 5.66 mmol, 1.3 eq) of di-t-butyl dicarbonate followed by 0.75 mL (0.56 g, 4.3 mmol, 1.0 eq) of diisopropylethylamine. The mixture was stirred for 2 hours at room temperature, then diluted with 50 mL of ethyl acetate and washed with 5% aqueous citric acid (2x) and saturated aqueous sodium chloride. The organic layer was separated, dried over magnesium sulfate, filtered and solvents removed under vacuum.The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (2:1), to give 1.022 g (3.70 mmol 86%) of the product as a white powder. 1H NMR (200MHz, CDC13): 1.40 (s, 9H), 2.00 (m, 1H), 2.65 (m, 2H), 2.95 (m, 1H), 4.29 (m, 1H), 5.42 (br d, 8Hz, 1H), 6.97 (d, 7Hz, 1H), 7.2 (m, 3H), 7.50 (br s, 1H). FAB-MS: calculated for C15H20N203 276; found 277 (M+1, 40%).
Step C: 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro 1-(phenylmethyl)-1H-1-benzazepin-2-one To a solution of 150 mg (0.54 mmol) of 3-t butogycarbonylamino-2,3,4,5-tetrahydro-15-1-benzaze- pin-2-one in 0.5 mL of dry dimethylformamide at room temperature under nitrogen was added 28 mg of 60% sodium hydride oil dispersion (17 mg NaH, 0.70 mmol, 1.3 eq). After 15 minutes, 0.077 mL of benzyl bromide was added and the mixture stirred for 2 hours at room temperature, then added to 30 mL of ethyl acetate and washed with water (2x) and brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum.
The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (1:1), to afford 190 mg (0.52 mmol, 95%) of the title compound. 1H NMR (200MHz, CDCl3): 1.38 (s, 9H), 1.90 (m, 1H), 2.35-2.55 (m, 3H), 4.25 (m, 1H), 4.83 (d, 15Hz, 1H), 5.21 (d, 15Hz, 1H), 5.53 (d, 7Hz, 1H), 7.19 (m, 2H), 7.2 (m, 7H).
FAB-MS: calculated for C22H26N203 366; found 367 (M+1, 23%).
EXAMPLE 2 3(R)-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1- (phenylmethyl)-1H-1-benzazepin-2-one Step A: 3(R)-Amino-2,3,4,5-tetrahydro-1H-1-benzaze p in-2-one A mixture of 2.37g (13.5 mmol) of 3-amino 2,3,4,5-tetrahydro-lH-l-benzazepin-2-one example 1, Step A) and 2.02 g (13.5 mmol) of L-tartaric acid were suspended in 40 mL of ethanol. The mixture was gently heated and complete dissolution achieved by dropwise addition of 5 mL of distilled water. The solution was cooled to room temperature and aged overnight. The solid that formed was removed by filtration, washed with ethanol/diethyl ether (1:1) and dried under vacuum to afford 1.75 g of crude L-tartrate salt.The mother liquors were evaporated to dryness under vacuum, redissolved in 40 mL of water and the pH adjusted to 10-11 by the addition of solid potassium carbonate. The mixture was extracted with chloroform (6x20 mL) and the combined extracts washed with water (lx) and brine (1x), dried over potassium carbonate, filtered and solvents removed under vacuum to afford 1.29 g (7.33 mmol) of partially enriched 3(R) amine.
The original 1.75 g batch of L-tartrate salt was recrystallized twice from aqueous ethanol to afford 1.03 g (3.17mmol, 24%) of purified L-tartrate salt with [&alpha;]D=-212 (c=l, H2O). The purified L-tartrate salt was dissolved in 20 mL of water and the pH adjusted to 10-11 by the addition of solid potassium carbonate. The mixture was extracted with chloroform (5x10 mL); combined extracts were washed with water and brine then dried over potassium carbonate, filtered and solvents removed under vacuum to afford 522 mg (2.96 mmol, 22% overall) of the 3(S) amine, [&alpha;]D=-446 (c=l, CH30H).
The remaining 1.29 g (7.33 mmol) of partially enriched 3(R) amine was treated with 1.10 g (7.33 mmol) of D-tartaric acid as described above and the resulting salt recrystallized twice from aqueous ethanol to afford 1.20 g of purified D-tartrate salt, Fc']D=+2140 (c=l, H20). The purified D-tartrate salt was dissolved in 20 mL of water and the free base isolated as described above to give 629 mg (3.57 mmol, 26% overall) of the 3(R) amine, [&alpha;]D=+455 (c=1, CH3OH).
Step B: 3(R)-t-Butoxycarbonylamino-2,3,4,5-tetra hydro-1-(phenylmethyl)-1H-1-benzazepin-2-one The title compound was prepared from 3(R)- amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one by the methods described in Example 1, Steps B and C. 1H NMR (200MHz, CDCl3): 1.38 (s, 9H), 1.88 (m, 1H), 2.45 (m, 3H), 4.24 (m, 1H), 4.83 (d, 15Hz, 1H), 5.21 (d, 15Hz, 1H), 5.45 (d, 7Hz, 1H), 7.18 (m, 2H), 7.2 (m, 7H). FAB-MS: calculated for C22H26N203 366; found 367 M+1, 457.). [&alpha;]D +172 (c=1.01, CHC13).
