WO1998025897A1 - Piperidines, pyrrolidines et hexahydro-1h azepines favorisent la liberation de l'hormone de croissance - Google Patents

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

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WO1998025897A1
WO1998025897A1 PCT/US1997/022725 US9722725W WO9825897A1 WO 1998025897 A1 WO1998025897 A1 WO 1998025897A1 US 9722725 W US9722725 W US 9722725W WO 9825897 A1 WO9825897 A1 WO 9825897A1
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alkyl
aryl
group
phenyl
hydrogen
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PCT/US1997/022725
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English (en)
Inventor
Meng H. Chen
Zhijian Lu
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 GBGB9702954.0A external-priority patent/GB9702954D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU55998/98A priority Critical patent/AU5599898A/en
Publication of WO1998025897A1 publication Critical patent/WO1998025897A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

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.
  • 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
  • Non peptidal growth hormone secretagogues are disclosed in e.g., U.S. Patent Nos 5,206,235, 5,283,241, 5,284,841, 5,310,737, 5,317,017, 5,374,721, 5,430,144, 5,434,261, 5,438,136, 5,494,919, 5,494,920, 5,492,916 and 5,536,716.
  • growth hormone secretagogues are disclosed e.g., in PCT Patent Publications WO 94/13696, WO 94/19367, WO 95/03289, WO 95/03290, WO 95/09633, WO 95/11029, WO 95/12598, WO 95/13069, WO 95/14666, WO 95/16675, WO 95/16692, WO 95/17422, WO 95/17423, WO 95/34311, and WO 96/02530.
  • the instant compounds are low molecular weight peptide analogs for promoting the release of growth hormone which have good stability in a variety of physiological environments and which may be administered parenterally, nasally or by the oral route.
  • 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. DESCRIPTION OF THE INVENTION
  • Rl is selected from the group consisting of:
  • aryl is phenyl or naphthyl
  • heteroaryl is selected from indolyl, thiophenyl, benzofuranyl, benzothiopheneyl, aza-indolyl, pyridinyl, quinolinyl, and benzimidazolyl, wherein aryl and heteroaryl are unsubstituted or substituted with phenyl, phenoxy, halophenyl, 1 to 3 of -Ci-C ⁇ alkyl, 1 to 3 of halo, 1 to 2 of -OR 2 , methylenedioxy, -S(0) m R 2 , 1 to 2 of
  • R* a is hydrogen or C1-C4 alkyl
  • R2 is selected from the group consisting of: hydrogen, -Ci-C ⁇ alkyl, -C3-C7 cycloalkyl, and -CH2-phenyl, wherein the alkyl or the cyloalkyl is unsubstituted or substituted with hydroxyl, C1-C3 alkoxy, thioalkyl, C(O)OR2a ? and where, if two -C1-C6 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;
  • R 2a i hydrogen or C1-C6 alkyl
  • B is selected from:
  • R ⁇ is selected from: hydrogen, -(CH2)rphenyl, -(CH2)rPyridyl, -(CH2)rthienyl, -(CH2)rbenzimidazolyl, -(CH2)rquinolinyl, -(CH2)rnaphthyl, -(CH2)rindolyl, -C1-C10 alkyl, -C3-C7 cycloalkyl, where the phenyl, pyridyl, naphthyl, indolyl, thienyl, benzimidazolyl, quinolinyl, and C3-C7 cycloalkyl rings may be substituted by 1 to 3 substituents selected from the group consisting of: Ci-C ⁇ alkyl, halogen, -OR2, -NHSO2CF3, -(CH2) r OR 6 , -(CH2)rN(R2)(R6), -(CH2) r (R 6 ), -
  • R ⁇ a and R ⁇ b are independently selected from: hydrogen, phenyl, phenoxy, halophenyl, -Ci-C ⁇ alkyl, halogen, -OR2, methylenedioxy, -S(0) m R 2 , -CF3, -OCF3, nitro, -N(R 2 )(R2), -N(R2)C(0)(R 2 ), -C(O)OR2, -C(0)N(R2)(R2), -S ⁇ 2N(R2)(R2), -N(R2)S02-aryl, and -N(R2)S0 2 R2 ;
