EP0669830A1 - Substituierte dipeptidanaloge, welche die freisetzung von wachstumshormon unterstützen - Google Patents

Substituierte dipeptidanaloge, welche die freisetzung von wachstumshormon unterstützen

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Publication number
EP0669830A1
EP0669830A1 EP94900505A EP94900505A EP0669830A1 EP 0669830 A1 EP0669830 A1 EP 0669830A1 EP 94900505 A EP94900505 A EP 94900505A EP 94900505 A EP94900505 A EP 94900505A EP 0669830 A1 EP0669830 A1 EP 0669830A1
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Prior art keywords
amino
methyl
biphenyl
alkyl
phenyl
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EP94900505A
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English (en)
French (fr)
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EP0669830A4 (de
Inventor
Judith M. Pisano
William R. Schoen
Matthew J. Wyvratt
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Merck and Co Inc
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Merck and Co Inc
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Publication of EP0669830A1 publication Critical patent/EP0669830A1/de
Publication of EP0669830A4 publication Critical patent/EP0669830A4/de
Withdrawn legal-status Critical Current

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    • C07D257/00Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04Five-membered rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/25Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
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    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/29Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/30Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
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    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/10Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07DHETEROCYCLIC COMPOUNDS
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    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/10Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic 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
    • C07D403/12Heterocyclic 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 chain containing hetero atoms as chain links
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    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06008Dipeptides with the first amino acid being neutral
    • C07K5/06017Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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    • C07KPEPTIDES
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    • C07K5/06Dipeptides
    • C07K5/06191Dipeptides containing heteroatoms different from O, S, or N

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, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone- releasing hormone or all of these.
  • 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 substituted dipeptide analogs 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 produc ⁇ tive animal.
  • a still further object of this invention is to describe compositions containing the substituted dipeptide analogs 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
  • Rl, R2, Rla, R2a, Rib, and R2b are independently hydrogen, halogen, C1-C7 alkyl, C1 -C3 perfluoroalkyl, C1 -C3 perfluoroalkoxy, -S(0) m - R7a, cyano, nitro, R7b ⁇ (CH2) v -, R7bCOO(CH2) v -, R7bOCO-(CH2)v, R4R5N(CH2)V-, R7bCON(R4)(CH2)v-, R4R5NCO(CH2)V-, R 4 R 5" NCOO(CH2)v-.
  • phenyl or substituted phenyl where the substituenis 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 0 to 3;
  • R3a and R3b are independently hydrogen, R9, C1-C6 alkyl substituted with R9, phenyl substituted with R9, or phenoxy substituted with R9;
  • Rl2a, Rl2b and Rl2c are independently R5a, OR5a, or COR5a ;
  • Rl2a and Rl2b, or Rl2b and Rl2c, 0 r Rl2a and Rl2c, or R4b and Rl2a, or R4b and Rl2a, or R4b and Rl2c, or Rl3 and Rl2c, 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 substituents are hydroxy, -N IORI 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, Cl-C6 alkoxy or hydroxy where RlO and Rl 1 are as defined;
  • Rl 4 is hydrogen, Rl , R2 independently disubstituted phenyl, Cl-ClO alkyl or substituted Cl-ClO alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(0)mR7a, C1-C6 alkoxy, C3- C7 cycloalkyl, Rl, R2 independently disubstituted phenyl, C1-C3 alkoxy, Rl , R2 independently disubstituted phenyl C1-C5 alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl or -NRlORl l where Rl , R2, RlO and Rl 1 are as defined;
  • Rl5 is hydrogen, trifluoromethyl, Rl , R independently disubstituted phenyl, Rl, R2 independently disubstituted naphthyl, C3-C7 cycloalkyl, Cl-ClO alkyl, substituted Cl-ClO alkyl where the substituents are from 1 to 3 of hydroxy, fluoro, S(0) m R7a, C1-C6 alkoxy, C3-C7 cycloalkyl, Rl, R2 independently disubstituted phenyl, Rl, R2 independently disub ⁇ stituted phenyl C1-C3 alkoxy, Rl, R2 independently disubstituted naphthyl, Rl , R2 independently disubstituted naphthyl C1-C3 alkoxy, C1-C5 alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl, -NRlORl 1 or R
  • R 4 , R4a, R4b, R5 and R5a 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- Cio 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 C1-C3 alkoxy, Rl , R2 independently disubstituted phenyl, Cl-C20-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl, or -NRlORl 1 where RlO and Rl 1 are independently hydrogen,
  • R6 is hydrogen, Cl-ClO alkyl, phenyl or phenyl Cl-ClO alkyl;
  • R8 and R8a are independently hydrogen, Cl-ClO alkyl, trifluoromethyl, phenyl, substituted C1 -C10 alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(0) R7a, C1-C6 alkoxy, C3- C7 cycloalkyl, Rl, R2 independently disubstituted phenyl C1-C3 alkoxy, Rl, R2 independently disubstituted phenyl, Cl-C5-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl, or -NRlORl 1 where RlO and Rl 1 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 one or both of R 4 and R5 to form alkylene bridges between the terminal nitrogen and 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.
  • 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 atom fluorine, chlorine, bromine and iodine.