EXAMPLE 3 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1-[[[1,1'biphenyl]-4-yl]methyl]-1H-1-benzazepin-2-one The title compound was prepared from 3-t-butoxycarbonylamino-2,3,4,5-tetrahydro-1H-1benzazepin-2-one (Example 1, Step B) and 4-chloromethyl-l,l'-biphenyl by the procedure described in Example 1, Step C. 1H NMR (200MHz, CDC13): 1.41 (s, 9H), 1.91 (m, 1H), 2.40-2.60 (m, 3H), 4.30 (m, 1H), 4.91 (d, 15Hz, 1H), 5.23 (d, 15Hz, 1H), 5.47 (d, 7Hz, 1H), 7.14 (m, 2H), 7.20-7.55 (m, llH).
FAB-MS: calculated for C28H30N203 442; found 443 (M+1, 33%).
EXAMPLE 4 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-(phenylmethyl)-1H-1-benzazepin-3-yl]butanamide Step A: 2.2-I)imethylbutanedioic acid. 4-methyl ester 2,2-Dimethylsuccinic acid (20 g, 137 mmol) dissolved in 200 mL of absolute methanol at 0 was treated dropwise with 2 mL of concentrated sulfuric acid. After the addition was complete, the mixture was allowed to warm to room temperature and stir for 16 hours. The mixture was concentrated under vacuum to 50 mL and slowly treated with 200 mL of saturated aqueous sodium bicarbonate. The mixture was washed with hexane (3x) and the aqueous layer removed and cooled in an ice bath. The mixture was acidified to pH 2 by slow addition of 6N HC1 then extracted with ether (8x).The combined extracts were washed with brine, dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was dried at room temperature under vacuum to afford 14.7 g (91.8 mmol, 67%) of the product as a viscous oil that slowly solidified upon standing. 1H NMR (200MEz, CDCl3): 1.29 (s, 6H), 2.60 (s, 2H), 3.65 (s, 3H).
Step B: Methyl 3-benzyloxycarbonylamino-3-methyl butanoate To 14.7 g (91.8 mmol) of 2,2-dimethylbutanedioic acid-4-methyl ester in 150 mL of benzene was added 13 mL of triethylamine (9.4 g, 93 mmol, 1.01 eq) followed by 21.8 mL of diphenylphosphoryl azide (27.8 g, 101 nimol, 1.1 eq). The mixture was heated under nitrogen at reflux for 45 minutes then 19 mL (19.9 g, 184 mmol, 2 eq) of benzyl alcohol was added and refluxing continued for 16 hours.
The mixture was cooled, filtered and the filtrate concentrated to a minimum volume under vacuum. The residue was redissolved in 250 mL of ethyl acetate, washed with water, saturated aqueous sodium bicarbonate (2x) and brine. The organic layer was removed, dried over magnesium sulfate, filtered and the filtrate concentrated to a minimum volume under vacuum. The crude product was purified by medium pressure liquid chromatography on silica, eluting with hexane/ethyl acetate (4:1), to afford 18.27 g (68.9 mmol, 75%) of the product. 1H NMR (200MHz, CDC13): 1.40 (s, 6H), 2.69 (s, 2H), 3.63 (s, 3H), 5.05 (s, 2H), 5.22 (br s, 1H), 7.32 (s, 5H).
Step C: 3-Benzyloxycarbonylamino-3-methylbutanoic acid A solution of 18.27 g (68.9 mmol) of methyl 3-benzyloxycarbonylamino-3-methylbutanoate in 20 mL of methanol at room temperature was treated dropwise with 51 mL of 2N NaOH (102 mmol, 1.5 eq). The mixture was stirred at room temperature for 16 hours then transferred to a separatory funnel and washed with hexane (3x).The aqueous layer was removed, cooled to 0 and slowly acidified to pH 2 (paper) by dropwise addition of 6N HC1. This mixture was extracted with ether (6x); combined extracts were washed with 1N HCl and brine, then dried over magnesium sulfate, filtered and solvent removed under vacuum to afford 17.26 g (68.7 mmol, 99%) of the product. 1H NMR (200MHz, CDCl3): 1.42 (s, 6H), 2.77 (s, 2H), 5.06 (s, 2H), 5.2 (br s, 1H), 7.3 (s, 5H).
Step D: 3-Amino-2,3,4,5-tetrahydro-1-(phenylmethyl) lH-l-benzazepin-2-one. hydrochloride A solution of 132 mg (0.36 mmol) of 3-t-butoxycarbonylamino-2,3,4,5-tetrahydro-1-(phenyl- methyl)-1H-1-benzazepin-2-one example 1) in 2 mL of methylene chloride at room temperature was treated with 2 mL of trifluoroacetic acid and the resulting mixture stirred for three hours. All volatiles were removed under vacuum and the residue dried under vacuum for 48 hours.
The residue was evaporated several times from aqueous 6N hydrochloric acid to give 110 mg (0.36 mmol, 100%) of the product as a white solid.
1H NMR (200MHz, CD30D): 2.18 (m, 1H), 2.49 (m, 3H), 3.81 (m, 1H), 4.79 (d, 15Hz, 1H), 5.37 (d, 15Hz, lH), 7.13 (br s, 7H), 7.33 (m, 2H). FAB-MS: calculated for C17H18N2O 266; found 267 (M+1, 100%).
Step E: 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5 tetrahydro-2-oxo-1-(phenylmethyl)-1H-1-benz azepin-3-yll-butanamide To a solution of 98 mg (0.32 mmol) of 3-amino-2,3,4,5-tetrahydro-1-(phenylmethyl)-lH-l- benzazepin-2-one, hydrochloride in 2 mL of methylene chloride at 0 C was added 100 mg (0.40 =01, 1.2 eq) of 3-benzyloxycarbonylamino-3-methylbutanoic acid, 0.17 mL (126 mg, 0.98 mmol, 3eq) of diisopropylethylamine and 210 mg (0.48 =ol, 1.5 eq) of benzotriazoll-yloxytris(dimethylamino)phosphonium hexafluorophosphate. The mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was diluted into 50 mL of ethyl acetate and washed twice with water and once with saturated aqueous sodium chloride.The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (1:1) to give 149 mg (0.30 mmol, 92%) of the title compound as a white foam.