  • E is selected from:
  • R4 and R ⁇ are independently selected from hydrogen, Ci-C ⁇ alkyl, and substituted C ⁇ -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(O) m - or -N(R 2 )-, d and e are independently 1 to 3 and R2 is as defined above;
  • 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)mR2, -C(0)OR2, -C(0)N(R2)(R2), -S ⁇ 2N(R2)(R2), or -
  • X is selected from the group consisting of: hydrogen, -C ⁇ N, -(CH2) q N(R2)C(O)R2, .(CH2) q N(R2)C(O)(CH2)taryl, -(CH2) q N(R2)S02(CH 2 )taryl, -(CH2) q N(R2)S02R 2 , -(CH2) q N(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2), -(CH2)qC(0)N(R2)(R2), -(CH 2 ) q C(O)N(R2)(CH2)taryl, -(CH 2 ) q C(0)OR2, -(CH2)qC(0)0(CH2)taryl, -(CH2) q OR2, -(CH2) q OC(O)R2, -(CH2) q OC(0)(CH2) t aryl, -
  • 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 , -OR 2 , -(CH2) q aryl, -C(0)R 2 , -C(O)(CH 2 ) q aryl, -SO 2 R 2 , -SO 2 (CH2) q aryl, -C(0)N(R2)(R2), -C(0)N(R2)(CH2) q aryl, -C(O)OR2, l-H-tetrazol-5-yl, -S ⁇ 2N(R 2 )aryl, -S02N(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, -O
  • n When n is 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 .
  • the 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.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, propargyl, 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 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 Ci-C ⁇ alkyl, 1 to 3 of halogen, 1 to 2 of OR2, methylenedioxy, -S(0) m R2, 1 to 2 of -CF3, -OCF3, nitro, -N(R2)
  • Preferred compounds of the instant invention include those of
  • Rl is selected from the group consisting of: Ci-Cio alkyl, -aryl-, aryl (C ⁇ -C 6 alkyl)-, heteroaryl-, heteroaryl(C ⁇ -C6 alkyl)-,
  • R2 and the alkyl groups may be further substituted with 1 to 9 halo, -S(O) m R2a j 1 to 3 of -OR 2 a, 0 r -C(O)OR 2 a, 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 -C ⁇ -C6 alkyl, 1 to 3 of halo, 1 to 2 of -OR , methylenedioxy, -S(O) m R 2 , 1 to 2
  • R 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(O)OR 2a , 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 ;
  • R a is hydrogen or Cl-C ⁇ alkyl
  • B is selected from:
  • R3 is selected from: hydrogen, phenyl, pyridyl, naphthyl, indolyl, benzimidazolyl, thienyl, quinolinyl, where the phenyl, pyridyl, naphthyl, benzimidazolyl, thienyl, quinolinyl, and indolyl may be substituted by 1 to 3 substituents selected from the group consisting of: C1-C6 alkyl, halogen, -OR 2 , -(CH2) r OR 6 , -(CH2) r N(R 2 )(R6), -(CH 2 ) r (R 6 ), -(CH2) r C(0)OR 2 , -(CH2) r C(0)OR6, -(CH 2 ) r C(0)R2, -(CH2) r C(O)R6, -(CH2)rC(0)N(R 2 )(R 2 ), -(CH2)rC
  • R ⁇ a and R ⁇ b are independently selected from: hydrogen, phenyl, phenoxy, halophenyl, -Ci-C ⁇ alkyl, halogen, -OR2, methylenedioxy, -S(0) m R2, -CF3,
  • E is selected from:
  • R 4 and R ⁇ are independently selected from hydrogen, C ⁇ -C6 alkyl, and substituted C -CQ 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-La(CH2)e- where L a is -C(R2)2", -O-, -S(O) m - or -N(R 2 )-, d and e are independently 1 to 3 and R2 is as defined above;
  • R 4a and R 4 b are independently selected from: hydrogen, Cl-C ⁇ alkyl, trifluoromethyl, phenyl, or substituted Ci-C ⁇ alkyl where the substituents are selected from: imidazolyl, naphthyl, phenyl, indolyl, p-hydroxyphenyl, -OR 2 , -S(0) m R 2 , -C(0)OR 2 , C3-C7 cycloalkyl,
  • R6 is selected from: hydrogen, C ⁇ -C6 alkyl, and (CH2)varyl, wherein the (CH2)v and alkyl groups may be optionally substituted by -O(R2), -S(0) m R 2 , -C(O)OR2, -C(0)N(R2)(R2), -SO2N(R 2 )(R2), or - N(R2)C(0)N(R2)(R2) ?
