WO1997036873A1 - Piperidines, pyrrolidines et hexahydro-1h-azepines declenchant la liberation de l'hormone de croissance - Google Patents

Piperidines, pyrrolidines et hexahydro-1h-azepines declenchant la liberation de l'hormone de croissance Download PDF

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WO1997036873A1
WO1997036873A1 PCT/US1997/005378 US9705378W WO9736873A1 WO 1997036873 A1 WO1997036873 A1 WO 1997036873A1 US 9705378 W US9705378 W US 9705378W WO 9736873 A1 WO9736873 A1 WO 9736873A1
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alkyl
aryl
phenyl
group
hydrogen
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PCT/US1997/005378
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English (en)
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Prasun K. Chakravarty
Meng H. Chen
Ravi Nargund
Arthur A. Patchett
James R. Tata
Mu Tsu Wu
Lihu Yang
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Merck & Co., Inc.
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Priority claimed from GBGB9609664.9A external-priority patent/GB9609664D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU27222/97A priority Critical patent/AU2722297A/en
Publication of WO1997036873A1 publication Critical patent/WO1997036873A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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 processes of the body: (1) Increased rate of protein synthesis in all cells of the body; (2) Decreased rate of carbohydrate utilization in cells of the body; (3) Increased mobilization of free fatty acids and use of fatty acids for energy.
  • a deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.
  • Various ways are known to release growth hormone.
  • chemicals such as arginine, L-3,4-dihydroxyphenyl- alanine (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.
  • GRF growth hormone releasing factor
  • the problem was generally solved by providing exogenous growth hormone or by administering GRF or a peptidal compound which stimulated growth hormone production and/or release.
  • 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.
  • Recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.
  • Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Patent 4,411,890.
  • Non peptidal growth hormone secretagogues are disclosed in e.g., U.S. Patent Nos 5,206,235, 5,283,241,
  • the instant invention is directed to certain piperidines, pyrrolidines, and hexahydro-lH-azepines which have the ability to stimulate the release of natural or endogenous growth hormone.
  • the compounds thus have the ability to be used to treat conditions which require the stimulation of growth hormone production or secretion such as in humans with a deficiency of natural growth hormone or in animals used for food or wool production where the stimulation of growth hormone will result in a larger, more productive animal.
  • a still further object of this invention is to describe compositions containing the piperidine compounds for the use of treating humans and animals so as to increase the level of growth hormone secretions. Further objects will become apparent from a reading of the following description.
  • Rl is selected from the group consisting of:
  • R 1 a is hydrogen or C 1 -C4 alkyl
  • R2 is selected from the group consisting of: hydrogen, -C1-C6 alkyl, -C3-C7 cycloalkyl, and -CH2-phenyl, wherein the alkyl or the cyloalkyl is unsubstituted or substituted with hydroxyl, C1-C3 alkoxy, thioalkyl, C(0)OR2a, and where, if two -Cl- C ⁇ alkyl groups are present on one atom, they may be joined to form a C3-C8 cyclic ring being selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, optionally substituted by hydroxyl;
  • R2a i hydrogen or C1-C6 alkyl
  • B is selected from:
  • R3 is selected from: hydrogen, -(CH2)rphenyl, -(CH2)rthienyl, -(CH2)rbenzimidazolyl, -(CH2)rquinolinyl, -(CH2)rna ⁇ hthyl, -(CH2)rindolyl, -Cl-ClO alkyl, -C3-C7 cycloalkyl, where the phenyl, naphthyl, indolyl, thienyl, benzimidazolyl, quinolinyl, and C3-C7 cycloalkyl rings may be substituted by 1 to 3 substituents selected from the group consisting of: C1-C6 alkyl, halogen, -OR 2 , -NHSO2CF3, -(CH 2 )rOR6, -(CH2)rN(R2)(R6), -(CH 2 )r(R 6 ), -(CH 2 ) ⁇ C(0)OR2, -(CH
  • R3a and R ⁇ b are independently selected from: hydrogen, phenyl, phenoxy, halophenyl, -Cl-C6 alkyl, halogen, -OR2, methylenedioxy, -S(0) m R2, -CF3, -OCF3, nitro, -N(R2)(R2), -N(R2)C(0)(R2), -C(0)OR2, -C(0)N(R2)(R2), -S ⁇ 2N(R2)(R2), -N(R2)S ⁇ 2-aryl, and -N(R 2 )S02R2;
  • R4 and R ⁇ are independently selected from hydrogen, C1-C6 alkyl, and substituted C1-C6 alkyl where the substituents are selected from halo, hydroxy, phenyl, and C1-C6 alkoxycarbonyl; or R5 and R 4 may be taken together to form -(CH2)d-L a (CH2)e- where L a is -C(R 2 )2-, -0-, -S(0) m - or -N(R 2 )-, d and e are independently 1 to 3 and R2 is as defined above;
  • R4 and R ⁇ b are independently selected from: hydrogen, C1-C6 alkyl, trifluoromethyl, phenyl, or substituted C1-C6 alkyl where the substituents are selected from: imidazolyl, naphthyl, phenyl, indolyl, p-hydroxyphenyl, -OR2, -S(0) m R 2 , -C(0)OR2, C3-C7 cycloalkyl, -N(R2)(R2), -C(0)N(R2)(R2) ; or R4a and R4 may independently be joined to one or both of R4 or R4c to form an alkylene bridge between the terminal nitrogen and the alkyl portion of the R4a or R4b anc ⁇ the R or R4c group, wherein the bridges contain 1 to 8 carbons atoms; or R4a and R4b ma y be joined to one another to form C3-C7 cycloalkyl;
  • R4c is selected from hydrogen, C1-C6 alkyl, and substituted C1-C6 alkyl where the substituents are selected from 1 to 5 halo, 1 to 3 hydroxy, phenyl, napthyl, imidazolyl, indolyl, and C1-C6 alkoxycarbonyl;
  • R6 is selected from: hydrogen, C1-C6 alkyl, and (CH2)varyl, wherein the (CH2)v and alkyl groups may be optionally substituted by -0(R2), -S(0) m R 2 , -C(0)OR2, -C(0)N(R2)(R2), -S ⁇ 2N(R2)(R2), O ⁇ -N(R 2 )C(0)N(R2)(R2), wherein the aryl group is selected from: phenyl, pyridyl, lH-tetrazolyl, triazolyl, oxadiazolyl, pyrazolyl, thiadiazoyl, and benzimidazol-2-yl, which is optionally substituted with C1-C6 alkyl, C3-C6 cycloalkyl, amino, or hydroxyl;
  • X is selected from the group consisting of: hydrogen, -C ⁇ N, -(CH2)qN(R2)C(0)R2, -(CH2)qN(R2)C(0)(CH2)taryl, -(CH2)qN(R2)S ⁇ 2(CH2)taryl, -(CH2)qN(R2)S ⁇ 2R 2 , -(CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2),
  • aryl is phenyl, naphthyl, pyridyl, thiazolyl, or lH-tetrazol-5-yl groups which may be optionally substituted with halogen, -OR2, -CON(R2)(R2), -C(0)OR2, C1-C4 alkyl, -S(0) m R2, or lH-tetrazol-5- yi;
  • Y is selected from the group consisting of: hydrogen, Cj -ClO alkyl, -(CH2)taryl,
  • D is selected from: -N(R?)-, -S(0) m -, -C(O)- and -C(H)(R7)-, wherein R? is selected from: -R2, -OR2, -(CH2) q aryl, -C(0)R 2 , -C(0)(CH2)qaryl, -S02R 2 , -S ⁇ 2(CH2) q aryl, -C(0)N(R2)(R2), -C(0)N(R2)(CH2) q aryl, -C(0)OR2, l-H-tetrazol-5-yl, -S ⁇ 2N(R2)aryl, -S ⁇ 2N(R2)(R2) and the (CH2)q may be optionally substituted by C1-C4 alkyl, and the R2 and aryl may be optionally further substituted with a substituent selected from: -OR 2 a, -0(CH2)q aryl, -C(0)OR 2 a,
  • n 0, 1 or 2
  • n 0, 1, or 2
  • q 0, 1, 2, 3, or 4
  • r 0, 1 , 2, or 3
  • t is O, 1, 2, or 3
  • v 0, 1, or 2;
  • n 1 a pyrrolidine ring is formed, when n is 2 a piperidine ring is formed, and when n is 3 the ring is designated a hexahydro- 1 -H-azepine.
  • alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration and if two carbon atoms or more they may include a double or a triple bond.
  • exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, propargyl, and the like .
  • the alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond.
  • alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.
  • halogen is intended to include the halogen atom fluorine, chlorine, bromine and iodine.
  • aryl within the present invention, unless otherwise specified, is intended to include aromatic rings, such as carbocyclic and heterocyclic aromatic rings selected the group consisting of: phenyl, naphthyl, pyridyl, l-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrrazinyl, or isothiazolyl, which may be optionally substituted by 1 to 3 of Cl-C6 alkyl, 1 to 3 of halogen, 1 to 2 of OR2, methylenedioxy, -S(0) R2, 1 to 2 of -CF3, -OCF3, nitro, -N(R2)C(0)(R2), -C(0)OR2, -C(0)N(R2)(R2), -1H- tetrazol
  • Preferred compounds of the instant invention include those of Formula Ia:
  • Rl is selected from the group consisting of:
  • -C(0)0-, -CR2 CR2- or -C ⁇ C-, wherein R2 and the alkyl groups may be further substituted with 1 to 9 halo, -S(0) m R2a, 1 to 3 of -OR 2 a 0 r -C(0)OR2a, and wherein aryl is phenyl or naphthyl, and heteroaryl is selected from indolyl, thiophenyl, benzofuranyl, benzothiopheneyl, aza-indolyl, pyrindinyl, quinolinyl, and benzimidazolyl, wherein aryl and heteroaryl are unsubstituted or substituted with phenyl, phenoxy, halophenyl, 1 to 3 of -Cl-C ⁇ alkyl, 1 to 3 of halo, 1 to 2 of -OR 2 , methylenedioxy, -S(0) m R 2 , 1 to 2 of 10 -
  • R2 is selected from the group consisting of: hydrogen, -Cl-C6 alkyl, -C3-C7 cycloalkyl, and -CH2-phenyl, wherein the alkyl or the cyloalkyl is unsubstituted or substituted with hydroxyl, C1-C3 alkoxy, thioalkyl, -C(0)OR 2 a, and wherein, if two -C1-C6 alkyl groups are present on one atom, the groups may be optionally joined to form a C3-C8 cyclic ring being selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine;
  • B is selected from:
  • R3 is selected from: hydrogen, phenyl, naphthyl, indolyl, benzimidazolyl, thienyl, quinolinyl, where the phenyl, naphthyl, benzimidazolyl, thienyl, quinolinyl, and indolyl may be substituted by 1 to 3 substituents selected from the group consisting of: C1-C6 alkyl, halogen, -OR2 -(CH2) ⁇ OR6, -(CH2) ⁇ N(R2)(R6), -(CH 2 )r(R 6 ), -(CH2)rC(0)OR2, -(CH2) r C(0)OR6, -(CH2) ⁇ C(0)R2, -(CH2)rC(0)R6, -(CH 2 )rC(0)N(R2)(R2), -(CH2)rC(0)N(R2)(R6), -(CH2)rC(0)N(R2)(R6), -(CH2)
  • R ⁇ and R ⁇ b are independently selected from: hydrogen, phenyl, phenoxy, halophenyl, -Cl-C6 alkyl, halogen, -OR2, methylenedioxy, -S(0) m R 2 , -CF3, -OCF3, nitro, -N(R2)(R2), -N(R2)C(0)(R2), -C(0)OR2, -C(0)N(R2)(R2), -S ⁇ 2N(R2)(R2), -N(R2)S ⁇ 2-aryl, and -N(R2)SQ2R2 ;
  • R4 and R ⁇ are independently selected from hydrogen, C1-C6 alkyl, and substituted C1-C6 alkyl where the substituents are selected from halo, hydroxy, phenyl, and C1-C6 alkoxycarbonyl; or R5 and R may be taken together to form -(CH2)d-La(CH2)e- where L a is -C(R 2 )2-, -0-, -S(0) m - or -N(R 2 )-, d and e are independently 1 to 3 and R2 is as defined above;
  • R4a and R b are independently selected from: hydrogen, C1-C6 alkyl, trifluoromethyl, phenyl, or substituted C1-C6 alkyl where the substituents are selected from: imidazolyl, naphthyl, phenyl, indolyl, p-hydroxyphenyl, -OR 2 , -S(0) m R 2 , -C(0)OR , C3-C7 cycloalkyl, -N(R2)(R2), -C(0)N(R2)(R2); 0 r R4a and R4b may independently be joined to one or both of R or R4c to form an alkylene bridge between the terminal nitrogen and the alkyl portion of the R4 or R4b and the R4 or R4c group, wherein the bridges contain 1 to 5 carbons atoms; or R4a and R4b ma y be joined to one another to form C3-C7 cycloalkyl;
  • R4c is selected from hydrogen, C1-C6 alkyl, and substituted C1-C6 alkyl where the substituents are selected from 1 to 5 halo, 1 to 3 hydroxy, phenyl, C1-C6 alkoxycarbonyl;
  • R6 is selected from: hydrogen, C1-C6 alkyl, and (CH2)varyl, wherein the (CH2)v and alkyl groups may be optionally substituted by -0(R 2 ), -S(0) m R 2 , -C(0)OR2, -C(0)N(R2)(R2), -S02N(R2)(R2), G r -N(R2)C(0)N(R2)(R2), wherein the aryl group is selected from: phenyl, pyridyl, lH-tetrazolyl, triazolyl, oxadiazolyl, pyrazolyl, thiadiazoyl, and benzimidazol-2-yl, which is optionally substituted with C1-C6 alkyl, C3-C6 cycloalkyl, amino, or hydroxyl;
  • X is selected from the group consisting of: hydrogen, -C ⁇ N, -(CH2)qN(R2)C(0)R2, -(CH2) q N(R2)C(0)(CH2)taryl, -(CH2)qN(R2)S ⁇ 2(CH2)taryl, -(CH2)qN(R2)S ⁇ 2R 2 , -(CH2)qN(R 2 )C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH2)qC(0)N(R2)(CH2)taryl, -(CH2)qC(0)OR2, -(CH2)qC(0)0(CH2) t aryl, -(CH2)qOR2, -(CH2)qOC(0)R2, -(CH2)qOC(0)(CH2) t aryl,
  • R2 (CH 2 )q and (CH2)t group may be optionally substituted with C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, N(R2)(R2) S CONH2, (0)mCH3, carboxylate C1-C4 alkyl esters, or lH-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or lH-tetrazol-5-yl groups which may be optionally substituted
  • Y is selected from the group consisting of: hydrogen, Cl-Cio alkyl, -(CH2)taryl,
  • D is selected from: -N(R?)-, -S(0) m -, -C(O)- and -C(H)(R?)-, wherein R 7 is selected from: -R2, -(CH2)qaryl, -C(0)R 2 , -S02R , -C(0)N(R2)(R2), -C(0)OR2, l-H-tetrazol-5-yl, -S ⁇ 2N(R2)aryl, -S ⁇ 2N(R2)(R2) and the (CH2)q may be optionally substituted by C1-C4 alkyl, and the R2 and aryl may be optionally further substituted with a substituent selected from: -OR 2 a, -C(0)OR2a, -C(0)N(R2a)(R2a) ?