1H NMR (200MHz, CDC13): 1.38 (s, 3H), 1.39 (s, 3H), 1.74 (m, 1H), 2.48 (s, 2H), 2.3-2.6 (m, 3H), 4.49 (m, 1H), 4.80 (d, 15Hz, 1H), 5.07 (br s, 2H), 5.25 (d, 15Hz, 1H), 5.55 (br s, 1H), 6.69 (d, 7Hz, 1H), 7.1-7.4 (m, 14H). FAB-MS: calculated for C30H33N304 499; found 500 (M+H, 100%).
EXAMPLE 5 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-(phenylmethyl)-1H-1-benzazepin-3(R)yl]-butanamide Step A: 3-Benzyloxycarbonylamino-3-methyl-N [2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin 3(R)-vll-butanamide To a solution of 252 mg (1.43 mmol) of 3(R)- amino-2,3,4,5-tetrahydro-lH-l-benzazepin-2-one example 2, Step A) in 4 mL of methylene chloride at room temperature was added 400 mg (1.60 mmol, 1.1 eq) of 3-benzyloxycarbonylamino-3-methylbutanoic acid followed by 760 mg (1.7 mmol, 1.2 eq) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphate and 0.50 mL of diisopropylethylamine (380 mg, 2.9 =ol, 2 eq).After 3 hours at room temperature, the mixture was diluted into 30 mL of ethyl acetate and washed with 5% aqueous citric acid, saturated aqueous sodium bicarbonate (2x) and brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate to afford 586 mg (1.43 mmol, 100%) of the product. 1H NMR (200MHz, CDC13): 1.38 (s, 3H), 1.39 (s, 3H), 1.82 (m, 1H), 2.52 (s, 2H), 2.5-3.0 (m, 3H), 4.51 (m, 1H), 5.07 (br s, 2H), 5.57 (br s, lH), 6.68 (d, 7Hz, 1H), 6.97 (d, 8Hz, lH), 7.1-7.4 (m, 8H), 7.61 (br s, 1H). FAB-MS: calculated for C23H27N304 409; found 410 (M+H, 100%).
Step B: 3-Benzyloxycarbonylamino-3-methyl-N [2,3,4,5-tetrahydro-2-oxo-1-(phenylmethyl) 1H-1-benzazepin-3(R)-yl]-butanamide The title compound was prepared from 3-benzyloxycarbonylamino-3-methyl-N-t2,3,4,5-tetra- hydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide and benzyl bromide by the procedure described in Example 1, Step C. 1H NMR (200MHz, CDCl3): 1.37 (s, 3H), 1.39 (s, 3H), 1.74 (m, 1H), 2.3-2.6 (m, 3H), 2.49 (s, 2H), 4.49 (m, 1H), 4.79 (d, 15Hz, 1H), 5.06 (br s, 2H), 5.25 (d, 15Hz, 1H), 5.63 (br s, 1H), 6.67 (d, 7Hz, lH), 7.1-7.4 (m, 14H). FAB-MS: calculated for C30H33N304 499; found 500 (M+H, 100%).
EXAMPLE 6 3-Benzyloxycarbonylamino-3-methyl-N-E2,3,4,5-tetra- hydro-2-oxo-1-[(1-naphthyl)methyl]-1H-1-benzazepin 3-vll-butanamide Step A: 3-Benzyloxycarbonylamino-3-methyl-N [2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin 3-yl]-butanamide Prepared from 3-amino-2,3,4,5-tetrahydro1H-1-benzazepin-2-one example 1, Step A) and 3-benzyloxycarbonylamino-3-methylbutanoic acid by the procedure described in Example 5, Step A. 1H NMR (200MHz, CDCl3): 1.38 (s, 3H), 1.39 (s, 3H), 1.82 (m, 1H), 2.52 (s, 2H), 2.5-3.0 (m, 3H), 4.51 (m, 1H), 5.07 (br s, 2H), 5.58 Cbr s, 1H), 6.68 (d, 7Hz, 1H), 6.96 (d, 8Hz, 1H), 7.1-7.4 (m, 8H), 7.62 (br s,.
1H). FAB-MS: calculated for C23H27N304 409; found 410 (M+H, 100%).
Step B: 3-Benzyloxycarbonylamino-3-methyl-N [2,3,4,5-tetrahydro-2-oxo-1-[(1-naphthyl) methyl]-1H-1-benzazepin-3-yl]-butanamide The title compound was prepared from 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-butanamide l-(bromomethyl)naphthalene by the procedure described in Example 1, Step C. 1H NMR (200MHz, CDCl3): 1.38 (s, 3H), 1.40 (s, 3H), 1.73 (m, 1H), 2.2-2.6 (m, 3H), 2.50 (s, 2H), 4.54 (m, 1H), 5.06 (br s, 2H), 5.24 (d, 15Hz, 1H), 5.68 (s, 1H), 5.79 (d, 15Hz, 1H), 6.75 (d, 7Hz, 1H), 7.0-7.2 (m, 2H), 7.2-7.4 (m, 9H), 7.48 (m, 2H), 7.72 (m, 1H), 7.82 (m, 1H), 8.08 (m, 1H).
