+

WO1995016675A1 - Lactames benzo condenses favorisant la liberation de l'hormone de croissance - Google Patents

Lactames benzo condenses favorisant la liberation de l'hormone de croissance Download PDF

Info

Publication number
WO1995016675A1
WO1995016675A1 PCT/US1994/014374 US9414374W WO9516675A1 WO 1995016675 A1 WO1995016675 A1 WO 1995016675A1 US 9414374 W US9414374 W US 9414374W WO 9516675 A1 WO9516675 A1 WO 9516675A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
methyl
oxo
biphenyl
tetrahydro
Prior art date
Application number
PCT/US1994/014374
Other languages
English (en)
Inventor
Hyun O. Ok
William R. Schoen
John Szumiloski
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU13718/95A priority Critical patent/AU1371895A/en
Publication of WO1995016675A1 publication Critical patent/WO1995016675A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • Growth hormone which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing.
  • growth hormone is known to have the following basic effects on the metabolic process of the body:
  • a deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.
  • growth hormone Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressi ⁇ , and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone- releasing hormone or all of these.
  • L-DOPA L-3,4-dihydroxyphenylalanine
  • GRF growth hormone releasing factor
  • the problem was generally solved by providing exogenous growth hormone or by administering an agent which stimulated growth hormone production and/or release.
  • an agent which stimulated growth hormone production and/or release In either case the peptidyl nature of the compound necessitated that it be administered by injection.
  • the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone.
  • Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.
  • the instant invention covers certain benzo-fused lactam compounds which have the ability to stimulate the release of natural or endogenous growth hormone.
  • the compounds thus have the ability to be used to treat conditions which require the stimulation of growth hormone production or secretion such as in humans with a deficiency of natural growth hormone or in animals used for food production where the stimulation of growth hormone will result in a larger, more productive animal.
  • 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 increase the level of growth hormone secretions. Further objects will become apparent from a reading of the following description. DESCRIPTION OF THE INVENTION
  • R7a and R b are independently hydrogen, C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl where the substitutents are phenyl or substituted phenyl; phenyl or substituted phenyl where the phenyl substitutents are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy or hydroxy;
  • R3a and R ⁇ b are independently hydrogen, R9, C1-C6 alkyl substituted with R9, phenyl substituted with R9 or phenoxy substituted with R9;
  • R5bRl2cNN(Rl2b)COO(CH2)v- R 5 Rl2bNCOO(CH2)v- or Rl30CON(Rl2a)(CH2)v- where v is 0 to 3.
  • Rl2a, Rl2b and Rl2c are independently R5a, OR5a or COR5a.
  • Rl2a and Rl2b, or Rl2b and Rl2c, or Rl2a and Rl2c, or Rl2b and R5b, 0 r Rl2c and R5b, 0 r Rl3 and Rl2a can be taken together to form -(CH2)r- B-(CH2)s- where B is CHRl, O, S(0) m or NRlO, m is 0, 1 or 2, r and s are independently 0 to 3 and Rl and R 10 are as defined.
  • Rl3 is C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl, where the substitutents are hydroxy, -NRlORll, carboxy, phenyl or substituted phenyl; phenyl or substituted phenyl where the substituents on the phenyl are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy or hydroxy.
  • RlO and Rll are independently hydrogen, C1-C6 alkyl, phenyl, phenyl C1-C6 alkyl, C1-C5 alkoxycarbonyl or C1-C5 alkanoyl-Cl-C6 alkyl;
  • R4, R4a ? R5, R5aand R5b are independently hydrogen, phenyl, substituted phenyl, Cl-ClO alkyl, substituted Cl-ClO alkyl, C3-C10 alkenyl, substituted C3-C10 alkenyl, C3-C10 alkynyl or substituted C3- ClO 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, Rl, R2 independently disubstituted phenyl, Rl, R 2 independently disubstituted phenyl C1-C3 alkoxy, Cl-C20-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl or -NRl ⁇ Rll where Rl, R 2 , RlO and Rl 1 are as
  • R ⁇ a and R° * b are independently hydrogen, Cl-ClO alkyl, trifluoromethyl, Rl, R 2 independently disubstituted phenyl, substituted Cl-ClO alkyl where the substitutents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, -S(0)mR 7a , Cl-Cfc alkoxy, C3-C7 cycloalkyl, Rl, R 2 independently disubstituted phenyl, R 1 , R 2 independently disubstituted phenyl C1-C3 alkoxy, C1-C5 alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl or -NRIORI 1 where Rl , R 2 , R 7a , RlO, Rl 1 and m are as defined above; or R ⁇ a and R ⁇ b can be taken together to form -(CH2)t- where t is 2 to 6
  • 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.
  • 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.
  • halogen is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
  • Rl, R2, Rla, R2a, Rib and R.2b are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, -S(0) m R 7a , R7b ⁇ (CH2)v-. R7bCOO(CH2)v- R7b ⁇ CO(CH2)v- phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-Q3 alkyl, C1-C6 alkoxy, or hydroxy;
  • R7a and R7b are independently hydrogen, C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl where the substitutents are phenyl; phenyl and v is 0 to 3;
  • R3a and R ⁇ b are independently hydrogen, R9, C1-C6 alkyl substituted with R9, phenyl substituted with R9 or phenoxy substituted with R ⁇ ; R9 IS
  • Rl2a, Rl2b and Rl2c are independently R5a, OR5a or COR5a.
  • Rl2a and Rl2b, 0 r Rl2b and Rl2c, 0 r Rl2a and Rl2c, or Rl2b and R5b, or Rl2c and R5b, 0 r Rl3 and Rl2a can be taken together to form - CH2)r- B-(CH2)s- where B is CHRl, o, S(0) m or NRlO, m is 0, 1 or 2, r and s are independently 0 to 3 and Rl and RlO are as defined.