  • 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,
  • R , (CH )q and (CH 2 )t group may be optionally substituted with C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, N R 2 ) ⁇ ), CONH2, S(0) m CH3, carboxylate C1-C4 alkyl esters, or lH-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or 1H- tetrazol-5-yl groups which may be optionally substituted with halogen,
  • Y is selected from the group consisting of: hydrogen, C1-C10 alkyl, -(CH2)taryl,
  • D is selected from: -N(R 7 )-, -S(0) m -, -C(O)- and -C(H)(R 7 )-, wherein R 7 is selected from: -R2, -(CH2) q aryl, -C(O)R 2 , -S02R 2 , -C(0)N(R2)(R2), -C(0)OR2, l-H-tetrazol-5-yl, -S ⁇ 2N(R 2 )aryl, -S02N(R2)(R2) and the (CH2)q may be optionally substituted by C1-C4 alkyl, and the R 2 and aryl may be optionally further substituted with a substituent selected from: -OR 2a , -C(0)OR 2a , -C(0)N(R 2a )(R 2a ), halogen, -C1-C4 alkyl, and the aryl is selected from of triazolyl, oxadia
  • 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, -C ⁇ -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(O)OR2a > a nd 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;
  • R2a s hydrogen, or C1-C4 alkyl
  • B is selected from:
  • 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: C ⁇ -C6 alkyl, halogen, -OR 2 , -(CH2) r OR 6 , -(CH2) r N(R 2 )(R 6 ), -(CH 2 )r(R 6 ), -(CH 2 ) r C(O)OR 2 , -(CH 2 ) r C(O)OR6, -(CH ) r C(0)R2, -(CH2) r C(O)R6, -(CH2) ⁇ C(O)N(R2)(R2) > -(CH2) r C(O)N(R2)(R6) 5 -(CH2)rS0 2 N(R2)(R6) ; -(CH 2 ) r SO 2 N(R2 ⁇ R2), -(CH 2 ) r S(0)mR 6 , and -(CH
  • R ⁇ a and R ⁇ b are independently selected from: hydrogen, -Ci-Cg alkyl and halogen;
  • E is selected from:
  • R 4 and R ⁇ are independently selected from hydrogen, Ci-C ⁇ alkyl, and substituted C ⁇ -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 _ La(CH2)e _ where La is -C(R 2 )2-, -0-, -S(O) m - or -N(R 2 )-, d and e are independently 1 to 3 and R2 is as defined above;
  • R 4a and R b are independently selected from: hydrogen, C1-C6 alkyl, or substituted C ⁇ -C6 alkyl where the substituents are selected from: imidazolyl, naphthyl, phenyl, indolyl, and p-hydroxyphenyl;
  • R6 is selected from: hydrogen, C ⁇ -C6 alkyl, and (CH2)v ryl, wherein the (CH2)v and alkyl groups may be optionally substituted by -0(R2), - S(0) m R 2 , -C(O)OR 2 , -C(0)N(R2)(R2), -S ⁇ 2N(R 2 )(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 Ci-C ⁇ alkyl, C3-C6 cycloalkyl, amino, or hydroxyl;
  • X is selected from the group consisting of: hydrogen,
  • heterocycle is optionally substituted with a substituent selected from: -N(R2)(R2), -O(R 2 ), C1-C3 alkyl, halogen, and trifluoromethyl ;
  • Y is selected from the group consisting of: hydrogen,
  • D is selected from: -N(R 7 )-, -S(O) m -, -C(0)- and -C(H)(R 7 )-, wherein R 7 is selected from: -R 2 , -(CH2) q aryl, -C(0)R 2 , -SO2R 2 , C(0)N(R2)(R2), -C(0)0R2, l-H-tetrazol-5-yl, -S ⁇ 2N(R 2 )aryl, - S ⁇ 2N(R 2 )(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(O)OR2a ; -C(0)N(R2a)(R2a )> halogen,
  • aryl is selected from of triazolyl, oxadiazolyl, 1H- tetrazolyl, and thiadiazolyl;
  • the most preferred compounds of the instant invention include compounds of the formula:
  • B is selected from the group consisting of: COOEt
  • the even more preferred compounds of the instant invention include compounds of the formula:
  • 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 S_- 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 (di) and diastereomer 2 (d2) are arbitrarily referred to as diastereomer 1 (di) 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
  • 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 is contraindicated by the presence of other potentially reactive functionality
  • removal of CBZ groups 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).