FAB-MS: calculated for C34H35N304 549; found 550 (M+H, 100%).
EXAMPLE 7 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[(1H-indole-3-yl)methyl]-1H-1-benzaze pin-3-vll-butanamide A solution of 24 mg (0.058 mmol) of 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2oxo-1H-1-benzazepin-3-yl]-butanamide in 2 mL of t butyl alcohol was treated with 10mg (0.058 mmol) of 3-(dimethylaminomethyl)indole followed by 6.5 mg (0.058 mmol) of potassium t-butoxide. The mixture was stirred at room temperature for 1 hour then heated at 60 C for 16 hours. The mixture was cooled, diluted with 20 mL of ethyl acetate, and washed with water and saturated aqueous sodium chloride. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum.
The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate, to give 9 mg (0.016 mmol, 28%) of the title compound. 1H NMR (200MHz, CDC13): 1.37 (s, 3H), 1.40 (s, 3H), 2.1-2.6 (m, 4H), 2.50 (s, 2H), 4.48 (m, 1H), 4.79 (d, 15Hz, 1H), 5.07 (br s, 2H), 5.64 (d, 15Hz, 1H), 5.69 (s, 1H), 6.73 (d, 7Hz, 1H), 7.0-7.2 (m, 4H), 7.2-7.45 (m, 9H), 7.98 9br s, 1H). FAB-MS: calculated for C32H34N404 538; found 539 M+1, 45%).
EXAMPLE 8 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-(phenylmethyl)-1,5-benzothiazepin-3 vll-butanamide Step A: 4. 4-Dimethylazetidin-2-one A 3-neck 3 L round bottom flask equipped with a magnetic stirrer, thermometer, cold finger condenser and nitrogen bubbler was charged with 1 L of ether. The flask was cooled to -65 C and into it was condensed 500-600 mL of isobutylene. The cold finger condenser was replaced with a dropping funnel and 200 mL (325 g, 2.30 mol) of chlorosulfonyl isocyanate was added dropwise over 1.5 hours.The mixture was maintained at -65 C for 1.5 hours then the dry ice/acetone cooling bath replaced with methanol/ice and the internal temperature slowly increased to -5 C at which time the reaction initiated and the internal temperature rose to 15"C with evolution of gas. The internal temperature remained at 15"C for several minutes then dropped back down to -5 C and the mixture stirred at -5 C for 1 hour. The methanol/ice bath was removed and the reaction mixture warmed to room temperature and stirred overnight.
The reaction mixture was transferred to a 3-neck 12 L round bottom flask fitted with a mechanical stirrer and diluted with 2 L of ether.
The well stirred reaction mixture was treated with 2 L of saturated aqueous sodium sulfite. After 1 hour, an additional 1 L of saturated aqueous sodium sulfite was added followed by sufficient sodium bicarbonate to adjust the pH to approximately 7. The mixture was stirred another 30 minutes then the layers allowed to separate. The ether layer was removed and the aqueous layer reextracted with 2x1 L of ether. The combined ether extracts were washed once with 500 mL of saturated aqueous sodium bicarbonate and once with 500 mL of saturated aqueous sodium chloride. The ether layer was removed, dried over magnesium sulfate, filtered and concentrated under vacuum to give 33 g of a pale yellow oil. The aqueous layer was made basic by the addition of solid sodium bicarbonate and extracted with 3x1 L of ether.The combined ether extracts were washed and dried as described above, then combined with the originaL 33 g of pale yellow oil and concentrated under vacuum to give 67.7 g of product. Further extraction of the aqueous layer with 4x1 L of methylene chloride and washing and drying as before gave an additional 74.1 g of product. Still further extraction of the aqueous layer with 4xl L of methylene chloride gave an additional 21.9 g of product. The combined product (163.7 g, 1.65 mol, 72%) was used in Step B without purification. 1E NMR -(200MHz, CDC13): 1.45 (s, 6H), 2.75 (d, 3Hz, 2H), 5.9 (br s, 1H).
Step B: N-(t-Butoxycarbonyl)-4,4-dimethylazetidin- 2-one A 5 L, 3-neck round bottom flask equipped with a magnetic stirrer, thermometer, nitrogen bubbler and addition funnel was charged with 88.2 g (0.89 mol) of 4,4-dimethylazetidin-2-one, 800 mL of methylene chloride, 150 mL of triethylamine (1.08 mol) and 10.9 g (0.089 mol) of 4-dimethylaminopyridine. To the stirred solution at room temperature was added dropwise over 15 minutes a solution of 235 g (1.077 mol) of di-t-butyldicarbonate in 300 mL of methylene chloride. The reaction mixture was stirred at room temperature overnight then diluted with 1 L of methylene chloride and washed with 500 mL of saturated aqueous ammonium chloride, 500 mL of water, and 500 mL of saturated aqueous sodium chloride. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under vacuum to afford 180.3 g of crude product as an orange solid. The material was used directly in Step C without purification. 1H NMR (200MHz, CDC13): 1.50 (s, 9H), 1.54 (s, 6H), 2.77 (s, 2H).
Step C: 3-t-Butoxycarbonylamino-3-methylbutanoic acid A 3 L, 3-neck round bottom flask equipped with a magnetic stirrer, thermometer, nitrogen bubbler and addition funnel was charged with 180.3 g CO .89 mol) of N-(t-butoxycarbonyl)-4,4-dimethylazetidin-2-one dissolved in 1 L of tetrahydrofuran.