  • halogen, -C1-C4 alkyl, and the aryl is selected from of triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, and lH-tetrazolyl;
  • More preferred compounds of the instant invention include those of Formula lb:
  • Rl is selected from the group consisting of:
  • R2 is selected from the group consisting of: hydrogen, -Cl-C6 alkyl, -C3-C7 cycloalkyl, and -CH2- ⁇ henyl, wherein the alkyl or the cyloalkyl is unsubstituted or substituted with hydroxyl, C1-C3 alkoxy, thioalkyl, -C(0)OR 2 a, and wherein, if two -C1-C6 alkyl groups are present on one atom, the groups may be optionally joined to form a C3-C8 cyclic ring being selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine;
  • R3 is selected from: hydrogen or phenyl, wherein the phenyl is substituted in the ortho position by a substituent selected from the group consisting of: Cl-C6 alkyl, halogen, -OR2, -(CH2) r OR 6 , -(CH2) ⁇ N(R2)(R6), -(CH2)r(R 6 ), -(CH2)rC(0)OR2, -(CH 2 ) ⁇ C(0)OR6, -(CH2) I C(0)R2, -(CH 2 )rC(0)R6, -(CH 2 )rC(0)N(R2)(R2), -(CH2)rC(0)N(R2)(R6), .(CH2)rS02N(R2)(R6), -(CH2)rS ⁇ 2N(R2)(R2), -(CH2)rS(0) m R6, and -(CH2) r S(0) m R 2 ;
  • R3 and R ⁇ b are independently selected from: hydrogen, -Cl-C6 alkyl and halogen;
  • R4 and R5 are independently selected from hydrogen, Cl-C6 alkyl, and substituted Cl-C6 alkyl where the substituents are selected from halo, hydroxy, phenyl, and -C6 alkoxycarbonyl; or R5 and R4 may be taken together to form -(CH2)d-La(CH2)e- where L a is -C(R2)2-, -0-, -S(0) m - or -N(R 2 )-, d and e are independently 1 to 3 and R2 is as defined above;
  • R4 and R b are independently selected from: hydrogen, Cl-C6 alkyl, or substituted Cl-C6 alkyl where the substituents are selected from: imidazolyl, naphthyl, phenyl, indolyl, and p-hydroxyphenyl;
  • R4c is selected from hydrogen, Cl-C6 alkyl, and substituted Cl-C6 alkyl where the substituents are selected from 1 to 5 halo, 1 to 3 hydroxy, phenyl, Cl-C6 alkoxycarbonyl;
  • R6 is selected from: hydrogen, C1-C6 alkyl, and (CH2)varyl, wherein the (CH2)v and alkyl groups may be optionally substituted by -0(R2), -S(0) m R 2 , -C(0)OR2, -C(0)N(R2)(R2), -S ⁇ 2N(R2)(R2) ⁇ or -N(R2)C(0)N(R2)(R2), wherein the aryl group is selected from: phenyl, pyridyl, lH-tetrazolyl, triazolyl, oxadiazolyl, pyrazolyl, thiadiazoyl, and benzimidazol-2-yl, which is optionally substituted with
  • X is selected from the group consisting of: hydrogen,
  • heterocycle is optionally substituted with a substituent selected from: -N(R2)(R2), -0(R 2 ), -C3 alkyl, halogen, and trifluoromethyl;
  • Y is selected from the group consisting of: hydrogen,
  • D is selected from: -N(R 7 )-, -S(0) m -, -C(O)- and -C(H)(R 7 )-, wherein R 7 is selected from: -R 2 , -(CH2)qaryl, -C(0)R 2 , -S02R 2 , -C(0)N(R2)(R2), -C(0)OR2, l-H-tetrazol-5-yl, -S ⁇ 2N(R2)aryl, -S ⁇ 2N(R2)(R2) and the (CH2)q may be optionally substituted by C1-C4 alkyl, and the R2 and aryl may be optionally further substituted with a substituent selected from: -OR 2 a, -C(0)OR 2 a, -C(0)N(R2a)(R2a) ; halogen, -C1-C4 alkyl, and the aryl is selected from
  • B is selected from the group consisting of:
  • Another embodiment of the most preferred compounds of the instant invention includes compounds of the formula:
  • B is selected from the group consisting of:
  • Another embodiment of the most preferred compounds of the instant invention includes compounds of the formula:
  • B is selected from the group consisting of:
  • B is selected from the group consisting of:
  • the compounds of the instant invention have at least two asymmetric centers when B is:
  • both X and Y are groups other than hydrogen and are different from each other. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixture and as pure or partially purified compounds are included within the ambit of this invention. In the case of the asymmetric center which bears the X and Y groups, in most cases, both R- and &- configurations are consistent with useful levels of growth hormone secretagogue activity. In addition configurations of many of the most preferred compounds of this invention are
  • diastereomer 1 (dl) and diastereomer 2 (d2) are arbitrarily referred to as diastereomer 1 (dl) and diastereomer 2 (d2) in this invention and, if desired, their independent syntheses or chromatographic separations may be achieved as described herein.
  • Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
  • 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, methane sulfonic 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.
  • the preparation of compounds of Formula I of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses detailing the preparation of the compounds of Formula I in a sequential manner are presented in the following reaction schemes.
  • standard peptide coupling reaction conditions is used repeatedly here, and it means coupling a carboxylic acid with an amine using an acid activating agent such as EDC, DCC, and BOP in a inert solvent such as dichloromethane in the presence of a catalyst such as HOBT.
  • an acid activating agent such as EDC, DCC, and BOP
  • a inert solvent such as dichloromethane
  • HOBT a catalyst
  • protective groups for amine and carboxylic acid to facilitate the desired reaction and minimize undesired reactions are well documented. Conditions required to remove protecting groups which may be present and can be found in Greene, T, and Wuts, P. G. M., Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, NY 1991. CBZ and BOC were used extensively in the synthesis, and their removal conditions are known to those skilled in the art.
  • removal of 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 nobel metal or its oxide such as palladium on activated carbon in a protic solvent such as ethanol.
  • catalytic hydrogenation can also be achieved by treatment with a solution of hydrogen bromide in acetic acid, or by treatment with a mixture of TFA and dimethylsulfide.
  • BOC protecting groups Removal of BOC protecting groups is carried out in a solvent such as methylene chloride or methanol or ethyl acetate, with a strong acid, such as trifluoroacetic acid or hydrochloric acid or hydrogen chloride gas.
  • a strong acid such as trifluoroacetic acid or hydrochloric acid or hydrogen chloride gas.
  • the protected amino acid derivatives 1 are, in many cases, commercially available, where the protecting group L is, for example, BOC or CBZ groups.
  • Other protected amino acid derivatives 1 can be prepared by literature methods (Williams, R. M. Synthesis of Optically Active a- Amino Acids, Pergamon Press: Oxford, 1989).