  • the compounds of general Formula I of the present invention may also be prepared in a convergent manner as described in Scheme 6.
  • 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
  • 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 R8 is alkyl, aryl, and (Cl-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 techni q ues.
  • 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 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).
  • TAA triethyl amine
  • the hydroxy group in 18 may also be converted to a good leaving group such as mesylate and displaced by a nucleophile such as cyanide, a thiol or an azide.
  • Reduction of the azide in compounds of Formula 20 to an amine 21 can be achieved by hydrogenation in the presence of a noble metal such as palladium or its oxide or Raney nickel in a protic solvent such as ethanol.
  • a noble metal such as palladium or its oxide or Raney nickel
  • a protic solvent such as ethanol.
  • 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.
  • asymmetric alkylation can also be utilized for the synthesis of optically active intermediate by introducing a removable chiral auxiliary in X or in place of L with subsequent chromatographic separation of diastereomers.
  • a sulfide 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.
  • 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” Pergamon Press: Oxford, 1989; Vol. 7).
  • 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.
  • 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 Rg 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 b-hydroxy-substituted alkyl or arylalkyl groups.
  • R? is hydrogen or most of the derivatives described above, can be demethylated or debenzylated to produce 55, wherein R" is hydrogen or most of the derivatives described above, as shown in Scheme 22.
  • 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.
  • the spiro heterocyclic compounds of formula 56 can be prepared by a number of methods, including the syntheses as described in Scheme 23. Allylic oxidation of the protected piperidine 58 is accomplished by classical methods familiar to those skilled in the art (Rabjohn, N. Org. React. 1976, 24, 261). The resulting allylic alcohol is treated with thionyl chloride in an inert solvent such as benzene to provide the corresponding chloride 59.
  • 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 incorporated 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. Carboxylation 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 incorporated 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 a- methylbenzylamine.
  • the absolute stereochemistry can be determined in a number of ways including X-ray crystallography of a suitable crystalline derivative.
  • 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.
  • an activated alcohol such as tosylate 70
  • 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-a- 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 incorporated 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 incorporated 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 incorporation into the subject compounds can be accomplished as described above.
  • the incorporation 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 growth hormone releasing compounds of Formula I are useful in vitro as unique tools for understanding how growth hormone secretion is regulated at the pituitary level. This includes use in the evaluation of many factors thought or known to influence growth hormone secretion such as age, sex, nutritional factors, glucose, amino acids, fatty acids, as well as fasting and non-fasting states. In addition, the compounds of this invention can be used in the evaluation of how other hormones modify growth hormone releasing activity. For example, it has already been established that somatostatin inhibits growth hormone release.