The solution was cooled to 0-5"C and treated dropwise with 890 mL of 1.0 M aqueous lithium hydroxide over 30 minutes. The reaction mixture was stirred at 0-5"C for 2 hours then diluted with 1 L of ether and 1 L of water. The layers were allowed to separate and the aqueous layer reextracted with an additional 1 L of ether. The aqueous layer was acidified by the addition of 1 L of saturated aqueous sodium bisulfate, then extracted with lxl L and 2x500 mL of ether. The combined organic layer and ether extracts were washed with 500 mL of saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under vacuum to 173 g of a yellow oil that solidified upon standing.The material was slurried with warm hexane then filtered and dried under high vacuum to afford 168.5 g (0.775 mol, 87%) of product as a white solid. 1H NMR (200MEz, CDC13): 1.39 (s, 6H), 1.44 (s, 9H), 2.72 (s, 2H).
FAB-MS: calculated for C10H19N04 217; found 218 (M+H, 54%).
Step D: 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5 tetrahydro-4-oxo-1,5-benzothiazepin-3(S) yli-butanamide Prepared from 3(S)-amino-2,3-dihydro-1,5benzothiazepin-4(5H)-one prepared from D-cysteine by the method of Slade, et al, J. Med. Chem., 28, 1517-1521 (1985)) and 3-t-butoxycarbonylamino-3methylbutanoic acid by the procedure described in Example 5, Step A. 1H NMR (200MHz, CDC13): 1.38 (s, 6H), 1.45 (s, 9H), 2.32 (d, 10Hz, 1H), 2.50 (d, 14Hz, 1H), 2.70 (d, 14Hz, 1H), 2.92 (t, 11Hz, 1H), 3.93 (dd; 7, 11Hz; 1H), 4.76 (m, 1H), 7.02 (d, 8Hz, 1H), 7.1-7.3 (m, 2H), 7.40 (t, 8Hz, 1H), 7.66 (d, 7Hz, 1H), 8.23 (br s, 1H). FAB-MS: calculated for C19H27N3O4S 393; found 394 (M+1, 36%).
Step D: 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5 tetrahydro-4-oxo-1,5-(phenylmethyl)-1,5-benzo thiazepin-3-vll-butanamide The title compound is prepared from 3-t-butoxycarbonylamino-3-methyl-N-E2,3,4,5-tetra- hydro-4-oxo-1,5-benzothiazepin-3(S)-yl]-butanamide and benzyl bromide by the procedure described in Example 1, Step C.
EXAMPLE 9 3-t-Butoxycarbonylamino-3-methyl-N-E2,3,4,5-tetra- hydro-4-oxo-5-[(1-naphthyl)methyl]-1,5-benzothiazepin-3(S)-yl]-butanamide The title compound is prepared from 3-t-butoxycarbonylamino-3-methyl]-N-[2,3,4,5]-tetra hydro-4-oxo-1,5-benzothiazepin-3(S)-yl]-butanamide and l-(bromomethyl)naphthalene by the procedure described in Example 1, Step C.
EXAMPLE 10 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-(1H-indole-3-yl)methyl]-1,5-benzothi azepin-3(S)-vll-butanamide The title compound is prepared from 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl]-butanamide and 3-Cdimethylaminomethyl)indole by the procedure described in Example 7.

Claims (15)

  1. WHAT IS CLAIMED IS:
    where L is
    n is 0 or 1; p is O to 3; q is 0 to 4; w is 0 or 1; u is 0 or 1; OH R10 X is C=O, O, S(O)mX -CH-, -N-, -CH=CH; m is 0 to 2; A is
    where x and y are independently 0 to 3; R, R2, Rla, R2a, Rlb, and R2b, are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, -S(O)mR7a, cyano, nitro, R7bO(CH2)v-, R7bCOO(CH2)v-, R7bOCO(CH2)v-, R4R4bN(CH2)v-, R7bCON(R4)(CH2)v-, R4R4bNCO(CH2)v-, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;R7a and R7b are independently hydrogen, C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl or substituted phenyl; phenyl or substituted phenyl where the phenyl substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy and v is O to 3; R3 is Rlb, R2b independently disubstituted phenyl, Rib, R2b independently disubstituted naphthyl, Rib, R2b independently disubstituted fluorenyl, Rlb, R2b independently di substituted indolyl or Rlb, R2b independently disubstituted quinolyl, where Rlb and R2b are as defined above;; R4 and R4b are independently hydrogen, phenyl, substituted phenyl, C1-C10 alkyl, substituted C1-C10 alkyl, C3-C10 alkenyl, substituted C3-C10 alkenyl, C3-C10 alkynyl, or substituted C3-C10 alkynyl where the substituents on the phenyl, alkyl, alkenyl or alkynyl are from 1 to 5 of hydroxy, C1-C6 alkoxy, C3-C7 cycloalkyl, fluoro, R1, R2 independently disubstituted phenyl C1-C3 alkoxy, R1, R2 independently disubstituted phenyl, C1-C20 alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl, or -NR10R11; where R10 and R11 are independently hydrogen, C1-C6 alkyl, phenyl, phenyl C1-C6 alkyl, C1-C5-alkoxycarbonyl, or C1-C5-alkanoyl-C1-C6 alkyl;; R4 and R4b can be taken together to form -(CH2)r-B-(CH2)S- where B is O or S(O)m, r and s are independently 1 to 3 and m is as defined; R5 is COR9, COOR9, CONR6bR9, S02R9 or SO2NR6bR9. .R6b and R9 can be taken together to form -(CH2)r-B-(CH2)s- where B is O, or S(O)m; r and s are independently 1 to 3 and m is as defined; R9 is hydrogen, C1-C3 perfluoroalkyl, C1-C6 alkyl, R1, R2 independently disubstituted phenyl, R1, R2 independently disubstituted naphthyl, R1, R2 independently disubstituted fluorenyl or substituted C1-C6 alkyl where the substituents are R1, R2 independently disubstituted phenyl, R1, R2 independently disubstituted naphthyl or R1, R2 independently disubstituted fluorenyl, with the proviso that when R5 is COOR9 or S02R9, R9 is other than hydrogen; R6a and R6b are independently hydrogen, C1-C10 alkyl, phenyl or phenyl C1-C10 alkyl;; R8 and R8a are independently hydrogen, C1-C10 alkyl, trifluoromethyl, phenyl, substituted C1-C10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O)mR7a, C1-C6 alkoxy, C3-C7 cycloalkyl, R1, R2 independently disubstituted phenyl C1-C3 alkoxy, R1, R2 independently di substituted phenyl, C1-C5-alkanoyloxy, C1-C5-alkoxycarbonyl, carboxy, form, or -NR10R11 where R1, R2, R10 and R11 are as defined above; or R8 and R8a can be taken together to form -(CE2)t- where t is 2 to 6; and R8 and R8a can independently be joined to R4 to form alkylene bridges between the terminal -nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms; and pharmaceutically acceptable salts thereof.