  • R 4 is substituted/ unsubstituted alkyl
  • 3-Monosubstituted piperidines of formula 13 can be prepared by the reduction of pyridine derivatives or their salts by hydrogenation in a suitable organic solvent such as water, acetic acid, alcohol, e.g. ethanol, or their mixture, in the presence of a noble metal catalyst such as platinum or an oxide thereof on a support such as activated carbon, and conveniently at room temperature and atmospheric pressure or under elevated temperature and pressure.
  • a noble metal catalyst such as platinum or an oxide thereof on a support such as activated carbon
  • 3-Monosubstituted pyrrolidines are commercially available or can be conveniently prepared by literature procedures. Shown in Scheme 9A is an example of the preparation of these compounds via pyrrolidine-3-carboxylic acid ester.
  • the commercially available compound methyl l-benzyl-4-oxo-3-pyrrolidinecarboxylate is reduced by borane (J. Chem. Soc 24. 1618-1619). Removal of the benzyl group by catalytic hydrogenolysis followed by ester exchange in an appropriate alcohol medium such as ethyl alcohol in the presence of acid gave the compound 13b.
  • the ester functionality may be further modified through conventional chemistry to other groups as defined by X.
  • 3 -Monosubstituted pyrrolidines may also be prepared by catalytic hydrogenation of 3-substituted pyrroles.
  • Hexahydro-lH-azepines are commercially available or may be prepared by the literature procedure.
  • Hexahydro-lH-azepine-3- carboxylic acid (Krogsgaard-Larsen, P. et al., Acta. Chem. Scand.. B32. 327, (1978)) is esterified in an alcohol solvent in the presence of acid.
  • the ester functionality may be further modified through conventional chemistry to other groups within the definition of X.
  • Illustrated in Scheme 10 is a general way to prepare di ⁇ substituted piperidines, pyrrolidines, and hexahydro-lH-azepines.
  • Compounds of Formula 13 wherein X is an electron withdrawing group such as -CN, -CO2R8, where R ⁇ is alkyl, aryl, and (C l -C4alkyl)aryl are known compounds or may be prepared by methods analogous to those used for the preparation of such known compounds.
  • the secondary amine of compounds of Formula 13 may be first protected by a protecting group L such as BOC and CBZ using the conventional techniques.
  • Introduction of the Y substitution can be achieved by first reacting compounds of Formula 14 with a strong base such as lithium bis(trimethylsilyl)amide, lithium diisopropylamide following by addition of alkylating or acylating reagents such as alkyl halides, aryl alkyl halides, acyl halides, and haloformates in a inert solvent such as THF at temperatures from -100° to room temperature.
  • Thio derivatives where the sulfur is attached directly to an alkyl or an aryl group can be prepared similarly by reacting with a disulfide.
  • the halides used in these reactions are either commercially available or known compounds in the literature or may be prepared by methods analogous to those used for the preparation of known compounds.
  • the protecting group L in compounds of formula 15 may be removed with conventional chemistry to give compounds of Formula 2.
  • the cyanoacetates of general formula 16 may be alkylated with an ethoxycarbonylalkyl bromide or reacted with ethyl acrylate to give compounds of Formula 18.
  • Reduction of the nitriles 18 by borane or by hydrogenation using Raney Ni as a catalyst gives the corresponding primary amines, which upon refluxing in ethanol gives lactam 19.
  • Reduction of the lactam 19 by borane gives compounds of Formula 2a.
  • a malonate of general formula 20 may be alkylated with cyanoalkyl bromide or can be reacted with acrylonitrile to form compounds of formula 21.
  • Reduction of the nitriles 21 by borane or by hydrogenation using Raney Ni as a catalyst gives the corresponding primary amines, which upon refluxing in ethanol gives lactam 22.
  • Reduction of the lactam 22 by borane gives compounds of formula 2a.
  • the X, Y functionalities in compounds of general structure 15 may be further elaborated to groups not accessible by direct alkylation.
  • the ester (provided that this is the only ester group in the molecule) can be saponified to the carboxylic acid, which can be further derivatized to amides or other esters.
  • the carboxylic acid can be converted into its next higher homologue, or to a derivative of the homologous acid, such as amide or ester by an Arndt-Eistert reaction.
  • the ester can be directly homologated by the protocol using ynolate anions described by C. J. Kowalski and R. E. Reddy in J. Org. Chem.. 57. 7194-7208 (1992).
  • the resulting acid and/or ester may be converted to the next higher homologue, and so on and so forth.
  • the protecting group L may be removed through conventional chemistry.
  • the ester in 15a may be reduced to an alcohol 18 in a 5 suitable solvent such as THF or ether with a reducing agent such as DIBAL-H and conveniently carried out at temperatures from -100°C to 0°C.
  • the alcohol may be acylated to Compound 19 in a suitable solvent such as dichloromethane using an acyl halide or acid anhydride in the presence of a base such as triethyl amine (TEA).
  • THF triethyl amine
  • R ⁇ duction of the a e in compounds of Formula 20 to an amine 21 can be achieved by hyc * genation in the presence of a noble metal such as palladium or its oxide or Raney nickel in a protic solvent such as
  • the nitrile can be reduced to afford the homologous amine.
  • the amine of Formula 21 may be further elaborated to amides, ureas sulfonamides as defined by X through conventional chemistry.
  • the protecting group L may be removed through conventional chemistry.
  • a convenient method involves the addition reaction by an activated form of an alkyl, aryl, alkylaryl group, such as lithium reagent, Grignard reagents, and the like with a ketone of general formula 28, which is commercially available. Further derivatization of the resulting hydroxy group by acylation, sulfonylation, alkylation, and the like gives compounds as defined by Y or X through conventional chemistry. Removal of the benzyl protective group may be carried out under the usual conditions to give compounds of general formula 2b. Shown in Scheme 16 is a general example of acylations.
  • a sulfide In cases where a sulfide is present in the molecule, it may be oxidized to a sulfoxide or to a sulfone with oxidizing agents such as sodium periodate, m-chloroperbenzoic acid or Oxone® in an solvent such as dichloromethane, alcohol or water or their mixtures.
  • oxidizing agents such as sodium periodate, m-chloroperbenzoic acid or Oxone® in an solvent such as dichloromethane, alcohol or water or their mixtures.
  • the compounds of the present invention may also be prepared from a variety of substituted natural and unnatural amino acids of formulas 46. The preparation of many of these acids is described in US Patent No. 5,206,237. The preparation of these intermediates in racemic form is accomplished by classical methods familiar to those skilled in the art (Williams, R. M. "Synthesis of Optically Active a-
  • amino acids 46 amino acids.
  • One of the common methods is to resolve amino or carboxyl protected intermediates by crystallization of salts derived from optically active acids or amines.
  • the amino group of carboxyl protected intermediates may be coupled to optically active acids by using chemistry described earlier. Separation of the individual diastereomers either by chromatographic techniques or by crystallization followed by hydrolysis of the chiral amide furnishes resolved amino acids.
  • amino protected intermediates may be converted to a mixture of chiral diastereomeric esters and amides. Separation of the mixture using methods described above and hydrolysis of the individual diastereomers provides (D) and (L) amino acids.
  • an enzymatic method to resolve N-acetyl derivatives of (DL)- amino acids has been reported by Whitesides and coworkers in J. Am. Chem. Soc. 1989, 111, 6354-6364.
  • Intermediates of formula 46 which are 0-benzyl-(D)-serine derivatives 51 are conveniently prepared from suitably substituted benzyl halides and N-protected-(D)-serine 50.
  • the protecting group L is conveniently a BOC or a CBZ group.