  • Rl, R2, Rla, R2a, Rib, and R2b are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, -S(0) m R7a, R7b ⁇ (CH2)v-, R7bCOO(CH2)v-, R7t>OCO(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 and v is 0 to 2;
  • R3a and R3b are independently hydrogen, R9, C1-C6 alkyl substituted with R9, phenyl substituted with R9, or phenoxy substituted with R9; R9 is as defined above;
  • Rl2a, Rl2b and Rl2c are independently R5a, OR5a, or COR5a ;
  • Rl2a and Rl2b, 0 r Rl2b and Rl2c, or Rl3 and Rl2b or Rl2a and R4b 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,
  • Rl is as defined above and RlO is hydrogen, Cl-C6 alkyl, phenyl Cl-C6 alkyl or C1-C5 alkanoyl-Cl-C6 alkyl;
  • Rl3 is C1-C3 perfluoroalkyl, C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are hydroxy, NRIORI I , 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;
  • Rl4 and Rl5 are as defined above;
  • R4, R4a, R4b, R5 and R5a are independently hydrogen, phenyl, substi ⁇ tuted phenyl, Cl-ClO alkyl, substituted Cl-ClO alkyl, where the substituents on the alkyl or phenyl are from 1 to 5 of hydroxy, C1-C6 alkoxy, C3-C7 cycloalkyl, fluoro, Rl substituted or Rl, R2 indepen ⁇ dently disubstituted phenyl C1-C3 alkoxy, Rl substituted or Rl , R2 independently disubstituted phenyl, Ci-C20-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy or formyl;
  • R4 and R5 can be taken together to form -(CH2)rB(CH2)s- where B is CHRl , o, S(0)m or N-RlO, r and s are independently 1 to 3 and Rl and RlO are as defined above;
  • R6 is hydrogen, Cl-ClO alkyl or phenyl Cl-ClO alkyl; A is
  • R8, R8a and R8b are independently hydrogen, Cl-ClO alkyl, substituted Cl-ClO alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(0) m R7a, Cl-C6 alkoxy, Rl , R2 independently disubstituted phenyl, Cl-C5-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy, formyl, -NRIORI I where RlO and RH are independently hydrogen, C1-C6 alkyl, or C1-C5 alkanoyl-Cl-C6 alkyl; 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 one or both of R4 and R5 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
  • Rl , R2, Rla, R2a, Rib, and R2b are independently hydrogen, halogen, C1-C7 alkyl, C1-C3 perfluoroalkyl, -S(0) m R7a, 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, Cl-C6 alkyl, substituted Ci - C6 alkyl, where the substituents are phenyl and v is 0 to 2;
  • R3a and R3b are independently hydrogen, R9, C1-C6 alkyl substituted with R9, phenyl substituted with R9, or phenoxy substituted with R9;
  • R9 is as defined above;
  • Rl2a, Rl2b and Rl2c are independently R5a or OR5a.
  • Rl2a and Rl2b, or Rl2b and Rl2c, 0 r Rl3 and Rl2b or Rl2a and R4b 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,
  • Rl is as defined above and RlO is hydrogen, Cl-C6 alkyl or C1-C5 alkanoyl-Cl-C6 alkyl;
  • Rl3 is C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl or substituted phenyl; phenyl or substituted phenyl where the substituents on the phenyl are from 1 to 3 of halogen, C1-C6 alkyl, Cl- C6 alkoxy or hydroxy;
  • Rl4 and Rl5 are as defined above;
  • R4, R4a, R4b, R5 and R5a are independently hydrogen, Cl-ClO alkyl, substituted Cl-ClO alkyl, where the substituents on the alkyl are from 1 to 5 of hydroxy, C1-C6 alkoxy, fluoro, Rl substituted or Rl , R2 independently disubstituted phenyl, Cl-C20-alkanoyloxy, C1-C5 alkoxycarbonyl or carboxy;
  • R6 is hydrogen or Cl-ClO alkyl
  • R8, R8a and R8b are independently hydrogen, Cl-ClO alkyl, substituted Cl-ClO alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(0)mR7a, Cl-C6 alkoxy, Rl substituted or Rl, R2 independently disubstituted phenyl, Cl-C5-alkanoyloxy, C1-C5 alkoxycarbonyl, carboxy; or R8 and R8a can be taken together to form -(CH2)t- where t is 2; or R8 and R8a can independently be joined to one or both of R4 and R5 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 0 or 1; p is 0 to 2; q is 1 ; w is 1;
  • X is O, S(0)m; m is 0 or 1;
  • Rl , R2, Rla, R2a, Rib, and R2b are independently hydrogen, halogen, C 1 -C7 alkyl, C 1 -C3 perfluoroalkyl, -S(0) m R7a, 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 Cl- C alkyl, where the substituents are phenyl and v is 0 or 1 ;
  • R3a and R3b are independently hydrogen, R9, or Cl-C6 alkyl substituted with R9;
  • R9 is as defined above;
  • Rl2a, Rl2b and Rl2c are independently R5a.
  • R 12a and Rl2b, or R 12b and R 12c, or Rl 3 and R 12b or R 12a and R4b 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, Rl is as defined above and RlO is hydrogen, Cl-C6 alkyl or C1-C5 alkanoyl C1-C6 alkyl;
  • Rl3 is C1-C6 alkyl, substituted C1-C6 alkyl, where the substituents are phenyl or substituted phenyl; phenyl or substituted phenyl where the substituents on the phenyl are from 1 to 3 of halogen, C1-C6 alkyl, Cl- C ⁇ alkoxy or hydroxy;
  • Rl4 and Rl5 are as defined above;
  • R4, R4a, R4b, R5 and R5a are independently hydrogen, Cl-ClO alkyl, substituted Cl-ClO alkyl, where the substituents on the alkyl are from 1 to 3 of hydroxy, C1-C3 alkoxy, fluoro, Rl substituted or Rl, R2 inde ⁇ pendently disubstituted phenyl, C1-C20 alkanoyloxy, C1-C5 alkoxy ⁇ carbonyl or carboxy;
  • R6 is hydrogen
  • R8, R8a and R8b are independently hydrogen, Cl-ClO alkyl, substituted Cl -ClO alkyl where the substituents are from 1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(0)mR7a, C1-C6 alkoxy, Rl substituted or Rl, R2 independently disubstituted phenyl, Cl-C5-alkanoyloxy, C1-C5 alkoxycarbonyl, 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 one or both of R4 and R5 to form alkylene bridges between the teiminal 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 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 prefened over the compound in which the 3-amino substituent is below the plane of the structure.