  • Rl3 is C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl, where the substitutents are hydroxy, -NRlORl 1, carboxy, phenyl or substituted phenyl; phenyl or substituted phenyl where the substituents on the phenyl are from 1 to 3 of halogen, C1-C6 alkyl, C1-C6 alkoxy or hydroxy.
  • RlO and Rl 1 are independently hydrogen, C1-C6 alkyl, phenyl Cl-Qj alkyl, or C1-C5 alkanoyl-Cl-C6 alkyl;
  • R4, R4a, R5, R5aand R5b are independently hydrogen, phenyl, substituted phenyl, Cl-ClO alkyl, substituted Cl-ClO alkyl where the substituents on the alkyl or phenyl are from 1 to 5 of hydroxy, Cl-C6 alkoxy, C3-C7 cycloalkyl, fluoro, Rl, R 2 independently disubstituted phenyl, Rl, R 2 independently disubstituted phenyl C1-C3 alkoxy, Cl- C20-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy or formyl; R4 and R5 can be taken together to form -(CH2)r-B-(CH2)s- where B is
  • R6 and R6D are independently hydrogen, Cl-ClO alkyl or phenyl Cl- C10 alkyl; or R6a and R 6b can be taken together to form -(CH2)r-B- (CH2)s- where B is O, S(0)m or N-RlO, ⁇ and s are independently 1 to 2, m is 0 and R and R O are as defined above;
  • R8a and R ⁇ b a re independently hydrogen, Cl-ClO alkyl, substituted Cl- Cio alkyl where the substitutents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, -S(0) m R 7a , C1-C6 alkoxy, C3-C7 cycloalkyl, Rl, R 2 independently disubstituted phenyl, Rl, R 2 independently disubstituted phenyl C1-C3 alkoxy, C1-C5 alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl or -NRIORI 1 where Rl, R 2 , R 7a , Rl°, Rl 1 and m are as defined above; or R ⁇ a and R ⁇ b can be taken together to form -(CH2)t- where t is 2 to 4; and R ⁇ a and R ⁇ b can independently be joined to R5 to form alkylene bridges
  • n O or 1
  • p is 0 to 2
  • q is 0 to 2
  • w is 0 or 1 ;
  • Rl, R2, Rla, R2a, Rib and R2b are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, -S(0) m R 7 a, R7b ⁇ (CH2)v- R7bC00(CH2)v- R7 b OCO(CH2)v- phenyl or substituted phenyl where the substituents are from 1 to 3 of halogen, C1-Q5 alkyl, C1-C6 alkoxy, or hydroxy;
  • R7a and R7t> are independently hydrogen, C1-C6 alkyl or substituted C1-C alkyl where the substitutents are phenyl and v is 0 to 2;
  • R3a and R3t> are independently hydrogen, R9, C1-C6 alkyl substituted with R9 or phenoxy substituted with R9;
  • R 4a R7 b O(CH2)v- R 7 COO(CH2)v- R 7 OCO(CH2)v ⁇ R 7b CO(CH2) v - R 5b Rl 2 N(CH2)v- R5bRl2bNCO(CH2) v - R 5b R 12c NN(Rl b )CO(CH2)v- R5bRl2bNCON(Rl 2a )(CH2)v- R5bRl2cNN(Rl2b)CSN(Rl2a)(CH2)v- R5bRl2cNN(Rl 2b )CON(Rl 2 a)(CH2)v- R5bRl2cNN(Rl2b)COO(CH2)v- R 5 Rl 2b NCOO(CH2)v- or Rl3 ⁇ CON(Rl2a)(CH2) v- or Rl3 ⁇ CON(Rl2a)(CH2) v- or Rl3 ⁇ CON(Rl2a)(CH2)
  • Rl2a, Rl2b and Rl 2 c are independently R5a or OR5a.
  • Rl2a and Rl 2b , or Rl 2b and Rl 2 c, or Rl 2 a and Rl 2 c, or Rl 2b and R5b, or Rl 2 c and R5b, or Rl3 and Rl2a can be taken together to form -(CH2)r ⁇ B- (CH2) S - where B is CHRl , o, S(0)m or NRlO, m is 0, 1 or 2, r and s are independently 0 to 2 and Rl and RlO are as defined.
  • Rl3 is C ⁇ -C6 alkyl, substituted C1-C6 alkyl, where the substitutents are phenyl or substituted phenyl; phenyl or substituted phenyl where the substituents on the phenyl are from 1 to 3 of halogen, Cl-C6 alkyl, Cl-C6 alkoxy or hydroxy.
  • RlO and Rl 1 are independently hydrogen, Cl-C6 alkyl, phenyl C1-C6 alkyl, or C1-C5 alkanoyl-Cl-C6 alkyl;
  • R4, R4a, R5, R5aand R5b are independently hydrogen, Cl -ClO alkyl or substituted C1-C10 alkyl where the substituents are from 1 to 5 of hydroxy, C1-C6 alkoxy, fluoro, Rl, R 2 independently disubstituted phenyl, Cl-C20-alkanoyloxy, C1-C5 alkoxycarbonyl or carboxy; where Rl and R 2 are as defined above;
  • R6a and R 6b are independently hydrogen or Cl-ClO; or R6a and R6b can be taken together to form -(CH2)r-B-(CH2)s- where B is O or S(0)m . r and s are 2, m is 0 and R and RlO are as defined above; A is
  • R8a and R ⁇ b are independently hydrogen, Cl-ClO alkyl, substituted Cl- ClO alkyl where the substitutents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, -S(0) m R 7a , Cl-C6 alkoxy, C3-C7 cycloalkyl, Rl , R 2 independently disubstituted phenyl, Rl, R 2 independently disubstituted phenyl C1-C3 alkoxy, C1-C5 alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl or -NRIORI 1 where Rl, R 2 , R 7a , Rl°, Rl 1 and m are as defined above; or R ⁇ a and R ⁇ b can be taken together to form -(CH2)t- where t is 2; and R ⁇ a and R ⁇ b can independently be joined to R5 to form alkylene bridges between the terminal nitrogen
  • Still further preferred compounds of the instant invention are realized in the above structural formula when; n is O or 1; p is 0 to 2; q is l; w is 1;
  • R7a and R7t> are independently hydrogen, C1-C6 alkyl or substituted C1-C6 alkyl where the substituents are phenyl and v is 0 or 1;
  • R3a and R ⁇ 0 are independently hydrogen, R or C1-C6 alkyl substituted with R9;
  • R7 b O(CH2)v- R 7b COO(CH2)v- R 7b OCO(CH2)v- R 7b CO(CH2)v- R 5b R i2b N(CH2)v- R5bRl2bNCO(CH2)v- R 5b R 12c NN(Rl 2b )CO(CH2)v- R5b R 12bNCON(Rl 2 a)(CH2)v- R5bRl2cNN(Rl2b)CON(Rl2a)(CH2)v- R5bRl2cNN(Rl2b)COO(CH2)v- R 5b Rl 2b NCOO(CH2)v- or Rl3 ⁇ CON(Rl2a)(CH2)v- where v is 0 to 2.
  • Rl2a, Rl2b and Rl2c are independently R5a.
  • Rl2a and Rl2b, or Rl2b and Rl2c, or Rl2a and Rl2c, or Rl2b and R5b, or Rl2c and R5b, or Rl3 and Rl2a can be taken together to form -(CH2)r-B-(C.H2)s- where B is CHRl, o, S(0)m or NRlO, m is 0, 1 or 2, r and s are independently 0 to 2 and Rl and RlO are as defined.
  • R 13 is C l -C6 alkyl, substituted C l -C6 alkyl, where the substitutents are phenyl or substituted phenyl; phenyl or substituted phenyl where the substituents on the phenyl are from 1 to 3 of halogen, Cl-C6 alkyl, Cl-C6 alkoxy or hydroxy.
  • RlO and Rl 1 are independently hydrogen, Cl-C6 alkyl or C1-C5 alkanoyl-Cl-C6 alkyl;