  • Benzylation of 64 can be achieved by a number of methods well known in the literature including deprotonation with two equivalents of sodium hydride in an inert solvent such as DMF followed by treatment with one equivalent of a variety of benzyl halides (Synthesis 1989, 36) as shown in Scheme 20.
  • the 0-alkyl-(D)-serine derivatives may also be prepared using an alkylation protocol.
  • the spiro piperidines of formula 52 may be prepared by a number of methods, including the syntheses described below.
  • the spiropiperidine of formula 43 is synthesized by methods that are known in the literature (for example H. Ong et al J. Med. Chem. 1983, 23, 981-986).
  • the indoline nitrogen of 54, wherein L is a protecting group such as methyl or benzyl can be reacted by with a variety of electrophiles to yield spiro piperidines of formula 54, wherein R9 can be a variety of functionalities.
  • Compound 54 can be reacted with, for example, isocyanates in an inert solvent like dichloromethane to yield urea derivatives, chloroformates in an inert solvent such as dichloromethane to yield carbamates, acid chlorides, anhydrides, or acyl imidazoles to generate amides, sulfonyl chlorides to generate sulfonamides, sulfamyl chlorides to yield sulfamides.
  • the indoline nitrogen of 53 can be reductively alkylated with aldehydes with conditions known in the art.
  • the aldehyde used in the reductive amination reaction is a protected glyoxylic acid of structure HCOCOOM, wherein M is a defined protecting group
  • M can be removed from the product and further derivatized.
  • 53 can be reacted with epoxides to produce 53, wherein R ⁇ is ⁇ -hydroxy- substituted alkyl or arylalkyl groups.
  • demethylation can be carried out by a number methods familiar those skilled in the art.
  • demethylation of 54 be accomplished by reacting it with cyanogen bromide and potassium carbonate in an inert solvent solvent such as dichloromethane to yield a cyanamide which can reduced to give 55 by treatment with lithium aluminum hydride in refluxing tetrahydrofuran, refluxing strong acid like aqueous hydrochloric acid, or with Grignard reagents like methyl magnesium bromide.
  • demethylation of 54 can be effected with the ACE-C1 method as described in R. Olofson et al. J. Org. Chem. 1984, 49, 2795 and references therein.
  • cyclization of 60 can be accomplished by reaction with tributyltin hydride (Curran , D. P. Synthesis 1988, 417 and 489) in an inert solvent such as benzene to yield 57.
  • tributyltin hydride Curran , D. P. Synthesis 1988, 417 and 489
  • inert solvent such as benzene
  • oxidizing agents For example, sodium periodate is often used for the synthesis of sulfoxides and Oxone is used for the synthesis of sulfones. Removal of the protecting group provides the amine 56 which then can be inco ⁇ orated into a growth hormone secretagogue via the chemistry detaileds in Scheme 1 and 8 shown above which utilize generic intermediate 2.
  • spiroindanone 64 provides easy access to spiroindanyl intermediates containing acid and ester groups. This chemistry is described in Scheme 26. Treatment of 64 with a base in an inert solvent such as THF followed by the addition of a triflating agent provides the enol triflate. Carboxy lation of the enol triflate according to the procedure of Cacchi, S. Tetrahedron Letters. 1985. 1109-1112 provides the ester 66. The protecting group can then be removed as described above and the resulting amine can be inco ⁇ orated into the subject compound via the chemistry depicted in Schemes 1 and 8. A compound containing an acid function is readily available via saponification of the ester group as the final step of the synthesis .
  • Chiral acids are available by a variety of methods known to those skilled in the art including asymmetric catalytic hydrogenation and resolution of a pair of diastereomeric salts formed by reaction with a chiral amine such as D or L ⁇ -methylbenzylamine.
  • the absolute stereochemistry can be determined in a number of ways including X- ray crystallography of a suitable crystalline derivative.
  • Spiroindane intermediates for inco ⁇ oration into growth hormone secretagogues, can be further elaborated in the benzylic position by the chemistry detailed in the following schemes.
  • homologs of ester 69 can be conveniently prepared by a variety of methods known to those skilled in the art igncluding the displacement of an activated alcohol such as tosylate 70 by a malonate nucleophile followed by decarboxylation or a cuprate reaction followed by the adjustment of the chain length or oxidation state as appropiate.
  • Chiral esters and acids are available by a variety of methods known to those skilled in the art including asymmetric catalytic hydrogenation, chomatographic resolution of a pair of diasteromers, and via crystallization of salts formed from chiral amines such as D or L- ⁇ - methylbenzylamine.
  • the absolute stereochemistry can be determined in a number of ways including X-ray crystallography of a suitable crystalline derivative.
  • the ester can be reduced to an alcohol by treatment with LAH and to an aldehyde with DIBALH. Reductive alkylation of the aldehyde with ammonium acetate and sodium cyanoborohydride affords an amino methyl analog. These hydroxymethyl and aminomethyl analogs may then be further reacted to afford additional growth hormone secretagogues of the general formula 1.
  • ester 44 provides an acid which can be convenientlyly derivatized as for example reaction with an amine in the presence of a coupling reagent such as EDC gives amides which can be inco ⁇ orated into a secretagogue as detailed in Schemes 1 and 8.
  • a coupling reagent such as EDC
  • ester 44 Homologation of ester 44 is possible using a variety of methods known to those skilled in the art including the method described in J. Org. Chem. 1992. 57 7194-7208.
  • acylsulfonamides are readily available from acids such as 67 and 72.
  • Treatment of the spiroindane acid with a base in an inert solvent such as THF followed by the addition of oxalyl chloride provides an acid chloride which is then treated with a sodium salt of a sulfonamide.
  • the protecting group can then be removed using chemistry described above and the resulting amine can be inco ⁇ orated into a final compound using chemistry depicted in Schemes 1 and 8.
  • tetrazole spiroindane intermediates are available from nitriles of both the shorter and longer homolog series.
  • reaction of enol triflate 65 with a cyanide anion and a palladium catalyst in the presence of an inert solvent such as toluene provides the unsaturated nitrile which can be converted into the tetrazole by reaction with trimethylstannyl azide in an inert solvent at elevated temperatures.
  • Reduction of the indene double bond in 78 and 79 with catalysts such as Pd/C in ethanol affords the corresponding saturated analogs.
  • esters such as 69 can be conveniently acylated or alkylated next to the ester function by treatment with a variety of bases and alkylating or acylating agents.
  • reaction of 69 with potassium bis(trimethyl-silylamide) in an inert solvent such as THF followed by the addition of ethyl chloroformate provides 80 in good yield. Removal of the protecting group and inco ⁇ oration into the subject compounds can be accomplished as described above.
  • the inco ⁇ oration of aryl and heteroaryl groups into the benzylic position of spiroindanes is most coveniently carried out via the enol triflate 65.
  • Palladium catalysed reaction of the enol triflate with a variety of aryl or heteroarylstannanes in an inert solvent such as toluene provides the desired intermediates.
  • 2-trimethylstannyl-pyridine reacts with 65 in the presence of a catalytic amount of tetrakis(triphenylphosphene)palladium in toluene at refux to give the coupled product 82.
  • the enol triflate 65 can be converted into the vinyl stannane 83 by reaction with hexamethylditin and a palladium catalyst in an inert solvent such as toluene.
  • the vinyl stannane can then be coupled with a variety of aryl or hetero aryl bromides or triflates, for example coupling to 2-bromo- 3-carbo-methoxypyridine provides 84.