  • This center will be designated according to the R/S rules as either R or S depending upon the values of X, n, p and Rl5.
  • 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 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.
  • Amino acid intermediates 1 are, in some cases, commer ⁇ cially available in the form of their N-t-butoxycarbonyl or N- benzyloxycarbonyl derivatives. These intermediates can also be prepared by a variety of methods described in the literature and familiar to one skilled in the art. For example, the Strecker synthesis may be employed for the construction of racemic amino acid inter ⁇ mediates. Resolution can be achieved by classical methods, for example separation of diastereomeric salts by fractional crystallization. Alterna ⁇ tively, a chiral amino acid synthesis may be employed using the procedures described by R.M. Williams and M.N. Im (J. Amer. Chem. Soc, 1 13. 9276-9286, 1991.).
  • Conversion of the free amino acid product to its N-t-butoxycarbonyl (BOC) derivative can be achieved by a number of methods known in the art, for example, treatment with di- t-butyl dicarbonate in an inert solvent such as methylene chloride.
  • Benzyloxycarbonyl (CBz) protected derivatives are obtained by treatment of the amino acid with, for example, benzyl chloroformate.
  • benzyl ester 2 is carried out by treatment with benzyl alcohol in the presence of a coupling agent, such as l-(3-dimethylaminopropyl)-3-e ⁇ hylcarbodiimide hydrochloride (EDC), in methylene chloride with a catalytic amount of 4-dimethylaminopyridine.
  • a coupling agent such as l-(3-dimethylaminopropyl)-3-e ⁇ hylcarbodiimide hydrochloride (EDC)
  • EDC l-(3-dimethylaminopropyl)-3-e ⁇ hylcarbodiimide hydrochloride
  • Attachment of the amino acid sidechain to intermediates of formula II is accomplished by the route shown in Scheme 2. Coupling is conveniently carried out by the use of an appropriately protected amino acid derivative, such as that illustrated by formula HI, and 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.
  • BOP benzotriazol-l-yloxytris(dimethylamino)- phosphonium hexafluorophosphate
  • the protecting group G must be selected to be compatible with the conditions employed for removal of the specific class of ester present in 4. Hence, as illustrated for the benzyl ester 4, G is taken as t- butoxycarbonyl. It may further be appreciated that other combinations of protecting group G and ester functionality may be employed; for example, the benzyloxycarbonyl protecting group is inert to the standard conditions of aqueous sodium hydroxide employed to hydrolyze methyl or ethyl esters. SCHEME 2
  • the protected amino acid derivatives III are, in many cases, commercially available in t-butoxycarbonyl (BOC) or benzyloxy- carbonyl (CBz) forms.
  • BOC t-butoxycarbonyl
  • CBz benzyloxy- carbonyl
  • G is t-butoxycarbonyl or benzyloxycarbonyl
  • the substituted phenyl sidechains V are prepared from the conesponding alkylating agent VI by displacement of the leaving group Y with sodium azide as shown in Scheme 5. Reduction of the azide product by hydrogenation in the presence of a transition metal catalyst, or alternatively by reaction with triphenylphosphine followed by hydrolysis, gives the desired amine derivative 10. Conversion to the desired intermediate V is achieved by the aforementioned reductive alkylation procedure.
  • Y is a leaving group
  • an alternative route involves coupling of intermediate IV with R14NH2 using one of the coupling reagents described previously, followed by alkylation of the amide bond with VI.
  • Alkylation is carried out in an inert solvent, such as dimethylformamide, using a strong base such as sodium hydride or potassium t-butoxide at temperatures of 0°-100°C.
  • Alkylating agents VI are, in some cases, commercially available or may be prepared by the procedures described in the following schemes. SCHEME 6
  • G is t-butoxycarbonyl or benzyloxycarbonyl
  • Alkylating agents VI are, in some cases commercially available compounds or may be prepared by methods described in the literature and familiar to one skilled in the art.
  • Compounds of formula I wherein R3a or R3b is a tetrazole (13) are prepared as described in Scheme 7 by reaction of IV with a suitably substituted intermediate H containing a nitrile as tetrazole precursor.
  • Elaboration to the desired product j_3 is carried out by treatment with trimethyltin azide in boiling toluene.
  • R4R5NH is conveniently carried out by the use of a coupling reagent such as benzotriazol-l-yloxytris-(dimethylamino)phosphonium hexafluorophosphate ("BOP") in an inert solvent such as methylene chloride.
  • BOP benzotriazol-l-yloxytris-(dimethylamino)phosphonium hexafluorophosphate
  • G is t-butoxycarbonyl
  • reduction of the nitro group of 32 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 32 must be compatible with the experimental conditions anticipated for reduct ⁇ ion.