  • R4, R4a, R5, R5aand R5b are independently hydrogen, Cl-ClO alkyl or substituted Cl-ClO alkyl where the substituents are from 1 to 3 of hydroxy, C1-C3 alkoxy, fluoro, Rl, R 2 independently disubstituted phenyl, Cl-C20-alkanoyloxy, C1-C5 alkoxycarbonyl or carboxy; where Rl and R2 are as defined above;
  • R6a and R ⁇ b are hydrogen
  • x and y are independently 0 or 1 ;
  • R ⁇ a and R ⁇ b are independently hydrogen, C1-C10 alkyl, substituted Ci- C ⁇ o alkyl where the substitutents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, -S(0) m R 7 a, Cl -C6 alkoxy, C3-C7 cycloalkyl, Rl , R independently disubstituted phenyl, C1-C5 alkanoyloxy, C1-C5 alkoxycarbonyl or carboxy, where Rl, R 2 , R 7a , and m are as defined; or R8a and R ⁇ b can be taken together to form -(CH2)t- where t is 2; and R8a and R ⁇ b can independently be joined to R5 to form alkylene bridges between the terminal nitrogen and the alkyl portion of the A group wherein the bridge contains from one to five carbon atoms; and pharmaceutically acceptable salts thereof.
  • Representative preferred growth hormone releasing compounds of the present invention include the following:
  • 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 or partially purified optical isomers or racemic mixtures thereof, be included within the ambit of the instant invention.
  • the asymmetric center represented by the asterisk in Formula I it has been found that the compound in which the 3-amino substituent is above the plane of the structure, as seen in Formula la, is more active and thus more preferred over the compound in which the 3-amino substituent is below the plane of the structure.
  • the asymmetric center will be designated according to the R/S rules as either R or S depending upon the value of X.
  • the instant compounds are generally isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids.
  • acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic and the like.
  • certain compounds containing an acidic function such as a tetrazole or 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 ⁇ .
  • the preparation of these intermediates is described by Fisher, et ah, in U.S. Patent 5,206,235 and references cited therein.
  • Preparation of compounds (I) of the present invention from intermediates of Formula II is described in the following Schemes. ⁇
  • intermediates of Formula II are converted to the corresponding urea-, carbamate- or thiocarbamate intermediate IV as illustrated in Scheme 1.
  • Activation of the amine component of intermediate II is achieved by a variety of reagents known in the literature and familiar to one skilled in the art.
  • reagents such as TV ⁇ V'-carbonyldiimidazole or its sulfur analog, TV,TV'-thiocarbonyldiimidazole, phosgene, triphosgene or 4- nitrophenylchloroformate are all commonly used to activate amines.
  • Subsequent treatment of the activated amine with compound HI leads directly to ureas, carbamates or thiocarbamates.
  • Reductive alkylation of I 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 to give compound 2.
  • an inert solvent such as methanol or ethanol
  • Treatment of intermediate II with TV,TV'-carbonyldiimidazole in an inert solvent, such as methylene chloride or tetrahydrofuran (THF) rapidly leads to formation of an activated species which is further reacted with amine 2 to give the desired urea product 3.
  • 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.
  • urea compounds of Formula 3 may also be prepared by using 4-nitrophenylchloroformate as the activating reagent as shown in Scheme 3.
  • 4-nitrophenylchloroformate as the activating reagent as shown in Scheme 3.
  • G is f-butoxycarbonyl or benzyloxycarbonyl
  • G is f-butoxycarbonyl or benzyloxycarbonyl
  • carbamate compound 1O may also be prepared by using 4-nitrophenylchloroformate as the activating reagent as shown in Scheme 7.
  • 4-nitrophenylchloroformate as the activating reagent as shown in Scheme 7.
  • G is f-butoxycarbonyl or benzyloxycarbonyl
  • Thiocarbamate intermediates of Formula IV wherein K is S (12) are prepared by routes analogous to those described in Schemes 6 and 7 for the preparation of carbamate derivatives. As shown in Scheme 8, following activation of intermediate ⁇ by either of the methods described, reaction with thiol ⁇ affords the thiocarbamate prduct 12.
  • G is f-butoxycarbonyl or benzyloxycarbonyl
  • Intermediates of Formula VI are prepared as shown in Scheme 9 by treatment of the desired lactam intermediate IV with an alkylating agent V, wherein Y is a good leaving group such as Cl, Br, I, 0-methanesulfonyl or 0-(p-toluenesulfonyl).
  • Alkylation of intermediates of Formula IV is conveniently carried out in anhydrous dimethyl formamide (DMF) in the presence of bases such as sodium hydride or potassium r-butoxide for a period of 0.5 to 24 hours at temperatures of 20-100°C.
  • bases such as sodium hydride or potassium r-butoxide
  • Substituents on the alkylating agent V may need to be protected during alkylation.
  • a description of such protecting groups may be found in: Protective Groups in Organic Synthesis. T.W. Greene, John Wiley and Sons, New York, 1981. SCHEME 9
  • Y is a leaving group G is f-butoxycarbonyl or benzyloxycarbonyl
  • Alkylating agents V are, in some cases commercially available compounds or may be prepared as described in EPO publications 253,310; 291,969; 324,377 and the references cited therein.
  • Compounds of Formula I wherein R ⁇ a or R3b is a tetrazole are prepared as described in Scheme 10 by alkylation of IV with a suitably substituted alkylating agent V containing a nitrile as tetrazole precursor.
  • Elaboration of nitrile JJ3 to the desired tetrazole product 14 is carried out by treatment with trimethyltin azide in refluxing toluene.
  • Y is a leaving group G is f-butoxycarbonyl or benzyloxycarbonyl
  • G is f-butoxycarbonyl or benzyloxycarbonyl
  • a useful method to prepare a preferred alkylating agent 19 is own in reaction Scheme 11 , and in U.S. Patent 5,039,814. SCHEME 11