  • hormones that are important and in need of study as to their effect on growth hormone release include the gonadal hormones, e.g., testosterone, estradiol, and progesterone; the adrenal hormones, e.g., cortisol and other corticoids, epinephrine and norepinephrine; the pancreatic and gastrointestinal hormones, e.g., insulin, glucagon, gastrin, secretin; the vasoactive 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 endorphin peptides, on the pituitary to modify growth hormone release. Of particular scientific importance is the use of these compounds to elucidate the subcellular mechanisms mediating the release of growth hormone.
  • the compounds of Formula I can be administered to animals, including man, to 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, b-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 89/07111 and B-HT920 as well as hexarelin and GHRP-2 as described in WO 93/04081 or growth hormone releasing hormone (GHRH, also designated GRF) and its analogs or growth hormone and its analogs or somatomedins including IGF-1 and IGF-2 or a-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.
  • 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
  • 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 purposes of stimulating the release of endogenous growth hormone can have the same effects or uses as growth hormone itself.
  • These varied uses may be summarized as follows: stimulating growth hormone release in elderly humans; treating growth hormone deficient adults; prevention of catabolic side effects of glucocorticoids; treatment of osteoporosis; stimulation of the immune system, acceleration of wound healing; accelerating bone fracture repair; treatment of growth retardation; treating acute or chronic renal failure or insufficiency; treatment of physiological short stature, including growth hormone deficient children; treating short stature associated with chronic illness; treating 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 or following major surgery such as gastrointestinal surgery; treatment of intrauterine growth retardation, and skeletal dysplasia; treatment of hypercortisonism and Cushing's syndrome; treatment of peripheral neuron
  • 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 burns, 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 burns, in a
  • 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 resorption, 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.
  • daily oral dosage levels of 0.1 mg to 50 mg are combined for effective osteoporosis therapy with 0.01 mg/kg to 20 mg/kg of the growth hormone secretagogues of this invention.
  • 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.
  • 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 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 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 (DL)-N-Acetyl-2-amino-5-phenylpentanoic acid To a solution of sodium (2.3 g, 0.1 mol) in ethanol (60 mL) under nitrogen at room temperature, was added diethyl acetamido- malonate. The mixture was stirred at room temperature for one hour, and then l-bromo-3-phenylpropane was added dropwisely. After the addition, the mixture was stirred at room temperature for two hours, then refluxed overnight. It was cooled to room temperature and partitioned between water and ethyl acetate.
  • 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 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.
  • the title compound was prepared from the title compound of Step H by treatment with a saturated solution of HCl in ethyl acetate. Removal of the volitiles followed by azeotroping from dichloromethane and toluene provided the title compound as a white solid.
  • Step A N-acetyl-77zreo-(2R,3S)- ⁇ -methyltryptophan R-(+)- ⁇ - methylbenzyl amine salt
  • Racemic b-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- (+)-a-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 overnight, 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.
  • the mother liquors from the step A 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-(-)-a- methylbenzylamine was added followed by 1 L of 90% acetone/water. After a few minutes a solid mass formed. An additional 500 mL of acetone was added and the mixture heated on a steam bath for ca. 0.5 hr.
  • Step C N-acetyl-Erythro (2R,3R)- ⁇ -methyltryptophan R-(+)- ⁇ - methylbenzyl amine salt
  • the product was collected by filtration, washed with ethyl acetate and and sucked to a damp cake.
  • the salt was reslurried four times with hot ethyl acetate containing 2% water (1 x 2.5 L, 2 x 6 L, and 1 x 8 L).
  • Step D N-acetyl-£r;yt ⁇ ro (2S,3S)- ⁇ -methyltryptophan S-(-)- ⁇ - methylbenzyl amine salt
  • the mother liquors from the Step C were combined and concentrated to c ⁇ . 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-(-)-a-methylbenzylamine was added. After 10 min the resulting suspension was heated to boiling. The suspension was allowed to cool to ambient temperature with stirring overnight. The product was collected by filtration washed with ethyl acetate and and sucked to a damp cake.