  2. 2. A compound of Claim 1 wherein: n is 0 or 1; p is 0 to 3; q is 0 to 3; w is 0 or 1; u is O or 1; R10 X is, O, S(O)m, -N-, -CH=CH; m is 0 to 2; A is
    where x and y are independently 0 to 2; R1, R2 Rla, R2a, Rlb, and R2b, are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, -S(O)mR7a, R7bO(CH2)v-, R7bCoo(CH2)V-, R7bOCO(CH2)v-, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-Ce alkoxy, or hydroxy;R7a and R7b are independently hydrogen, C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl; phenyl v is 0 to 2; R3 is as defined above; R4 is hydrogen, phenyl, substituted phenyl, C1-C10 alkyl, substituted C1-C10 alkyl, the substituents are from 1 to 5 of hydroxy, C1-C6 alkoxy, C3-C7 cycloalkyl, fluoro, R1, R2 independently disubstituted phenyl C1-C3 alkoxy, R1, R2 independently disubstituted phenyl, C1-C20 alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl; R5 is COR9, COOR9, CONR6bR9, S02R9.R6b and R9 can be taken together to form -(CH2)r-B-(CH2)s- where B is O or S(O)m; r and B are independently 1 to 3 and m is as defined; R9 is C1-C3 perfluoroalkyl, C1-C6 alkyl, R1, R2 independently disubstituted phenyl, R1, R2 independently disubstituted naphthyl, R1, R2 independently di substituted fluorenyl or substituted C1-C6 alkyl where the substituents are R1, R2 independently disubstituted phenyl, R, R2 independently disubstituted naphthyl or R1, R2 independently disubstituted fluorenyl; R6a and R6b are independently hydrogen, C1-C10 alkyl, or phenyl C1-C10 alkyl;; R8 and R8a are independently hydrogen, C1-C10 alkyl, phenyl, substituted C1-C10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(o)mR7a, C1-C6 alkoxy, C3-C7 cycloalkyl, R1, R2 independently disubstituted phenyl C1-C3 alkoxy, R1, R2 independently disubstituted phenyl, C1-C5-alkanoyloxy, C1-C5-alkoxycarbonyl, carboxy, formyl, or -NR10Rll where R1, R2, R10 and Rll are as defined above; or R8 and R8a can be taken together to form -(CH2)t- where t is 2 to 4; and R8 and R8a can independently be joined to R4 to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms; and pharmaceutically acceptable salts thereof.
  3. 3. A compound of Claim 2 wherein: n is 0 or 1; p is 0 to 2; q is 0 to 2; w is O or 1; u is 0 or 1; X is S(O)m -CH=CH; m is 0 or 1; A is
    where x and y are independently 0 to 1; R, R2 Rla, R2a, Rlb, and R2b, are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, C1-C3 perfluoroalkoxy, -S(o)mR7a, R7bO(CH2)v-, R7bCOO(CH2)v-, R7bOCO(CH2)v-, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;R7a and R7b are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl and v is 0 to 2; R3 is as defined above; R4 is hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl, where the substituents are from 1 to 5 of hydroxy, C1-C6 alkoxy, fluoro, R1, R2 independently disubstituted phenyl, C1-C20 alkanoyloxy, C1-C5 alkoxycarbonyl, or carboxy; R5 is COR9, COOR9, or S02R9;; R9 is C1-C6 alkyl, R1, R2 independently disubstituted phenyl, R1, R2 independently disubstituted naphthyl, R1, R2 independently disubstituted fluorenyl or substituted C1-C6 alkyl where the substituents are R1, R2 independently disubstituted phenyl, R1, R2 independently disubstituted naphthyl or R1, R2 independently di substituted fluorenyl, R6a is hydrogen or C1-C10 alkyl;; R8 and R8a are independently hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, SCO)mR7, C1-C6 alkoxy, C3-C7 cycloalkyl, R1, R2 independently disubstituted phenyl C1-C3 alkoxy, R1, R2 independently disubstituted phenyl, C1-C5-alkanoyloxy, C1-C5-alkoxycarbonyl, carboxy, formyl, or -NR10R11 where R1, R2, R10 and R11 are as defined above; or R8 and R8a can be taken together to form (CH2)t- where t is 2; and R8 and R8a can independently be joined to R4 to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms; and pharmaceutically acceptable salts thereof.