  • intermediate 32 wherein G is t-butoxycarbonyl (BOC) are stable to the conditions of catalytic reduction employed in the conversion to 37.
  • Intermediate 37 may also be further elaborated to new intermediate 38 . by reductive alkylation with an aldehyde by the aforementioned procedures.
  • Terminally disubstituted compounds 40 can be obtained directly by reaction of 37 with a disubstituted carbamoyl chloride in an inert solvent such as methylene chloride in the presence of triethylamine or 4-dimethylaminopyridine.
  • monosubstituted compounds 41 wherein either R4b or R 12a is hydrogen are obtained from 37 by reaction with an isocyanate as shown in Scheme 18.
  • amine 32 is converted to an isocyanate 42 by treatment with phosgene or an equivalent reagent such as bis(trichloro- methyl)carbonate (triphosgene) as indicated in Scheme 19. Subsequent reaction of 42 with primary or secondary amines in an inert solvent such as methylene chloride gives the conesponding urea derivates 43 in good yield. Isocyanate 42 is also converted to substituted semi- carbazides 44 or hydroxy- or alkoxyureas 45 by reaction with substituted hydrazines or hydroxy- or alkoxy lamines, respectively.
  • phosgene or an equivalent reagent such as bis(trichloro- methyl)carbonate (triphosgene) as indicated in Scheme 19.
  • Isocyanate 42 is also converted to substituted semi- carbazides 44 or hydroxy- or alkoxyureas 45 by reaction with substituted hydrazines or hydroxy- or alkoxy lamines, respectively.
  • G is t-butoxycarbonyl or benzyloxycarbonyl SCHEME 20 (cont'd)
  • Reaction of 48 with an isocyanate leads directly to carbamate analogs 49.
  • treatment of 48 with N,N'- carbonyldiimidazole in dimethylformamide can form an activated intermediate which will react with substituted hydrazine reagents to give carbazate products 50.
  • Conversion of the carboxylic acid to the benzylamine derivative 52 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 52 can be further elaborated to 5 by the aforementioned reductive amination procedure.
  • G is benzyloxycarbonyl
  • G is benzyloxycarbonyl
  • Desilylation is carried out by treatment with tetra-n-butylammonium fluoride; conversion to the O-methanesulfonate 62 is achieved by reaction of the intermediate benzyl alcohol with methanesulfonic anhydride. Conversion to the requisite amine derivative V is achieved by the procedure described in Scheme 5.
  • BOC is t-butoxycarbonyl
  • Removal of t-butoxy ⁇ carbonyl (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.
  • 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.
  • 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, pinephrine 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, pinephrine and norepinephrine
  • the pancreatic and gastrointestinal hormones e.g., insulin, glucagon, gastrin, secretin
  • 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 produc ⁇ tion 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 pharmaceu ⁇ tical 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 prostaglan- dins, 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 still further use of the disclosed novel substituted dipeptide analogs is in combination with other growth hormone secretagogues such as GHRP-6, GHRP-1 as described in U.S. Patent Nos. 4,411,890; and publications WO 89/07110 and WO 89/07111 and B-HT920 or growth hormone releasing factor and its analogs or growth hormone and its analogs or somatomedins including IGF-1 and IGF-2.
  • a still further use of the disclosed novel substituted dipeptide analogs is in combination with ⁇ 2 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.
  • 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 burn patients; Treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushings syndrome; Induction of pulsati
  • 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 pharma ⁇ ceutically 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.
  • Zinc chloride (3.3 g, 24.3 mmol, 0.5 eq) was added to 15 mL of N,N-dimethylformamide in small portions while maintaining the temperature below 60°C.
  • the suspension of zinc chloride was cooled to room temperature and treated with 5.0 g of benzonitrile (48.5 mmol, 1.0 eq) followed by 3.2 g of sodium azide (48.5 mmol, 1.0 eq).
  • the heterogeneous mixture was heated at 115°C with agitation for 18 hours.
  • the mixture was cooled to room temperature, water (30 mL) was added and the mixture acidified by the addition of 5.1 mL of concentrated hydrochloric acid.
  • the mixture was cooled to 0°C and aged for one hour, then filtered and the filter cake washed with 15 mL of cold 0.1N HC1 then dried at 60°C under vacuum to afford 6.38 g (43.7 mmol, 90%) of the product.
  • Step B 5-Phenyl-2-trityltetrazole
  • Step C N-Triphenylmethyl-5-r2-(4'-methylbiphen-4-yl)ltetrazole
  • a solution of zinc chloride (6.3 g, 46.2 mmol, 0.6 eq) in 35 mL of tetrahydrofuran was dried over molecular sieves.
  • 5-Phenyl-2- trityltetrazole (30.0 g, 77.3 mmol, 1.0 eq) was dissolved in 300 mL of dry tetrahydrofuran and the solution gently stirred while being degassed three times by alternating vacuum and nitrogen purges.
  • the stirred solution was cooled to -15°C and treated slowly with 50.5 mL of 1.6 M n-butyllithium in hexane (80.0 mmol, 1.05 eq) so as to maintain the temperature below -5°C.
  • the solution was maintained at -5 to -15°C for 1.5 hours then treated with the dried zinc chloride solution and allowed to warm to room temperature.
  • the solution was warmed to room tempera ⁇ ture and added, under nitrogen purge, to the arylzinc solution.
  • the reaction mixture was stirred vigorously for 8 hours at room tempera ⁇ ture then quenched by the slow addition of a solution of 10 mL of glacial acetic acid (1.6 mmol, 0.02 eq) in 60 mL of tetrahydrofuran at a rate so that the temperature was maintained below 40°C.