  • the protecting group L can be removed from the coupled products using chemistry described above and the resulting amine can be included in the final compound as described in Schemes 1 and 8.
  • the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • the utility of the compounds of the present invention as growth hormone secretagogues may be demonstrated by methodology known in the art, such as an assay disclosed by Smith , et al., Science. 260. 1640-1643 (1993) (see text of Figure 2 therein).
  • all of the compounds prepared in the following examples had activity as growth hormone secretagogues in the aforementioned assay.
  • Such a result is indicative of the intrinsic activity of the present compounds as growth hormone secretagogues.
  • 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.
  • 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 peptides, e.g., bombesin, the neurokinins; 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,
  • 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 endo ⁇ hin peptides, on the pituitary to modify growth hormone release.
  • some of the pituitary hormones e.g., growth hormone and endo ⁇ hin peptides
  • endo ⁇ hin peptides e.g., growth hormone and endo ⁇ hin 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, to improve feed efficiency 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 pharma ⁇ ceutical compositions can comprise an anabolic 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 growth permittant or an agent to treat osteoporosis or in combination with a corticosteroid to minimize the latter's catabolic side effects or with other pharmaceutically active materials wherein the combination enhances efficacy and minimizes side effects.
  • Growth promoting and anabolic agents include, but are not limited to, TRH, diethylstilbesterol, amino acids, estrogens, ⁇ -agonists, theophylline, anabolic steroids, enkephalins, E series prostaglandins, retinoic acid, 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 compounds of this invention is in combination with other growth hormone secretagogues such as the growth hormone releasing peptides GHRP-6, GHRP-1 as described in U.S. Patent Nos. 4,411,890 and publications WO 89/07110, WO
  • GHRH growth hormone releasing hormone
  • IGF-1 and IGF-2 growth hormone releasing hormone
  • ⁇ -adrenergic agonists such as clonidine or serotonin 5HTID agonists such as sumitriptan or agents which inhibit somatostatin or its release such as physostigmine and pyridostigmine.
  • the compounds of this invention may be used in combination with growth hormone releasing factor, an analog of growth hormone releasing factor, IGF-1, or IGF-2.
  • a compound of the present invention may be used in combination with IGF-1 for the treatment or prevention of obesity.
  • a compound of this invention may be employed in conjunction with retinoic acid to improve the condition of musculature and skin that results from intrinsic aging.
  • the present invention is further directed to a method for the manufacture of a medicament for stimulating the release of growth hormone in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
  • the known and potential uses of growth hormone are varied and multitudinous.
  • the administration of the compounds of this invention for pu ⁇ oses of stimulating the release of endogenous growth hormone can have the same effects or uses as growth hormone itself.
  • the instant compounds are useful for increasing feed efficiency, promoting growth, increasing milk production and improving the carcass quality of livestock.
  • the instant compounds are useful in a method of treatment of diseases or conditions which are benefited by the anabolic effects of enhanced growth hormone levels that comprises the administration of an instant compound.
  • the instant compounds are useful in the prevention or treatment of a condition selected from the group consisting of: osteoporosis; catabolic illness; immune deficiency, including that in individuals with a depressed T4/T8 cell ratio; bone fracture, including hip fracture; musculoskeletal impairment in the elderly; growth hormone deficiency in adults or in children; short stature in children; obesity; sleep disorders; cachexia and protein loss due to chronic illness such as AIDS or cancer; and treating patients recovering from major surgery, wounds or bums, in a patient in need thereof.
  • a condition selected from the group consisting of: osteoporosis; catabolic illness; immune deficiency, including that in individuals with a depressed T4/T8 cell ratio; bone fracture, including hip fracture; musculoskeletal impairment in the elderly; growth hormone deficiency in adults or in children; short stature in children; obesity; sleep disorders; cachexia and protein loss due to chronic illness such as AIDS or cancer; and treating patients recovering from major surgery, wounds or bums, in
  • the instant compounds may be useful in the treatment of illnesses induced or facilitated by corticotropin releasing factor or stress- and anxiety-related disorders, including stress-induced depression and headache, abdominal bowel syndrome, immune suppression, HIV infections, Alzheimer's disease, gastrointestinal disease, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, and fertility problems.
  • corticotropin releasing factor or stress- and anxiety-related disorders including stress-induced depression and headache, abdominal bowel syndrome, immune suppression, HIV infections, Alzheimer's disease, gastrointestinal disease, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, and fertility problems.
  • the therapeutic agents and the growth hormone secretagogues of this invention may be independently present in dose ranges from one one-hundredth to one times the dose levels which are effective when these compounds and secretagogues are used singly.
  • Combined therapy to inhibit bone reso ⁇ tion, prevent osteoporosis and enhance the healing of bone fractures can be illustrated by combinations of bisphosphonates and the growth hormone secretagogues of this invention.
  • the use of bisphosphonates for these utilities has been reviewed, for example, by Hamdy, N.A.T. Role of Bisphosphonates in Metabolic Bone Diseases. Trends in Endocrinol. Metab., , 4, 19-25 (1993).
  • Bisphosphonates with these utilities include alendronate, tiludronate, dimethyl - APD, risedronate, etidronate, YM- 175, clodronate, pamidronate, and BM-210995.
  • oral daily dosage levels of the bisphosphonate of between 0.1 mg and 5 g and daily dosage levels of the growth hormone secretagogues of this invention of between 0.01 mg/kg to 20 mg/kg of body weight are administered to patients to obtain effective treatment of osteoporosis.
  • Osteoporosis and other bone disorders may also be treated with compounds of this invention in combination with calcitonin, estrogens, raloxifene and calcium supplements such as calcium citrate or calcium carbonate.
  • Anabolic effects especially in the treatment of geriatric male patients are obtained with compounds of this invention in combination with anabolic steroids such as oxymetholone, methyltesterone, fluoxymesterone and stanozolol.
  • the compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated in dosage forms appropriate for each route of administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • 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, and 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 examples include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and com 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 inco ⁇ orating 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 10 mg/kg. of body weight daily are administered to patients and animals, e.g., mammals, to obtain effective release of growth hormone. Preferably, the dosage level will be about 0.001 to about 25 mg/kg per day; more preferably about 0.01 to about 10 mg/kg per day.
  • Step A (DLVN-Acetyl-2-amino-5-phenylpentanoic acid
  • the product above was suspended in 190 mL of 2.5 N NaOH in water and refluxed for two hours. The mixture was cooled to 0°C, and it was carefully neutralized with 6 N HCl to pH2. The precipitate was collected using a glass sinter funnel and washed with a small amount of cold water and air dried. The solid was then suspended in 300 mL of water and refluxed for four hours. The solution was cooled and acidified to pHl and the solid was collected by filtration (15.3 g, 67%).
  • Step B (D -N- Acetyl- 2-amino-5-phenylpentanoic acid
  • Step C (DVN-t-Boc-2-amino-5-phenylpentanoic acid
  • step B The intermediate from step B (4.2 g, 17.8 mmol) was suspended in 2 N HCl (100 mL) and refluxed for two hours. The reaction mixture was evaporated in vacuo to remove water and hydrochloric acid to yield a white solid. To a solution of this solid in 50 mL of water, was added 3 N NaOH until the pH 11, then di-t-butyl dicarbonate (4.66 g, 21.4 mmol) was added with vigorous stirring. After four hours, the reaction mixture was acidified to pH2 with 3 N HCl and it was extracted with ethyl acetate (100 mLX3). The organic extracts were combined and evaporated to give a white solid (6.56 g, crude) which was used without purification.