  • Step E N-acetyl- ⁇ reo-(2S.3R)- ⁇ -methyltryptophan
  • Step F tJEreo-(2S.3R)- ⁇ -methyltrvptophan
  • the wet cake from Step E was suspended in with 400 mL of 1 N HCl and refluxed for 12 hours. The solution was cooled to 20°C, and half of the solution was used for Step G.
  • Step G N- ⁇ -BOC-t ⁇ reo-(2S.3R)- ⁇ -methyltryptophan
  • the pH of the aqueous solution from Step F 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 overnight. 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 affording 21.2 g of the title compound.
  • Step H N-acetyl-£ ⁇ reo-(2R.3S)- ⁇ -methyltryptophan
  • the title compound was prepared following the procedure of
  • Step I t7treo-(2R.3S)- ⁇ -methyltryptophan
  • Step J N- ⁇ BOC-t reo-(2R.3S)- ⁇ -methyltrvptophan
  • Step K N-acetyl-Jgr t ⁇ ro (2S.3S)- ⁇ -methyltrvptophan
  • Step K The product from Step K was suspended in with 500 mL of 2 N HCl and refluxed for 4 hours. The solution was cooled to 20°C, and half of the solution was used for Step M. The title compound isolated as a foam by concentrating the solution in vacuo.
  • Step M N-t-BOC-Erythro (2S.3S)- ⁇ -methyltrvptophan
  • the pH of the aqueous solution from Step F 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 overnight.
  • the reaction was extracted twice with ether
  • the combined ethyl acetate extracts were washed with brine, dried with MgS ⁇ 4 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.
  • Step N N-acetyl-t ⁇ reo-(2R.3R)- ⁇ -methyltryptophan
  • Step O ⁇ rgo-(2R.3R)- ⁇ -methyltryptophan
  • Step P N- ⁇ -BOC-t ⁇ reo-(2R.3R)- ⁇ -methyltrvptophan
  • the BOC protected title compound (889 mg, 1.59 mmol) was prepared from the hydrochloride salt of the title compound in Example 1 Step G (960 mg, 3.0 mmol) and the intermediate prepared in Step M (960 mg, 3.0 mmol) according to the procedure in Example 1 Step H. Removal of the BOC group with a saturated solution of HCl in ethyl acetate as in Example 1 Step I gave the title compound (739 mg, 1.5 mmol).
  • the BOC protected title compound (64 mg, 0.093 mmol) was obtained from the title compound of the previous step (39 mg, 0.159 mmol) and the title compound from Example 8 Step B (79 mg, 0.159 mmol) according to the procedure for Example 8 Step A.
  • the title compound (55 mg, 088 mmol) was prepared by removal of the BOC group with a saturated solution of HCl in ethyl acetate followed by MPLC (LH20, methanol) purification. Selected IH NMR (CD3OD, 1:1 mix of rotamers,
  • Step D cid
  • Step A Prepared from the intermediate obtained in Step A (68.3 g, 225 mmole) which was dissolved in 300 ml of methanol, hydrogenated over Pd(0H)2 (3.7 g) at 40 psi for 6 hours and then one atmosphere for 16 hours. The mixture was filtered through Celite to remove Pd catalyst. The filtrate was concentrated under vacuum to give the cis acid (68.9 g).
  • Step C The intermediate from Step C (19 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. (13.6 g).
  • Step D Step D:

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Abstract

L'invention porte sur certaines pipéridines, pyrrolidines et hexahydro-1H azépines de formule générale (1) où B est choisi entre (2) et (3) et R?1, R1a, R2a, R3a, R3b, R4, R4a, R4b, R4c, R5¿, D, X, Y, n, x, et y sont définis dans la description. Lesdits composés favorisent la libération de l'hormone de croissance chez l'homme et l'animal. Cette propriété peut servir à accélérer la croissance d'animaux de boucherie pour améliorer le rendement de la production de produits carnés comestibles, et chez l'homme, à traiter des états physiologiques ou médicaux caractérisés par une déficience de la sécrétion de l'hormone de croissance, tels que la petite stature des enfants présentant une déficience en hormone de croissance, ou pour traiter des états médicaux améliorés par les effets anabolisants de l'hormone de croissance. L'invention porte également sur des compositions de libération de l'hormone de croissance comportant lesdits composés comme principes actifs.