  • the mixture was stirred for 30 minutes and 150 mL of 80% saturated aqueous sodium chloride was added; the reaction mixture was extracted for 30 minutes and the layers allowed to separate.
  • the organic layer was removed and washed with 150 mL of 80% saturated aqueous sodium chloride buffered to pH >10 by the addition of ammonium hydroxide.
  • the organic phase was removed and concentrated under vacuum to approximately 50 mL then 250 mL of acetonitrile was added.
  • the mixture was again concentrated under vacuum to 50 mL and acetonitrile added to make the final volume 150 mL.
  • the resulting slurry was cooled at 5°C for 1 hour then filtered and washed with 50 mL of cold acetonitrile followed by 150 mL of distilled water.
  • Step D N-Triphenylmethyl-5-[2-(4'-bromomethylbiphen4- vDltetrazole
  • Step E N-Triphenylmethyl-5-[2-(4'-azidomethylbiphen-4- vDltetrazole
  • Step F N-Triphenylmethyl-5-[2-(4'-aminomethylbiphen-4- vDltetrazole
  • Step G (R)- ⁇ -[t-Butoxycarbonylamino]-N-[[2'-(N-triphenyl- methyl-tetrazol-5-yl)[l, -biphenyl]-4-yl]methyl]benzene- butanamide
  • Step F To a solution of 30.5 mg (0.11 mmol) of N-BOC-D- homophenylalanine in 1 mL of methylene chloride at room temperature under a nitrogen atmosphere was added 54 mg (0.11 mmol, 1 eq) of N- triphenylmethyl-5-[2-(4'aminomethylbiphen-4-yl)]tetrazole (Step F), 25 mg (0.13 mmol, 1.2 eq) of l-(3-dimethylaminopropyl)-3-ethylcarbodii- mide hydrochloride and 13 mg (0.13 mmol, 1.2 eq) of triethylamine.
  • the reaction was stirred at room temperature for 16 hours, then transferred to a separatory funnel and washed with 2 mL of 5% aqueous citric acid and 2 mL of saturated aqueous sodium bicarbonate. The organic layer was removed, dried over magnesium sulfate, filtered and evaporated to dryness under vacuum. The residue was chromato- graphed on a silica flash column, eluting with hexane/ethyl acetate (5: 1), to give 29 mg (35%) of the product.
  • Step H (R)- ⁇ -[t-Butoxycarbonylam ⁇ o]-N-[[2'-(lH-tetrazol-5- yl)r 1.1 '-biphenyl 1-4-yl .methyl 1-benzene-butanamide
  • a solution of 29 mg (0.038 mmol) of the intermediate obtained in Step G in 1 mL of methanol was hydrogenated at room temperature and one atmosphere over 4 mg of 20% palladium hydroxide on carbon for two hours.
  • the reaction mixture was then filtered through Celite to remove the catalyst, the solvent removed under vacuum and the residue flash chromatographed on silica to yield 19 mg (95%) of the title compound.
  • Step I (R)- ⁇ -Amino-N-[[2'-(lH-tetrazol-5-yl)[l ,1 '-biphenyl]-
  • Step J 2.2-Dimethylbutanedioic acid. 4-methyl ester
  • 2,2-Dimethylsuccinic acid (20 g, 137 mmol) dissolved in 200 mL of absolute methanol at 0°C 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.
  • Step K 3-Benzyloxycarbonylamino-3-methylbutanoic acid, methyl ester
  • Step L 3-Benzyloxycarbonylamino-3-methylbutanoic acid
  • a solution of 18.27 g (68.9 mmol) of 3-benzyloxycar- bonylamino-3-methylbutanoic acid methyl ester in 20 mL of methanol at room temperature was treated dropwise with 51 mL of 2N NaOH (102 mmol).
  • the mixture was stined 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°C and slowly acidified to pH 2 (paper) by dropwise addition of 6N HCl.
  • Step M 3-Benzyloxycarbonylamino-3-methylbutanoic acid, N- hydroxysuccinimide ester
  • Step N (R)- ⁇ -[(3-Benzyloxycarbonylamino-3-methyl- 1 -oxo- butyl)amino]-N-[[2'-(lH-tetrazol-5-yl)-[l ,1 '-biphenyl]- 4yllmethyllbenzenebutanamide
  • a solution of 12 mg (0.023 mmol) of the intermediate obtained in Step I in 0.5 mL of methylene chloride at room temperature was treated with 9.2 mg (0.027 mmol, 1.2 eq) of 3-benzyloxy- carbonylamino-3-methylbutanoic acid, N-hydroxysuccinimide ester (Step M) and 3.5 mg (0.027 mmol, 1.2 eq) of diisopropylethylamine.
  • Step O (R)- ⁇ -[(3-Amino-3-methyl-l-oxobutyl)amino]-N-[[2'-(lH- tetrazol-5-yl)[l ,1 '-biphenyl] -4-yl]methyl] benzenebutana- mide. tri-fluoroacetate
  • Step A (R)- ⁇ -[t-Butoxycarbonylamino]-N-[[2'-(N-triphenyl- memyl-tetrazol-5-yl)[l, -biphenyl]-4-yl]methyl]-(Nim- formyl)indole-3-propanamide
  • Step B (R)-a-[t-Butoxycarbonylamino]-N-[[2'-(lH-tetrazol-5- yl)[l ,l'-biphenyl]-4-yl]methyl]-(Nim-formyl)indole-3- propanamide
  • Step C (R)- ⁇ -Amino-N-[[2'-(lH-tetrazol-5-yl)[l ,l '-biphenyll-4- yl]methyl]-(Nim-formyl)indole-3-propanamide, trifluoroacetate
  • Step D 4.4-Dimethylazetidin-2-one
  • a 3-neck 3L round bottom flask equipped with a magnetic stiner, thermometer, cold finger condenser and nitrogen bubbler was charged with IL 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 12L round bottom flask fitted with a mechanical stiner and diluted with 2L of ether.