  • Racemic ⁇ -methyltryptophan was prepared by the method of Snyder and Matteson (J. Am. Chem. Soc. 1957, 79, 2217). Isomer A (lOOg) was suspended in 1.25L of 90/10 acetone water at 20°C and 50 mL of R-(+)-oc-methylbenzylamine was added in one portion. The suspension cleared briefly before a thick white suspension formed which quickly turned to a solid mass. After aging ovemight, an additional 500 mL of acetone was added to facilitate agitation and filtration. The suspension was filtered and the cake washed with 500 mL of acetone and sucked to a damp cake.
  • N-acetyl-77zreo-(2S,3R)- ⁇ -methyltryptophan S-(-)- ⁇ -methylbenzyl amine salt The mother liquors from Example 1 were combined and concentrated to ca. 1 L and 400 mL of 1 N HCl was added. The resulting suspension was stirred for 1 hr initially at 20°C then at 0°C. The product was filtered and washed with water until the filtrate was neutral. The product was sucked to a damp cake weighing 79 g. The solid was suspended in IL of 95% acetone/water and 40 mL of S-(-)- ⁇ - methylbenzylamine was added followed by 1 L of 90% acetone/water. After a few minutes a solid mass formed.
  • the salt was re-slurried four times with hot ethyl acetate containing 2% water (1 x 2.5 L, 2 x 6 L, and 1 x 8 L).
  • the mother liquors from Example 3 were combined and concentrated to ca. 2 L and washed twice with 500 mL 1 N HCl. The washes were back extracted once with ethyl acatate, and the combined ethyl acetate extracts washed twice with brine. The solution was diluted to 6 L with ethyl acatate and 60 mL of S-(-)- ⁇ -methylbenzylamine was added. After 10 min the resulting suspension was heated to boiling. The suspension was allowed to cool to ambient temperature with stirring ovemight. The product was collected by filtration washed with ethyl acetate and and sucked to a damp cake.
  • the pH of the aqueous solution from Example 6 was adjusted to 7 with sodium hydroxide and cooled to 0°C. 20 g of potassium carbonate, 19 g of di-t-butyldicarbonate, and 150 mL of THF were added. The mixture was allowed to warm slowly to ambient temperature ovemight. The reaction was extracted twice with ether, the aqueous acidified with 2 N HCl and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried with MgS ⁇ 4, filtered and concentrated affording 21.2 g of the title compound.
  • Example 4 The salt from Example 4 (65 g) was stirred with 250 mL 1 N HCl and 1.5 L of ethyl acetate at ambient temperature for 5 min. The layers were partitioned and the ethyl acetate layer was washed with IN HCl, H2 ⁇ and brine, dried with MgS04, filtered and concentrated to afford the title compound as a brittle foam.
  • the pH of the aqueous solution from Example 6 was adjusted to 7 with sodium hydroxide and cooled to 0°C. 24 g of potassium carbonate, 22 g of di-t-butyldicarbonate, and 150 mL of THF were added. The mixture was allowed to warm slowly to ambient temperature ovemight. The reaction was extracted twice with ether The aqueous acidified with 2 N HCl.and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried with MgS04 filtered and concentrated. The solid was redissolved in ether, and the ether removed in vacuo while flushing with hexanes. The resulting slurry was filtered and dried affording 20.1 g of the title compound.
  • the organic layer was discarded.
  • the aqueous layer was extracted with ether (3X), brine, dried over sodium sulfate and concentrated to give the desired acid (68.3 g).
  • Step A The intermediate from Step A (68.3 g, 225 mmole) was dissolved in 300 ml of methanol and hydrogenated over Pd(OH)2 (3.7 g) at 40 psi for 6 hours and then at one atmosphere for 16 hours. The mixture was filtered through Celite to remove Pd catalyst and the filtrate was concentrated under vacuum to give the cis acid (68.9 g).
  • Step B The intermediate obtained in Step B (68.9 g) and (S)- ⁇ - methylbenzylamine (28.9 ml, 225 mmole) were dissolved in methanol with heating. The solution was left in refrigerator for 16 hours and the crystals that were formed were filtered off (25 g). Recrystallization from 1500 ml of ethyl acetate/methanol (5/1) gave the desired amine salt (19 g). The stereochemistry of this compound was determined by X-ray crystallographic analysis.
  • Step E The intermediate from Step C (19 g) was suspended in IN HCl and was extracted with ether. The organic extracts were combined, dried over sodium sulfate, and evaporated to give the title compound as a white solid. (13.6 g).
  • Step C The intermediate from Step A (4.3 g) was suspended in IN HCl and was extracted with ether. The extracts were combined, dried over sodium sulfate and evaporated to give a white solid. (3.0g).
  • Example 38 Step G The intermediate from Example 38 Step G was deprotected with ethyl acetate / HCl and the resulting product (200 mg, 0.68 mmol) was coupled to (2R)-N-t-Boc-5-phenylpentanoic acid (240 mg, 0.81 mmol) using EDC (190 mg, lmmol), HOBT (130 mg, 1.0 mmol) and NMM (0.097 ml, 0.88 mmol). The BOC protected title compound (130 mg) was obtained after purification (Prep TLC dichlormethane / acetone 9 : 1). The title compound was obtained after treatment with ethyl acetate / HCl.
  • N-Boc-Gly-OBn (4.5 g).
  • N-Boc-Gly-OBn (1.32 g) in THF (10 ml) was added potassium bis(trimethylsilyl)amide (1.19 g) in THF (20 ml) at -78°C. After 30 minutes at -78°C allyl bromide (0.52 ml) was added to the reaction mixture slowly.
  • Step D cid
  • Ethyl 3 (S)-benzyl nipecotate L-tartaric acid salt (39.74 g) was suspended in 70 mL of 3N NaOH and 70 mL of water, followed by extraction with dichloromethane. The extracts were combined, dried, and evaporated to give a thick oil.
  • N-t- Boc D-T ⁇ OH (30.43 g) and HOBt (13.5 g) in dichloromethane (200 mL) at 0°C
  • EDC 23 g

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Abstract

L'invention concerne certaines pipéridines, pyrrolidines et hexahydro-1H-azépines représentées par la formule générale (I); dans laquelle B est sélectionné parmi (a) et (b) et R?1, R1a, R2a, R3a, R3b, R4, R4a, R4b, R4c, R5¿, D, X, Y, n, x et y sont tels qu'ils sont définis. Ces composés déclenchent la libération de l'hormone de croissance chez l'homme et chez l'animal. On peut utiliser cette propriété chez l'animal afin d'accentuer la croissance d'animaux destinés à l'alimentation, de manière à optimiser la production de produits carnés comestibles, ainsi que chez l'homme, afin de traiter des états physiologiques ou pathologiques caractérisés par une déficience de la sécrétion de l'hormone de croissance, tels qu'une petite taille chez des enfants présentant une déficience de l'hormone de croissance, et pour traiter des états pathologiques soulagés par les effets anabolisants de l'hormone de croissance. L'invention concerne également des compositions libérant l'hormone de croissance contenant ces composés en tant qu'ingrédients actifs.