  4. 4. A compound of Claim 3 wherein: n is 0 or 1; p is 0 to 2; q is 0 to 2; w is O or 1; u is O or 1; X is SCO)m or -CH=CH; m is O; A is
    where x and y are independently 0 to 1; R, R2 Rla, R2a, Rlb, and R2b, are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, -S(o)mR7a, R7bo(CH2)V-, R7bCOO(CH2)v-, phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;R7a and R7b are independently hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl and v is O to 1; R3 is as defined above; R4 is hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl, where the substituents are from 1 to 3 of hydroxy, G1-C3 alkoxy, fluoro, R1, R2 independently disubstituted phenyl, C1-C20 alkanoyloxy, C1-C5 alkoxycarbonyl, or carboxy; R5 is COR9, COOR9 or S02R9; R9 is C1-C6 alkyl, R1, R2 independently disubstituted phenyl, R1, R2 independently disubstituted naphthyl, R1, R2 independently disubstituted fluorenyl or substituted C1-C6 alkyl where the substituents are R1, R2 independently disubstituted phenyl, R1, R2 independently disubstituted naphthyl or R1, R2 independently disubstituted fluorenyl, R6a is hydrogen;; R8 and R8a are independently hydrogen, C1-C10 alkyl, substituted C1-C10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, SCO)mR7, C1-C6 alkoxy, R1, R2 independently di substituted phenyl, C1-C5-alkanoyloxy, Cl-C5-alkoxycarbonyl or carboxy; or R8 and R8a can be taken together to form (CH2)t- where t is 2; and R8 and R8a can independently be joined to R4 to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from 1 to 5 carbon atoms; and pharmaceutically acceptable salts thereof.
  5. 5. A compound of Claim 1 which is: 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1- (phenylmethyl)-1H-l-benzazepin-2-one; 2-t-Butoxycarbonylamino-2-methyl-N-[2,3,4,5-tetra hydro-2-oxo-1-(phenylmethyl)-1H-1-benzazepin-3 yl3-propanamide; 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetra hydro-2-oxo-1-(phenylmethyl)-lH-l-benzazepin-3- yl)-butanamide; 3-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-1- (phenylmethyl)-1H-1-benzazepin-2-one; 2-Benzyloxycarbonylamino-2-methyl-N-[2,3,4,5tetrahydro-2-oxo-1-(phenylmethyl)-1H-1-benzazepin3-yl]-propanamide; 3-Benzyloxycarbonylamino-3-methyl-N-F2, 3,4,5- tetrahydro-2-oxo-1-(phenylmethyl)-lH-l-benzazepin- 3-yl]-butanamide; 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1-E(1- naphthyl)methyl)-1H-l-benzazepin-2-one; 2-t-Butoxycarbonylamino-2-methyl-N-E2,3,4,5-tetra hydro-2-oxo-1-[(1-naphthyl)methyl]-1H-1 benzazepin-3-yl)-propanamide; 3-t-Butoxycarbonylamino-3-methyl-N-E2,3,4,5-tetra- hydro-2-oxo-1-[(1-naphthyl)methyl]-1H-1 benzazepin-3-yl]-butanamide; 3-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-1- [(1-naphthyl)methyl]-1H-1-benzazepin-2-one; 2-Benzyloxycarbonylamino-2-methyl-N-[2,3,4,5tetrahydro-2-oxo-1-[(1-naphthyl)methyl]-1H-1 benzazepin-3-yl)-propanamide; 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5tetrahydro-2-oxo-1-[(1-naphthyl)methyl]-1H-1benzazepin-3-yl]-butanamide; 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1 [[[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin2-one; 2-t-Butoxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1[[[1,1'-biphenyl)-4-yl]methyl]-1H1-benzazepin-3-yl]-propanamide; 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1[[[1,1'-biphenyl)-4-yl]methyl]-1H1-benzazepin-3-yl]-butanamide; 3-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-1 [[[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin2-one; 2-Benzyloxycarbonylamino-2-methyl-N-[2,3,4,5tetrahydro-2-oxo-1-[[[1,1'-biphenyl]-4-yl]methyl]1H-1-benzazepin-3-yl]-propanamide; 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5tetrahydro-2-oxo-1-[[[1,1'-biphenyl]-4-yl]methyl]1H-1-benzazepin-3-yl]-butanamide; 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-1-[(1Hindole-3-yl)methyl]-1H-1-benzazepin-2-one; 2-t-Butoxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[(1H-indole-3-yl)methyl]-1H-1 benzazepin-3-yl)-propanamide; 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[(1H-indole-3-yl)methyl]-1H-1 benzazepin-3-yl]-butanamide; 3-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-1- [(1H-indole-3-yl)methyl]-1H-1-benzazepin-2-one; 2-Benzyloxycarbonylamino-2-methyl-N-[2,3,4,5tetrahydro-2-oxo-1-[(1H-indole-3-yl)methyl]-1H-1 benzazepin-3-yl)-propanamide; 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5tetrahydro-2-oxo-1-[(1H-indole-3-yl)methyl]-1H-1 benzazepin-3-yl]-butanamide; 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-5 (phenylmethyl)-1,5-benzothiazepin-4-one; 2-t-Butoxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-(phenylmethyl)-1,5-benzothiazepin-3yl]-propanamide; 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetra hyd ro-4-oxo-5- (phenylmethyl )-1 , 5-benzothi azepin-3- yl]-butanamide; 3-Benzyloxycarbonylamino 2,3,4,5-tetrahydro-5- (phenylmethyl)-1,5-benzothiazepin-4-one; 