  • the well-stined reaction mixture was treated with 2L of saturated aqueous sodium sulfite. After 1 hour, an additional IL 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 2 x 1 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 3 x IL 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 concen ⁇ trated under vacuum to give 67.7 g of product.
  • Further extraction of the aqueous layer with 4 x IL 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 4 x IL of methylene chloride gave an additional 21.9 g of product.
  • reaction mixture was stined at room temperature overnight then diluted with IL 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 aqueous layer was acidified by the addition of IL of saturated aqueous sodium bisulfate, then extracted with 1 x IL and 2 x 500 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 give 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.
  • lH NMR 200 MHz, CDCI3: 1.39 (s, 6H), 1.44 (s, 9H), 2.72 (s, 2H).
  • FAB-MS calculated for C10H19NO4 217; found 218 (M+H, 54%).
  • Step G (R)- ⁇ - [(3 -t-Butoxycarbonylamino-3 -methyl- 1 -oxo- butyl)amino]-N-[[2'-(lH-tetrazol-5-yl)-[l,l'-biphenyl]-4- yl .methy l .- ( Nirp-formyl)-indole-3 -propanamide
  • reaction mixture was evaporated to dryness under vacuum and the residue was dissolved in 1 mL of anisole and treated with 4 mL of trifluoroacetic acid.
  • the mixture was stined at room temperature for 30 minutes the concentrated under vacuum.
  • the residue was taken up in methanol and the solids removed by filtration.
  • the filtrate was concentrated under vacuum; the residue was purified by reverse phase high pressure liquid chromatography on C18 to yield 31 mg (42%) of the product.
  • Step H (R)- ⁇ -[(3-Amino-3-methyl-l-oxobutyl)amino]-N-[[2'-(lH- tetrazol-5-y 1) [1,1 '-biphenyl] -4-yl]methyl]- 1 H-indole-3 - propanamide.
  • Step A (R)-2-(t-Butoxycarbonylamino)-N-phenyl-butanamide Prepared from N-BOC-D-2-aminobutanoic acid and aniline by the method described in Example 1, Step G.
  • lH NMR 200 MHz, CDC13: 1.00 (t, 6Hz, 3H), 1.45 (s, 9H), 1.82 (m, 2H), 4.30 (m, IH), 5.59 (d, 7Hz, IH), 7.00-7.62 (m, 5H), 8.90 (br s, IH).
  • FAB-MS calculated for C15H22N2O3 278; found 279 (M+l, 40%).
  • Step B (R)-2-(t-Butoxycarbonylamino)-N-phenyl-N-[[2'-(N- triphenylmethyl-tetrazol-5-yl)-[l,l'-biphenyl]-4-yl]methyl]- butanamide
  • the mixture was stiTred at room temperature for 2 hours, then quenched by the addition of 2 mL of water.
  • the mixture was extracted several times with ethyl acetate; the combined extracts were washed with 5% aqueous citric acid, saturated aqueous sodium bicarbonate then dried over magnesium sulfate, filtered and the filtrate dried under vacuum.
  • the crude material was chromatographed on a flash silica column, eluting with hexane/ethyl acetate (1:1), to give 91 mg (48%) of the product.
  • Step C (R)-2-(t-Butoxycarbonylamino)-N-phenyl-N-[[2'-( 1H- tetrazol-5-yl)-ri. -biphenyl1-4-yllmethyl1butanamide Prepared from the intermediate obtained in Step B by the procedure described in Example 1, Step H.
  • lH NMR 200 MHz, CDCI3: 0.74 (t, 6Hz, 3H), 1.36 (s, 9H), 1.55 (m, 2H), 4.13 (m, IH), 4.70 (d, 14Hz, IH), 5.02 (d, 14Hz, IH), 5.22 (m, IH), 7.00-7.62 (m, 12H), 8.01 (m, IH).
  • Step E 3-t-Butoxycarbonylamino-3-methylbutanoic acid, N- hydroxysuccinimide ester
  • Step F (R)-2-[(3-t-Butoxycarbonylamino-3-methyl-l -oxobutyl)- amino]-N-phenyl-N-[[2'-(lH-tetra-zol-5-yl)[l,l'-biphenyl]-
  • Step G (R)-2-[(3-Amino-3-methyl-l -oxobutyl)amino]-N-phenyl-N- [[2'-(lH-tetrazol-5-yl)[l ,l'-biphenyl]-4-yl]methyl]- butanamide. trifluoroacetate
  • Step A 2-t-Butoxycarbonylamino-N-[[2'-(N-triphenylmethyl- tetrazol-5-yl)[l.r-biphenvn-4-y 11 -methy 11 acetamide Prepared from N-triphenylmethyl-5-[2-(4'-aminomethyl- biphen-4-yl)]tetrazole (Example 1, Step F) and N-BOC-glycine by the procedure described in Example 1 , Step G.