PCT/US1997/005378 1996-04-03 1997-03-31 Piperidines, pyrrolidines et hexahydro-1h-azepines declenchant la liberation de l'hormone de croissance WO1997036873A1 (fr)

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US1479796P 1996-04-03 1996-04-03
US60/014,797 1996-04-03
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GBGB9609664.9A GB9609664D0 (en) 1996-05-09 1996-05-09 Piperidines pyrrolidines and hexahydro-1H-azepines promote release of growth hormone

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0831823A1 (fr) * 1995-06-07 1998-04-01 Merck & Co., Inc. ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a
WO1999058501A1 (fr) * 1998-05-11 1999-11-18 Novo Nordisk A/S Composes possedant des proprietes de liberation d'hormone de croissance
US6303620B1 (en) 1998-05-11 2001-10-16 Novo Nordisk A/S Compounds with growth hormone releasing properties
EP1159964A2 (fr) 2000-05-31 2001-12-05 Pfizer Products Inc. Compositions et methodes pour stimuler la motilité gastrointestinale
EP1181933A3 (fr) * 2000-06-29 2002-04-10 Pfizer Products Inc. Utilisation d'un secretagogue de l'hormone de croissance comme comme inducteur de la faim
JP2003504369A (ja) * 1999-07-13 2003-02-04 メルク エンド カムパニー インコーポレーテッド アミドスピロピペリジン類による成長ホルモン放出の促進
US6541634B2 (en) 1999-02-26 2003-04-01 Pfizer Inc. Process for preparing growth hormone secretagogues
WO2005021502A1 (fr) * 2003-08-29 2005-03-10 Takeda Pharmaceutical Company Limited Procede de production d'un derive de threo-$g(b)-alkyltryptophane actif optiquement et de son intermediaire
WO2007098716A1 (fr) 2006-02-28 2007-09-07 Centro De Ingeniería Genética Y Biotecnología Composés analogues aux sécrétagogues peptidiques de l'hormone de croissance et préparations contenant ceux-ci
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
US7622496B2 (en) 2005-12-23 2009-11-24 Zealand Pharma A/S Modified lysine-mimetic compounds
US8084469B2 (en) 2009-05-27 2011-12-27 Bayer Pharma Aktiengesellschaft Substituted piperidines
US8119663B2 (en) * 2007-11-30 2012-02-21 Bayer Pharma Aktiengesellschaft Heteroaryl-substituted piperidines
EP2457925A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Procédé pour la préparation d'un modulateur macrocyclique du récepteur de ghréline et intermédiaires
US8202862B2 (en) 2009-05-27 2012-06-19 Bayer Intellectual Property Gmbh Substituted piperidines
EP2644618A1 (fr) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. Intermédaires dans la synthese de modulateurs macrocycliques du récepteur de la ghréline
US8927590B2 (en) 2006-12-21 2015-01-06 Zealand Pharma A/S Synthesis of pyrrolidine compounds
US8987248B2 (en) 2009-03-23 2015-03-24 Bayer Intellectual Property Gmbh Substituted piperidines as Par-1 antagonists
US11324799B2 (en) 2017-05-05 2022-05-10 Zealand Pharma A/S Gap junction intercellular communication modulators and their use for the treatment of diabetic eye disease
CN114805305A (zh) * 2022-04-20 2022-07-29 成都诺和晟泰生物科技有限公司 一种化合物及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5283241A (en) * 1992-08-28 1994-02-01 Merck & Co., Inc. Benzo-fused lactams promote release of growth hormone
US5438136A (en) * 1993-11-02 1995-08-01 Merck & Co., Inc. Benzo-fused macrocycles promote release of growth hormone
US5494919A (en) * 1993-11-09 1996-02-27 Merck & Co., Inc. 2-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5283241A (en) * 1992-08-28 1994-02-01 Merck & Co., Inc. Benzo-fused lactams promote release of growth hormone
US5438136A (en) * 1993-11-02 1995-08-01 Merck & Co., Inc. Benzo-fused macrocycles promote release of growth hormone
US5494919A (en) * 1993-11-09 1996-02-27 Merck & Co., Inc. 2-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0831823A4 (fr) * 1995-06-07 1998-10-21 Merck & Co Inc ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a
US6075038A (en) * 1995-06-07 2000-06-13 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
EP0831823A1 (fr) * 1995-06-07 1998-04-01 Merck & Co., Inc. ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a
WO1999058501A1 (fr) * 1998-05-11 1999-11-18 Novo Nordisk A/S Composes possedant des proprietes de liberation d'hormone de croissance
US6303620B1 (en) 1998-05-11 2001-10-16 Novo Nordisk A/S Compounds with growth hormone releasing properties
CZ301276B6 (cs) * 1998-05-11 2009-12-30 Novo Nordisk A/S Piperidinový derivát vykazující schopnost uvolnování rustového hormonu
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
US6673929B2 (en) 1999-02-26 2004-01-06 Pfizer Inc. Process for preparing growth hormone secretagogues
US6541634B2 (en) 1999-02-26 2003-04-01 Pfizer Inc. Process for preparing growth hormone secretagogues
JP2003504369A (ja) * 1999-07-13 2003-02-04 メルク エンド カムパニー インコーポレーテッド アミドスピロピペリジン類による成長ホルモン放出の促進
EP1159964A2 (fr) 2000-05-31 2001-12-05 Pfizer Products Inc. Compositions et methodes pour stimuler la motilité gastrointestinale
EP1181933A3 (fr) * 2000-06-29 2002-04-10 Pfizer Products Inc. Utilisation d'un secretagogue de l'hormone de croissance comme comme inducteur de la faim
WO2005021502A1 (fr) * 2003-08-29 2005-03-10 Takeda Pharmaceutical Company Limited Procede de production d'un derive de threo-$g(b)-alkyltryptophane actif optiquement et de son intermediaire
EP2457893A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Intermédiaires pour des modulateurs macrocycliques du récepteur de ghréline
EP2457925A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Procédé pour la préparation d'un modulateur macrocyclique du récepteur de ghréline et intermédiaires
US8431540B2 (en) 2005-12-23 2013-04-30 Zealand Pharma A/S Modified lysine-mimetic compounds
US7622496B2 (en) 2005-12-23 2009-11-24 Zealand Pharma A/S Modified lysine-mimetic compounds
WO2007098716A1 (fr) 2006-02-28 2007-09-07 Centro De Ingeniería Genética Y Biotecnología Composés analogues aux sécrétagogues peptidiques de l'hormone de croissance et préparations contenant ceux-ci
US9469609B2 (en) 2006-12-21 2016-10-18 Zealand Pharma A/S Synthesis of pyrrolidine compounds
US8927590B2 (en) 2006-12-21 2015-01-06 Zealand Pharma A/S Synthesis of pyrrolidine compounds
EP2644618A1 (fr) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. Intermédaires dans la synthese de modulateurs macrocycliques du récepteur de la ghréline
US8119663B2 (en) * 2007-11-30 2012-02-21 Bayer Pharma Aktiengesellschaft Heteroaryl-substituted piperidines
US8987248B2 (en) 2009-03-23 2015-03-24 Bayer Intellectual Property Gmbh Substituted piperidines as Par-1 antagonists
US8440657B2 (en) 2009-05-27 2013-05-14 Bayer Intellectual Property Gmbh Substituted piperidines
US8202862B2 (en) 2009-05-27 2012-06-19 Bayer Intellectual Property Gmbh Substituted piperidines
US8084469B2 (en) 2009-05-27 2011-12-27 Bayer Pharma Aktiengesellschaft Substituted piperidines
US11324799B2 (en) 2017-05-05 2022-05-10 Zealand Pharma A/S Gap junction intercellular communication modulators and their use for the treatment of diabetic eye disease
CN114805305A (zh) * 2022-04-20 2022-07-29 成都诺和晟泰生物科技有限公司 一种化合物及其应用
CN114805305B (zh) * 2022-04-20 2024-04-26 成都诺和晟泰生物科技有限公司 一种化合物及其应用

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