  • benzonitrile is treated with sodium azide and zinc chloride to give 5-phenyltetrazole 15 which is converted to the N-trityl derivative 16 by treatment with triphenylmethyl chloride and triethylamine.
  • the zinc reagent 17 was prepared by treatment with n-butyllithium followed by zinc chloride. Coupling with 4-iodotoluene using the catalyst bt triphenylphosphine)nickel(ll) dichloride gives the biphenyl product 18 in high yield.
  • a radical initiator such as benzoyl peroxide or 2,2'-azobisisobutyronitrile (AIBN)
  • Y is a leaving group G is f-butoxycarbonyl or benzyloxycarbonyl
  • reduction of the nitro group of 20 is achieved by hydrogenation in the presence of a metal catalyst, such as palladium on carbon, in a protic solvent such as methanol or ethanol.
  • a metal catalyst such as palladium on carbon
  • a protic solvent such as methanol or ethanol.
  • alternative methods of reduction are indicated, such as chemical reduction with stannous chloride under acidic conditions.
  • the protecting group G in intermediate 20 must be compatible with the experimental conditions anticipated for reduction.
  • intermediate 20 wherein G is f-butoxycarbonyl (BOC) is stable to the conditions of catalytic reduction employed in the conversion to 25.
  • Intermediate 25 may also be further elaborated to a new intermediate 26 by the aforementioned reductive alkylation conditions.
  • G is f-butoxycarbonyl
  • G is f-butoxycarbonyl
  • Terminally disubstituted compounds 29 can be obtained directly by reaction of 26 with a disubstituted carbamoyl chloride 28 in an inert solvent such as methylene chloride in the presence of triethylamine or 4-dimethylaminopyridine.
  • mono- substituted compound 31 wherein either R5b or R 12b is hydrogen is obtained from 26 by reaction with an isocyanate 30 as shown in Scheme 16.
  • Terminally unsubstituted urea 31, wherein Rl2b is hydrogen, is also prepared from amine 26 by reaction with trimethylsilyl isocyanate (30; R 12 b is (CH3)3Si).
  • G is f-butoxycarbonyl
  • G is f-butoxycarbonyl
  • amine 25 is converted to an isocyanate 32 by treatment with phosgene or an equivalent reagent such as btXtrichloro- methyl)carbonate (triphosgene) as indicated in Scheme 17. Subsequent reaction of 32 with primary or secondary amines in an inert solvent such as methylene chloride gives the corresponding urea derivative 29 in good yield. Isocyanate 32 is also converted to substituted semicarbazides 33 or hydroxy- or alkoxyureas 34 by reaction with substituted hydrazines or hydroxy- or alkoxylamines, respectively.
  • G is f-butoxycarbonyl or benzyloxycarbonyl
  • G is f-butoxycarbonyl or benzyloxycarbonyl
  • G is f-butoxycarbonyl or benzyloxycarbonyl
  • treatment of 37 with ⁇ ,/V'-carbonyldii ⁇ nidazole in dimethylformamide can form an activated intermediate which will react with substituted hydrazine reagents to give the carbazate product 39.
  • CON(Rl2a)CH2- or Rl3 ⁇ CON(Rl2a)CH2- are prepared from the f -butyl ester intermediate 40 as described in Scheme 19. Removal of the ?-butyl ester through the use of trifluoroacetic acid gives the carboxylic acid 4L It may be appreciated by one skilled in the art that the protecting group G in 40 must therefore be compatible with the strongly acidic conditions employed for ester cleavage; hence G is taken as benzyloxycarbonyl.
  • Conversion of the carboxylic acid 4 , to the benzylamine derivative 42 can be achieved by a five-step sequence consisting of: 1) formation of a mixed anhydride with isobutyl chloroformate; 2) reduction with sodium borohydride to the benzyl . alcohol; 3) formation of the mesylate with methanesulfonyl chloride; 4) formation of the azide by reaction with sodium azide, and finally, 5) reduction of the azide with tin(II) chloride.
  • the benzylamine intermediate 42 can be further elaborated to 43 by the aforementioned reductive amination procedure.
  • G is benzyloxycarbonyl
  • G is benzyloxycarbonyl
  • G is benzyloxycarbonyl
  • G is benzyloxycarbonyl
  • G is benzyloxycarbonyl
  • hydrazide compound 47 can be prepared from intermediate 43 by a two-step procedure consisting of activation of the amine via treatment with ⁇ '-carbonyldiimidazole followed by treatment with the appropriately substituted hydrazine derivative R5bRl2c (Rl2b)H.
  • G is benzyloxycarbonyl
  • 52 is achieved by treatment with tetrabutylammonium fluoride followed by methanesulfonyl chloride. Reaction of 52 with compounds of Formula IV is carried out using the conditions described in Scheme 9.
  • G is f-butoxycarbonyl or benzyloxycarbonyl
  • nitrile 13 treatment of nitrile 13 with hydrogen peroxide and a strong base, such as potassium carbonate, in a polar solvent, such as dimethylsulfoxide at temperatures of 25°C to 150°C results in formation of the amide derivative 53.
  • a polar solvent such as dimethylsulfoxide
  • the precursor 13 is prepared from an appropriate alkylating agent V, where R3a is cyano, as described in Scheme 10.
  • G is benzyloxycarbonyl
  • Coupling of the carboxylic acid derivative 41 with R5 Rl2bNH j s conveniently carried out by the use of a coupling reagent such as benzotriazol-l-yloxytris(dimethylamino)phosphonium hexa ⁇ fluorophosphate (“BOP”) orbenzotriazol-1-yloxytripyrrolidino- phosphonium hexafluorophosphate (“PyBOP”) in an inert solvent such as methylene chloride.
  • BOP benzotriazol-l-yloxytris(dimethylamino)phosphonium hexa ⁇ fluorophosphate
  • PyBOP benzotriazol-1-yloxytripyrrolidino- phosphonium hexafluorophosphate
  • the requisite carboxylic acid precursors are prepared as illustrated in Scheme 26 for the biphenyl compound 60. SCHEME 26
  • G is benzyloxycarbonyl 50