  • Step B 2-t-Butoxycarbonylamino-N-[[2'-(lH-tetrazol-5-yl)[l ,1 '- biphenyl1-4-yl1methyl1acetamide
  • Step C 2-Amino-N-[[2'-(lH-tetrazol-5-yl)[l,l'-bi-phenyl]-4- yllmethyllacetamide. hvdrochloride
  • Step D 2-[(3-Benzyloxycarbonylamino-3-methyl- 1 -oxo-butyl)- amino]-N-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4yl]- methy 11 acetamide
  • Step E 2-[(3-Amino-3-methyl-l-oxobutyl)amino]-N-[[2'-(lH- tetrazol-5-yl)[l , -biphenyl]-4-yl]methyl]acetamide, trifluoroacetate
  • Step A N-(t-Butoxycarbonyl)-D-tryptophan benzyl ester
  • Finely divided t-butoxycarbonyl-D-tryptophan (3 g, 10 mmol) was suspended in methylene chloride and benzyl alcohol (1.08 mL, 10 mmol) and 4-dimethylaminopyridine (0.12 g, 1 mmol) were added and stined at room temperature.
  • Solid l-(3-dimethylamino- propyl)-3-ethylcarbodiimide hydrochloride (1.92 g, 10 mmol) was then added in three roughly equal portions over 5 minutes. The reaction mixture was stined for 3 hours at room temperature during which time the reaction mixture became a homogeneous solution.
  • the reaction mixture was poured into water (100 mL) and extracted with methylene chloride (2 x 50 mL). The combined methylene chloride layers were washed with 5% aqueous citric acid solution (100 mL) and 5% aqueous sodium bicarbonate solution (100 mL). The resulting methylene chloride layer was dried over magnesium sulfate, filtered and evaporated under vaccum to give an off-white solid. This solid material was chromatographed on silica gel using ethyl acetate/hexanes (2:3 v/v) as eluant. This afforded 3.56 g (91%) of the desired benzyl ester as a white amorphous powder.
  • Step B D-Tryptophan benzyl ester
  • N-(t-Butoxycarbonyl)-D-tryptophan benzyl ester (3.5 g, 8.87 mmol) was dissolved in methylene chloride (10 mL) and stined at room temperature and trifluoroacetic acid (20 mL) was added dropwise to the ester. The reaction mixture was stined at room temperature for one hour during which time the reaction darkened. The reaction mixture was directly evaporated under vacuum to give a white solid. This solid was dissolved in chloroform (100 mL) and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with chloroform (2 x 25 mL) and the combined chloroform layers were dried over potassium carbonate.
  • Step C (R)- ⁇ -[(2-t-Butoxycarbonylamino-2-methyl-l-oxopropyl)- aminol-lH-indole-3-propanoic acid, benzyl ester
  • the chloroform layer was separated and washed with 5% aqueous citric acid solution (25 mL) and 5% aqueous sodium bicarbonate solution (25 mL).
  • the chloroform layer was dried over magnesium sulfate, filtered and evaporated under vacuum to afford a thick oily foam. Chromatography on silica gel using ethyl acetate/hexanes (2:3 v/v) afforded a yellow foam (0.822 g 50%).
  • Step D (R)- ⁇ -[(2-t-Butoxycarbonylamino-2-methyl- 1 -oxopropyl)- aminol-lH-indole-3-propanoic acid
  • the benzyl ester (0.82 g, 1.71 mmol) obtained in Step C and 10% palladium on carbon (150 mg) were stined together in ethyl acetate (5 mL).
  • the solution was degassed and a hydrogen atmosphere introduced over the reactants using a balloon for 32 hours.
  • the reaction products were isolated by filtering the reaction mixture through a Celite plug. The plug was washed with additional ethyl acetate (3 x 10 mL). The combined filtrates were evaporated under vacuum to afford the product (680 mg, 102%).
  • Step E 4-Methyl-2'-nitro- 1.1 '-biphenyl
  • Step F 4-Bromomethy l-2'-nitro- 1.1 '-biphenyl
  • Step G 4-Azidomethyl-2'-nitro- 1.1 '-biphenyl
  • Step H 4-Aminomethyl-2'-nitro- 1.1 '-biphenyl
  • Step I (R)- ⁇ -[(2-t-Butoxycarbonylamino-2-methyl- 1 -oxopropyl)- amino]-N-[[(2'-nitro)[ 1 ,1 '-biphenyl] -4-yl]methyl]-lH- indole-3-propanamide
  • reaction mixture was stined togerther for 3.5 hours then the reaction was quenched by adding saturated aqueous sodium chloride (10 mL) and extracted with methylene chloride (3 x 20 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated under vacuum. The resulting thick gum was chromatographed on silica gel using ethyl acetate/hexanes (1 :2 v/v) to give 297 mg (50%) of an orange semi-solid.
  • Step J (R)- ⁇ -[(2-t-Butoxycarbonylamino-2-methyl-l -oxopropyl)- amino] -N-[ [(2'-amino) [1,1 '-biphenyl] -4-y ljmethy 1] - 1 H- indole-3 -propanamide
  • the amide (142 mg, 0.24 mmol) from Step I was dissolved in ethanol (5 mL) and 10% palladium on carbon (15 mg) was added.
  • the ethanolic mixture was degassed and a hydrogen atmosphere introduced and maintained above the reaction mixture for 2.5 hours using a balloon.
  • the hydrogenation catalyst was removed by filtration through a Celite pad. The pad was washed carefully with methylene chloride (4 x 5 mL). The combined filtrates were evaporated under vacuum to give a powdery white foam (124 mg, 92%).