PCT/US1997/022725 1996-12-12 1997-12-10 Piperidines, pyrrolidines et hexahydro-1h azepines favorisent la liberation de l'hormone de croissance WO1998025897A1 (fr)

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US3264996P 1996-12-12 1996-12-12
US60/032,649 1996-12-12
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EP0995748A1 (fr) * 1998-08-21 2000-04-26 Pfizer Products Inc. Secretagogues d'hormone de croissance
US6294534B1 (en) 1998-06-11 2001-09-25 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
US6350760B1 (en) 1999-06-04 2002-02-26 Merck & Co., Inc. Substituted piperidines as melanocortin-4 receptor agonists
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
WO2004054581A2 (fr) * 2002-12-13 2004-07-01 Smithkline Beecham Corporation Composes de cyclohexyle utiles en tant qu'antagonistes du ccr5
DE102004023632A1 (de) * 2004-05-10 2005-12-08 Grünenthal GmbH Substituierte Cyclohexylcarbonsäure-Derivate
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
US8927590B2 (en) 2006-12-21 2015-01-06 Zealand Pharma A/S Synthesis of pyrrolidine compounds
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs
WO2017134212A1 (fr) 2016-02-05 2017-08-10 Siegfried Ag Procédé de préparation de l'acide trans-4-amino-1-cyclohexane carboxylique et ses dérivés
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury
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

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6294534B1 (en) 1998-06-11 2001-09-25 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
US6410548B2 (en) 1998-06-11 2002-06-25 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
US6559150B2 (en) 1998-08-21 2003-05-06 Pfizer Inc. Growth hormone secretagogues
EP0995748A1 (fr) * 1998-08-21 2000-04-26 Pfizer Products Inc. Secretagogues d'hormone de croissance
US6358951B1 (en) 1998-08-21 2002-03-19 Pfizer Inc. Growth hormone secretagogues
US6686359B2 (en) 1998-08-21 2004-02-03 Pfizer Inc. Growth hormone secretagogues
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
US6350760B1 (en) 1999-06-04 2002-02-26 Merck & Co., Inc. Substituted piperidines as melanocortin-4 receptor agonists
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
WO2004054581A2 (fr) * 2002-12-13 2004-07-01 Smithkline Beecham Corporation Composes de cyclohexyle utiles en tant qu'antagonistes du ccr5
WO2004054581A3 (fr) * 2002-12-13 2005-02-03 Smithkline Beecham Corp Composes de cyclohexyle utiles en tant qu'antagonistes du ccr5
US7589207B2 (en) 2002-12-13 2009-09-15 Smithkline Beecham Corporation Cyclohexyl compounds as CCR5 antagonists
DE102004023632A1 (de) * 2004-05-10 2005-12-08 Grünenthal GmbH Substituierte Cyclohexylcarbonsäure-Derivate
US7241802B2 (en) 2004-05-10 2007-07-10 Gruenenthal Gmbh Substituted cyclohexylcarboxylic acid amide compounds
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
US8927590B2 (en) 2006-12-21 2015-01-06 Zealand Pharma A/S Synthesis of pyrrolidine compounds
US9469609B2 (en) 2006-12-21 2016-10-18 Zealand Pharma A/S Synthesis of pyrrolidine compounds
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury
US10617740B2 (en) 2014-02-05 2020-04-14 The Regents Of The University Of California Methods of treating mild brain injury
US11241483B2 (en) 2014-02-05 2022-02-08 The Regents Of The University Of California Methods of treating mild brain injury
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs
WO2017134212A1 (fr) 2016-02-05 2017-08-10 Siegfried Ag Procédé de préparation de l'acide trans-4-amino-1-cyclohexane carboxylique et ses dérivés
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

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