  • Removal of benzyloxycarbonyl (CBz) groups can be achieved by a number of methods known in the art; for example, catalytic hydrogenation with hydrogen in the presence of a platinum or palladium catalyst in a protic solvent such as methanol. In cases where catalytic hydrogenation is contraindicated by the presence of other potentially reactive functionality, removal of benzyloxycarbonyl groups can also be achieved by treatment with a solution of hydrogen bromide in acetic acid. Removal of f-butoxycarbonyl (BOC) protecting groups is carried out by treatment of a solution in a solvent such as methylene chloride or methanol, with a strong acid, such as hydrochloric acid or trifluoroacetic acid. Conditions required to remove other protecting groups which may be present can be found in Protective Groups in Organic Synthesis T.W. Greene, John Wiley and Sons, NY. 1981.
  • the growth hormone releasing 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.
  • 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.
  • 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, secret
  • 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.
  • some of the pituitary hormones e.g., growth hormone and endorphin peptides
  • endorphin peptides e.g., endorphin peptides
  • the compounds of Formula I can be administered to animals, including man, to release growth hormone in vivo.
  • the compounds can be administered to commercially important animals such as swine, cattle, sheep and the like to accelerate and increase their rate and extent of growth, and to increase milk production in such animals.
  • these compounds can be administered to humans in vivo as a diagnostic tool to directly determine whether the pituitary is capable of releasing growth hormone.
  • the compounds of Formula I can be administered in vivo to children. Serum samples taken before and after such administration can be assayed for growth hormone. Comparison of the amounts of growth hormone in each of these samples would be a means for directly determining the ability of the patient's pituitary to release growth hormone.
  • 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.
  • the active ingredient of the pharmaceutical compositions can comprise a growth promoting agent 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.
  • Growth promoting agents include, but are not limited to, TRH, diethylstilbesterol, theophylline, enkephalins, E series prosta- glandins, compounds disclosed in U.S. Patent No. 3,239,345, e.g., zeranol, and compounds disclosed in U.S. Patent No. 4,036,979, e.g., sulbenox or peptides disclosed in U.S. Patent No. 4,411,890.
  • a further use of the disclosed novel benzo-fused lactam growth hormone secretagogues is in combination with other growth hormone secretagogues such as GHRP-6, GHRP-1 or GHRP-2 as described in U.S. Patent Nos. 4,411,890; and publications WO 89/07110 and WO 89/07111 and B-HT 920 or in combination with growth hormone releasing factor and its analogs or growth hormone and its analogs.
  • a still further use of the disclosed novel benzo-fused lactam growth hormone secretagogues is in combination with cc2 adrenergic agonists or ⁇ 3 adrenergic agonists in the treatment of obesity or in combination with parathyroid hormone or bisphosphonates, such as MK- 217 (alendronate), in the treatment of osteoporosis.
  • a still further use of the disclosed novel benzo-fused lactam growth hormone secretagogues is in combination with IGF-1 to reverse the catabolic effects of nitrogen wasting as described by Kupfer, et al., J. Clin. Invest., 21, 391 (1993).
  • growth hormone As is well known to those skilled in the art, the known and potential uses of growth hormone are varied and multitudinous. Thus, the administration of the compounds of this invention for purposes of stimulating the release of endogenous growth hormone can have the same effects or uses as growth hormone itself.
  • These varied uses of growth hormone may be summarized as follows: stimulating growth hormone release in elderly humans; prevention of catabolic side effects of glucocorticoids; treatment of osteoporosis; stimulation of the immune system; treatment of retardation; acceleration of wound healing; accelerating bone fracture repair; treatment of growth retardation, treating renal failure or insufficiency resulting in growth retardation; treatment of physiological short stature, including growth hormone deficient children; treating short stature associated with chronic illness; treatment of obesity and growth retardation associated with obesity; treating growth retardation associated with Prader-Willi syndrome and Turner's syndrome; accelerating the recovery and reducing hospitalization of bum patients; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushings syndrome; induction of pulsati
  • hyperinsulinemia including nesidioblastosis; adjuvant treatment for ovulation induction; to stimulate thymic development and prevent the age-related decline of thymic function; treatment of immunosuppressed patients; improvement in muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis, renal hemeostasis in the frail elderly; stimulation of osteoblasts, bone remodelling, and cartilage growth; stimulation of the immune system in companion animals and treatment of disorders of aging in companion animals; growth promotant in livestock and stimulation of wool growth in sheep.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 release of growth hormone.
  • Step A l-Benzyloxycarbonylamino-2-amino-2-methylpropane
  • Step B 1 -Benzyloxycarbonylamino-2-f-butoxy carbonylamino-2- methylpropane
  • Step C 1 -Amino-2- -butoxycarbonylamino-2-methylpropane, hydrochloride
  • Step D ⁇ -(2-?-Butoxycarbonylamino-2-methylpropyl)- '-[2,3 ,4,5- tetrahydro-2-oxo-lH-l-benzazepin-3(R)-yllurea l-Amino-2-f-butoxycarbonylamino-2-methylpropane hydrochloride (777 mg, 3.46 mmol) was dissolved in 2 mL of methanol and to this solution was added triethylamine (357 mg, 3.53 mmol, 1.02 eq) dropwise. The reaction mixture was triturated with ether (100 mL) and the solid was filtered off through Celite.
  • Patent 5,206,235 in 5 mL of methylene chloride was added by syringe.
  • the white suspension was stirred at room temperature under a nitrogen atmosphere for 2 hours and then the solvent was removed under vacuum.