  • Step K (R)- ⁇ -[(2-t-Butoxycarbonylamino-2-methyl-l -oxopropyl)- amino]-N-[[2'-[[(methylamino)-carbonyl]amino][l ,1 '- biphenyl]-4-yl]methyll-lH-indole-3-propanamide
  • Step L (R)- ⁇ -[(2-Amino-2-methyl-l-oxopropyl)amino]-N-[[2'-
  • Step K The intermediate obtained in Step K (15 mg, 0.023 mmol) and anisole (0.01 mL, 0.09 mmol) were dissolved in methanol (0.5 mL) and hexanes (0.5 mL). To this solution 0.5 mL of 9 N aqueous hydro ⁇ chloric acid was added. The reactants were stined at room temperature for 30 minutes then the hexane layer was removed using a pipette. The aqueous methanolic layer was evaporated at atmospheric pressure using a fast stream of nitrogen at room temperature.

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EP94900505A 1992-11-06 1993-10-29 Substituierte dipeptidanaloge, welche die freisetzung von wachstumshormon unterstützen. Withdrawn EP0669830A4 (de)

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US97314292A 1992-11-06 1992-11-06
PCT/US1993/010551 WO1994011012A1 (en) 1992-11-06 1993-10-29 Substituted dipeptide analogs promote release of growth hormone
US973142 2001-10-09

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US20020111461A1 (en) 1999-05-21 2002-08-15 Todd C. Somers Low molecular weight peptidomimetic growth hormone secretagogues
JPH08325248A (ja) * 1995-05-26 1996-12-10 Chugoku Kayaku Kk テトラゾール類の新規な合成試薬及びそれを用いたテトラゾール類の製造方法
EP0828754B1 (de) * 1995-05-29 2005-02-02 Pfizer Inc. Dipeptide, die die ausschüttung von wachstumshormonen stimulieren
JP3798024B2 (ja) 1995-12-13 2006-07-19 メルク エンド カンパニー インコーポレーテッド 成長ホルモン分泌促進物質レセプターアッセイ
US6531314B1 (en) 1996-12-10 2003-03-11 Merck & Co., Inc. Growth hormone secretagogue receptor family
GB2308362A (en) * 1995-12-19 1997-06-25 Lilly Industries Ltd Pharmaceutical indole derivatives
WO1998058947A1 (en) 1997-06-25 1998-12-30 Pfizer Inc. Dipeptide derivatives as growth hormone secretagogues
UA53716C2 (uk) 1997-06-25 2003-02-17 Пфайзер Продактс Інк. Тартратна сіль заміщеного дипептиду, спосіб її одержання, проміжні сполуки та спосіб їх одержання, фармацевтична композиція (варіанти), спосіб підвищення рівнів ендогенного гормону росту та спосіб лікування або профілактики захворювань (варіанти)
UA64751C2 (uk) 1997-06-25 2004-03-15 Пфайзер Продактс Інк. Спосіб лікування інсулінової толерантності речовинами, які посилюють секрецію гормону росту (варіанти) та фармацевтична композиція (варіанти)
US6682908B1 (en) 1998-07-10 2004-01-27 Merck & Co., Inc. Mouse growth hormone secretagogue receptor
WO2000002919A1 (en) 1998-07-13 2000-01-20 Merck & Co., Inc. Growth hormone secretagogue related receptors and nucleic acids
CA2340095A1 (en) 1998-08-10 2000-02-24 Merck & Co., Inc. Canine growth hormone secretagogue receptor
US6358951B1 (en) 1998-08-21 2002-03-19 Pfizer Inc. Growth hormone secretagogues
CA2362290A1 (en) 1999-02-18 2000-08-24 Kaken Pharmaceutical Co., Ltd. Novel amide derivatives as growth hormone secretagogues
ATE446758T1 (de) 2000-05-31 2009-11-15 Pfizer Prod Inc Verwendung von wachstumshormonsekretagoga zur förderung der beweglichkeit des verdauungstrakts
DE602004014321D1 (de) * 2003-01-16 2008-07-24 Teva Pharma Neue synthese von irbesartan
US7476653B2 (en) 2003-06-18 2009-01-13 Tranzyme Pharma, Inc. Macrocyclic modulators of the ghrelin receptor
UA87854C2 (en) 2004-06-07 2009-08-25 Мерк Энд Ко., Инк. N-(2-benzyl)-2-phenylbutanamides as androgen receptor modulators
CU23558A1 (es) 2006-02-28 2010-07-20 Ct Ingenieria Genetica Biotech Compuestos análogos a los secretagogos peptidicos de la hormona de crecimiento
EP1931648A2 (de) * 2006-08-29 2008-06-18 Teva Pharmaceutical Industries Ltd. Verfahren zur synthese von 5-phenyl-1-trityl-1h-tetrazol
EP2644618B1 (de) 2007-02-09 2016-08-17 Ocera Therapeutics, Inc. Intermediaten für die Synthese von Makrozyklische Ghrelin-Rezeptormodulatoren
WO2008134828A2 (en) 2007-05-04 2008-11-13 Katholieke Universiteit Leuven Tissue degeneration protection
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US9119832B2 (en) 2014-02-05 2015-09-01 The Regents Of The University Of California Methods of treating mild brain injury
BR112016027778A2 (pt) 2014-05-30 2017-08-15 Pfizer Usos de derivados de carbonitrila, sua combinação e sua composição farmacêutica
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