2-Benzyloxycarbonylamino-2-methyl-N-[2,3,4,5- tetrahydro-4-oxo-5-(phenylmethyl)-1,5-benzothi- azepin-3-yl)-propanamide; 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5 tetrahydro-4-oxo-5-(phenylmethyl)-1,5-benzothi- azepin-3-yl]-butanamide; 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-5-[(1naphthyl)methyl]-1,5-benzothiazepin-4-one; 2-t-Butoxycarbonylamino-2-methyl-N-[2,3,4,5-tetra- hydro-4-oxo-5-[(1-naphthyl)methyl]-1,5-benzothi azepin-3-yl)-propanamide; 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetra- hydro-4-oxo-5-[(1-naphthyl)methyl]-1,5-benzothi azepin-3-yl)-butanamide; 3-Benzyloxyearbonylamino-2,3,4,5-tetrahydro-5-t(l- naphthyl)methyl]-1,5-benzothiazepin-4-one; 2-Benzyloxycarbonylamino-2-methyl-N-[2,3,4,5- tetrahydro-4-oxo-5-[(1-naphthyl)methyl]-1,5-benzo thiazepin-3-yl)-propanamide; 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5 tetrahydro-4-oxo-5-E(1-naphthyl)methyl]-1,5-benzo- thiazepin-3-yl)-butanamide; 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-5 [[[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin4-one; 2-t-Butoxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[[1,1'-biphenyl]-4-yl]methyl]1,5benzothiazepin-3-yl]propanamide; 2-t-Butoxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[[1,1'-biphenyl'-4-yl]methyl]-1,5benzothiazepin-3-yl]-butanamide; 3-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-5 [[[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin4-one; 2-Benzyloxycarbonylamino-2-methyl-N-[2,3,4,5tetrahydro-5-[[[1,1'-biphenyl]-4-yl]methyl]1,5-benzothiazepin-3-yl]-propanamide; 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5tetrahydro-5-[[[1,1'-biphenyl]-4-yl]methyl]1,5-benzothiazepin-3-yl]-butanamide; 3-t-Butoxycarbonylamino-2,3,4,5-tetrahydro-5-[(1Hindole-3-yl)methyl]-1,5-benzothiazepin-4-one; 2-t-Butoxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[(1H-indole-3-yl)methyl]-1,5-benzothiazepin-3-yl]-propanamide; 3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[(1H-indole-3-yl)methyl]-1,5-benzothiazepin-3-yl]-butanamide; 3-Benzyloxycarbonylamino-2,3,4,5-tetrahydro-5- [(1H-indole-3-yl)methyl]-1,5-benzothiazepin-4-one; 2-Benzyloxycarbonylamino-2-methyl-N-[2,3,4,5- tetrahydro-4-oxo-5-[(1H-indole-3-yl)methyl]-1,5 benzothiazepin-3-yl]-propanamide; or 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5 tetrahydro-4-oxo-5-[(1E-indole-3-yl)methyl]-1,5- benzothiazepin-3-yl]-butanamide.
  6. 6. A process for the preparation of a compound of Claim 1 which comprises reacting a compound having a formula:
    where R1, R2, R6a, X, n and p are as defined in Claim 1 with a compound having the formula: 0 R8 HO-C-(CH2)x-C-(CH2)y-NH-G R8a V where R8, R8a, x and y are as defined in Claim 1 and G is protecting group; which step is either followed by or preceded by the treatment of the compound with R3-(L)W-(CH2 )q~Y IX where R3, L, q and w are as defined in Claim 1, and Y is a leaving group, followed by replacement of the protecting group G with R5.
  7. 7. The process of Claim 7 where compound III is first reacted with compound V followed by reaction with compound IX.
  8. 8. A process for the preparation of a compound of Claim 1 which comprises reacting a compound having a formula:
    where R1, R2, R5, R6a, A, X, n, p and u are as defined in Claim 1, with a compound having the formula: R3-(L)W~(CE2)q~Y IX where R3, L, q and q are as defined in Claim 1, and Y is a leaving group.
  9. 9. The process of Claim 6 where the protecting group G is t-butoxycarbonyl or benzyloxycarbonyl.
  10. 10. A method for decreasing levels of endogenous growth hormone in a human or an animal which comprises administering to such human or animal an effective amount of a compound of Claim 1.
  11. 11. A composition useful for decreasing the endogenous production or release of growth hormone in a human or an animal which comprises an inert carrier and an effective amount of a compound of Claim 1.
  12. 12. A method for decreasing levels of endogenous growth hormone in a human or an animal which comprises administering to such human or animal an effective amount of a compound of Claim 1 in combination with a somatostatin analog such as stilamino or sandostatine.
  13. 13. A composition for decreasing levels of endogenous growth hormone in a human or an animal which comprises an effective amount of a compound of Claim 1 in combination with a somatostatin analog such as stilamine or sandostatine.
  14. 14. A method for decreasing levels of endogenous growth hormone in a human or an animal which comprises administering to such human or animal an effective amount of a compound of Claim 1 in combination with His-D-Trp-D-Lys-Trp-D-Phe-Lys-NR2.
  15. 15. A composition for decreasing levels of endogenous growth hormone in a human or an animal which comprises an effective amount of a compound of Claim 1 in combination with His-D-Trp-D-Lys-Trp-D-Phe-Lys-NH2.
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