  • the residue was purified by column chromatography on silica gel (eluant ethyl acetate) to give the product as a white solid (664 mg, 73%).
  • Step E -(2 ⁇ Butoxycarbonylamino-2-methylpropyl)-/v " '-[2,3 ,4,5- tetrahydro-2-oxo- 1 -[[2'-( ⁇ triphenylmethyl)tetrazol-5-yl- r 1.1 '-biphenyll -4-yllmethy 11 - 1 H-benzazepin-3(R)-yl1urea
  • THF dry tetrahydrofuran
  • DMF dimethyl- formamide
  • Step F V-(2-Amino-2-methylpropyl)- '-[2,3,4,5-tetrahydro-2-oxo- l-[[2'-(lH-tetrazol-5-yl)[l,r-biphenyl]-4-yl]methyl]-lH- benzazepin-3(R)-yllurea. trifluoroacetate
  • Step A -[2-[2(T )-Benzyloxypropyl]amino-2-methylpropyl]- ⁇ '- [2,3,4,5-tetrahydro-2-oxo-l-[[2'-(lH-tetrazol-5-yl)[l,r- biphenyl]-4-yl]methyl]-lH-benzazepin-3(R)-yl]urea, trifluoroacetate
  • Step B V-[2-[2(R)-Hydroxypropyl]amino-2-methylpropyl]- ⁇ '- [2,3,4,5-tetrahydro-2-oxo-l -[[2'-(lH-tetrazol-5-yl)[ 1,1'- biphenyl] -4-yl]methyl] - 1 H-benzazepin-3(R)-yl]urea, trifluoroacetate
  • Step A 4-Methyl-2'-nitro-l .1 '-biphenyl
  • Step B 4-Bromomethyl-2'-nitro- 1.1 '-biphenyl
  • Step C 4-Hvdroxymethyl-2'-nitro- 1.1 '-biphenyl
  • Step D 4-(Tetrahydropyranyloxy)methyl-2'-nitro-l .1 '-biphenyl
  • Step E 4-(Tetrahydropyranyloxy)methyl-2'-amino-l .1 '-biphenyl
  • Step F 4-(Tetrahydropyranyloxy)memyl-2'-[(me yla ⁇ nino- carbonyDaminol -1.1 '-biphenyl
  • Step H 4-Bromomemyl-2'-[(methylaminocarbonyl)amino] -1 , 1 '- biphenyl
  • Step I 7V-[4'-[[3(R)-[[[(2-f-Butoxycarbonylamino-2-methylpropyl)- amino]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-lH- benzazepin- 1 -y llmethyll IT .1 '-biphenyll -2-yll -TV'-methylurea
  • 7V-(2-f-butoxy- carbonylamino-2-methylpropyl)-N'-I2,3,4,5-tetrahydro-2-oxo-lH- l-benzazepin-3(R)-yl]urea (Example 1, Step D) in 3 mL of dry THF/DMF (5:1) under a nitrogen atmosphere at room temperature was added 8.9 mg (0.22 mmol, 1.2 eq.) of 60% sodium hydride oil dispersion.
  • Step J -[4'-[[3(R)-[[[(2-Ammo-2-memylpropyl)amino]carbonyl]- amino] -2,3 ,4,5-tetrahy dro-2-oxo- 1 H-benzazepin- 1 -yl] - methyl] IT .1 '-biphenyll -2-y l]-7V'-methylurea.
  • trifluoroacetate A solution of 95 mg (0.13 mmol) of the intermediate obtained in Step I in 4 mL of dry methylene chloride was treated with trifluoroacetic acid (1.0 mL). After stirring at room temperature overnight, the reaction mixture was evaporated under vacuum.
  • Step A V-(2-r-Butoxycarbonylamino-2-methylpropyl)-7V'-[2,3,4,5- tetrahydro-2-oxo- 1 -[ [2'-nitro[ 1 , 1 '-biphenyl] -4-yl]methyl] -
  • Step B - -(2 ⁇ Butoxycarbonylarnino-2-methylpropyl)- ⁇ '-[2,3 ,4,5- tetrahy dro-2-oxo- 1 -[ [2'-amino[ 1 , 1 '-biphenyl] -4-yl]methy 1] -
  • Step C V-[4'-[[3(R)-[[[(2-r-Butoxycarbonylamino-2-methylpro ⁇ yl)- amino]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-lH- benzazepin-1 -yl]methyl] [1,1 '-biphenyl] -2-yl] -TV- [2-(2- propenylcarboethoxy)ethyl]urea
  • Step D ⁇ -[4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino] -2,3 ,4,5-tetrahy dro-2-oxo- 1 H-benzazepin- 1 -yl] - methyl][ 1 , 1 '-biphenyl]-2-yl]-W-[2-(2-propenylcarbo- ethoxy)ethynurea. trifluoroacetate
  • Step E ⁇ -[4'-[[3(R)-[[[(2-Amino-2-methylpropyl)amino]carbonyl]- amino]-2,3,4,5-tetrahydro-2-oxo-lH-benzazepin-l-yl]- methyl] [1,1 '-biphenyl]-2-yl]-N'-(2-hydroxyethyl)urea, trifluoroacetate
  • Step A ⁇ K2 ⁇ Butoxycarbonylammo-2-memylpropyl)- ⁇ '-[2,3,4,5- tetrahydro-2-oxo- 1 -[ [2'-nitro[ 1 , 1 '-biphenyl] -4-yl]methyl] - lH-benzazepin-3(R)-yl1urea
  • Step B 7V-(2 ⁇ Butoxycarbonylamino-2-methylpropyl)-7V'-[2,3,4,5- tetrahydro-2-oxo-l-[[2'-amino[l,l'-biphenyl]-4-yl]methyl]-
  • Step C ⁇ r -(2-r-Butoxycarbonylamino-2-methylpropyl)-7V'-[2,3 ,4,5- tetrahydro-2-oxo- 1 -[ [2'-(methylcarbony lamino) [ 1,1'- biphenyll -4- yllmethyll - 1 H-benzazepin-3 (R)-yllurea
  • a solution of 64 mg (0.11 mmol) of the intermediate obtained in Step B in 1 mL of dry methylene chloride was added to a solution of acetic anhydride (1.00 mL of a 0.127 M solution in methylene chloride, 0.127 mmol, 1.1 eq) in the presence of excess triethylamine at 0°C (wet ice bath).
  • Step D -(2-Amino-2-methylpropyl)W-[2,3,4,5-tetrahydro-2-oxo- 1 -[[2'-(methylcarbonylamino)[ 1 , 1 '-biphenyl] -4-yl]methyl]- lH-benzazepin-3(R)-yllurea. trifluoroacetate
  • Step A ⁇ -(2 ⁇ Butoxycarbonylamino-2-methylpropyl)- '-[2,3,4,5- tetrahydro-2-oxo- 1 -[ [2'-[ [(acetoxymethyl)carbonyl] amino] - T 1.1 '-biphenyll -4-yllmethyll - 1 H-benzazepin-3 (R)-y llurea
  • a solution of 123 mg (0.215 mmol) of N-(2-t- butoxycarbonylamino-2-methylpropyl)-/> '-[2,3 ,4,5-tetrahydro-2-oxo- 1 - [[2'-amino [ 1 , l'-biphenyl] -4-yl]methyl] - 1 H-benzazepin-3(R)-yl]urea (Example 5, Step B) in 1 mL of dry methylene chloride was added to a solution of acetoxyacetyl chloride (1
  • Step B 7V-(2-Amino-2-methylpropyl)- ⁇ '-[2,3,4,5-tetrahydro-2-oxo- 1 -[[2'-[[(acetoxymethyl)carbonyl]amino] [1,1 '-biphenyl]-4- yllmethyll- lH-benzazepin-3(R)-yl1urea.
  • trifluoroacetate A solution of 51 mg (0.87 mmol) of the intermediate obtained in Step A in 3 mL methanol was treated with 1 mL of 9 N hydrochloric acid. After stirring at room temperature for 6 hours, the solvent was removed under vacuum.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Endocrinology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouveaux composés dits lactames benzo condensés favorisant la libération de l'hormone de croissance chez l'homme et l'animal. Cette propriété peut s'appliquer aux animaux de boucherie pour améliorer le rendement de production de viande et à l'homme pour accroître la taille d'individus souffrant d'une sécrétion insuffisante d'hormone de croissance. L'invention porte également sur des compositions à base desdits composés favorisant la croissance.
PCT/US1994/014374 1993-12-13 1994-12-09 Lactames benzo condenses favorisant la liberation de l'hormone de croissance WO1995016675A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU13718/95A AU1371895A (en) 1993-12-13 1994-12-09 Benzo-fused lactams promote release of growth hormone

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US149,482 1988-01-28
US14948293A 1993-12-13 1993-12-13

Publications (1)

Publication Number Publication Date
WO1995016675A1 true WO1995016675A1 (fr) 1995-06-22

Family

ID=22530482

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/014374 WO1995016675A1 (fr) 1993-12-13 1994-12-09 Lactames benzo condenses favorisant la liberation de l'hormone de croissance

Country Status (2)

Country Link
AU (1) AU1371895A (fr)
WO (1) WO1995016675A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6239131B1 (en) * 1996-12-10 2001-05-29 Zeria Pharmaceutical Co., Ltd. 1,5 Benzodiazepine derivatives
US6242199B1 (en) 1995-12-13 2001-06-05 Merck & Co., Inc. Assays for growth hormone secretagogue receptors
WO2001085695A1 (fr) * 2000-05-11 2001-11-15 Bristol-Myers Squibb Co. Analogues de tetrahydroisoquinoline servant de secretagogues d'hormones de croissance
US6380184B1 (en) 1998-10-28 2002-04-30 Bristol-Myers Squibb Co. Benzoazepines and analogs thereof useful as growth hormone secretagogues
LT4958B (lt) 1999-03-12 2002-10-25 Bristol-Myers Squibb Company Heterocikliniai aromatiniai junginiai naudingi kaip augimo hormonų išskyrimą didinantys preparatai
US6525203B1 (en) 1999-03-12 2003-02-25 Bristol-Myers Squibb Company Heterocyclic aromatic compounds useful as growth hormone secretagogues
US6531314B1 (en) 1996-12-10 2003-03-11 Merck & Co., Inc. Growth hormone secretagogue receptor family
US6599718B1 (en) 1998-07-13 2003-07-29 Merck & Co., Inc. Growth hormone secretagogue related receptors and nucleic acids
US6645726B1 (en) 1998-08-10 2003-11-11 Merck & Co., Inc. Canine growth hormone secretagogue receptor
US6649606B1 (en) 2001-11-09 2003-11-18 Bristol-Myers Squibb Co. Tetrahydroisoquinoline analogs as modulators of chemokine receptor activity
US6682908B1 (en) 1998-07-10 2004-01-27 Merck & Co., Inc. Mouse growth hormone secretagogue receptor
WO2005120477A2 (fr) 2004-06-07 2005-12-22 Merck & Co., Inc. N- (2-benzyl) -2-phenylbutanamides modulant le recepteur d'androgene
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
WO2008134828A2 (fr) 2007-05-04 2008-11-13 Katholieke Universiteit Leuven Protection contre la dégénérescence tissulaire
WO2013190520A2 (fr) 2012-06-22 2013-12-27 The General Hospital Corporation Agents de libération de gh dans le traitement d'une sténose vasculaire et d'états associés
WO2015181676A1 (fr) 2014-05-30 2015-12-03 Pfizer Inc. Dérivés carbonitriles en tant que modulateurs sélectifs du récepteur des androgènes
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury
WO2023275715A1 (fr) 2021-06-30 2023-01-05 Pfizer Inc. Métabolites de modulateurs sélectifs du récepteur des androgènes

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5374721A (en) * 1992-10-14 1994-12-20 Merck & Co., Inc. Benzo-fused lactams promote release of growth hormone

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5374721A (en) * 1992-10-14 1994-12-20 Merck & Co., Inc. Benzo-fused lactams promote release of growth hormone

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6242199B1 (en) 1995-12-13 2001-06-05 Merck & Co., Inc. Assays for growth hormone secretagogue receptors
US6239131B1 (en) * 1996-12-10 2001-05-29 Zeria Pharmaceutical Co., Ltd. 1,5 Benzodiazepine derivatives
US6531314B1 (en) 1996-12-10 2003-03-11 Merck & Co., Inc. Growth hormone secretagogue receptor family
US6682908B1 (en) 1998-07-10 2004-01-27 Merck & Co., Inc. Mouse growth hormone secretagogue receptor
US6599718B1 (en) 1998-07-13 2003-07-29 Merck & Co., Inc. Growth hormone secretagogue related receptors and nucleic acids
US6645726B1 (en) 1998-08-10 2003-11-11 Merck & Co., Inc. Canine growth hormone secretagogue receptor
US6380184B1 (en) 1998-10-28 2002-04-30 Bristol-Myers Squibb Co. Benzoazepines and analogs thereof useful as growth hormone secretagogues
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
US6525203B1 (en) 1999-03-12 2003-02-25 Bristol-Myers Squibb Company Heterocyclic aromatic compounds useful as growth hormone secretagogues
US6969727B2 (en) 1999-03-12 2005-11-29 Bristol-Myers Squibb Company Heterocyclic aromatic compounds useful as growth hormone secretagogues
LT4958B (lt) 1999-03-12 2002-10-25 Bristol-Myers Squibb Company Heterocikliniai aromatiniai junginiai naudingi kaip augimo hormonų išskyrimą didinantys preparatai
US6660760B1 (en) 1999-03-12 2003-12-09 Bristol-Myers Squibb Co. Heterocyclic aromatic compounds useful as growth hormone secretagogues
US7053110B2 (en) 1999-03-12 2006-05-30 Bristol-Myers Squibb Company Heterocyclic aromatic compounds useful as growth hormone secreagogues
US6908938B2 (en) 1999-03-12 2005-06-21 Bristol-Myers Squibb Company Heterocyclic aromatic compounds useful as growth hormone secretagogues
WO2001085695A1 (fr) * 2000-05-11 2001-11-15 Bristol-Myers Squibb Co. Analogues de tetrahydroisoquinoline servant de secretagogues d'hormones de croissance
US6469024B2 (en) 2000-05-11 2002-10-22 Bristol-Myers Squibb Company Tetrahydroisoquinoline analogs useful as growth hormone secretagogues
US6649606B1 (en) 2001-11-09 2003-11-18 Bristol-Myers Squibb Co. Tetrahydroisoquinoline analogs as modulators of chemokine receptor activity
WO2005120477A2 (fr) 2004-06-07 2005-12-22 Merck & Co., Inc. N- (2-benzyl) -2-phenylbutanamides modulant le recepteur d'androgene
WO2008134828A2 (fr) 2007-05-04 2008-11-13 Katholieke Universiteit Leuven Protection contre la dégénérescence tissulaire
WO2013190520A2 (fr) 2012-06-22 2013-12-27 The General Hospital Corporation Agents de libération de gh dans le traitement d'une sténose vasculaire et d'états associés
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury
US10617740B2 (en) 2014-02-05 2020-04-14 The Regents Of The University Of California Methods of treating mild brain injury
US11241483B2 (en) 2014-02-05 2022-02-08 The Regents Of The University Of California Methods of treating mild brain injury
WO2015181676A1 (fr) 2014-05-30 2015-12-03 Pfizer Inc. Dérivés carbonitriles en tant que modulateurs sélectifs du récepteur des androgènes
US10328082B2 (en) 2014-05-30 2019-06-25 Pfizer Inc. Methods of use and combinations
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs
WO2023275715A1 (fr) 2021-06-30 2023-01-05 Pfizer Inc. Métabolites de modulateurs sélectifs du récepteur des androgènes

Also Published As

Publication number Publication date
AU1371895A (en) 1995-07-03

Similar Documents

Publication Publication Date Title
EP0659179B1 (fr) Lactames a benzofusion stimulant la liberation de l'hormone de croissance
AU676501B2 (en) Benzo-fused lactams promote release of growth hormone
AU676525B2 (en) Substituted dipeptide analogs promote release of growth hormone
WO1995009633A1 (fr) Lactanes benzo-fusionnes promoteurs de la liberation de l'hormone de croissance
WO1995016675A1 (fr) Lactames benzo condenses favorisant la liberation de l'hormone de croissance
WO1995003290A1 (fr) Lactames benzo-fusionnes promoteurs de la liberation de l'hormone de croissance
US5606054A (en) Heterocyclic-fused lactams promote release of growth hormone
WO1995003289A1 (fr) Lactames benzofuses promoteurs de la secretion de l'hormone de croissance
US5726307A (en) Benzo-fused lactams promote release of growth hormone
US5284841A (en) Benzo-fused lactams promote release of growth hormone
US5438136A (en) Benzo-fused macrocycles promote release of growth hormone
RO117326B1 (ro) Derivati de lactame benzo-condensate, procedeu de preparare si compozitie care ii contine
US5726319A (en) Biphenyl substituted dipeptide analogs promote release of growth hormone
US6211174B1 (en) Naphtho-fused lactams promote release of growth hormone

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AM AU BB BG BR BY CA CN CZ EE FI GE HU JP KG KR KZ LK LR LT LV MD MG MN NO NZ PL RO RU SI SK TJ TT UA US UZ

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD SZ AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载