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WO1998010653A1 - Piperidines, pyrrolidines et hexahydro-1h-azepines favorisant la secretion d'hormone de croissance - Google Patents

Piperidines, pyrrolidines et hexahydro-1h-azepines favorisant la secretion d'hormone de croissance Download PDF

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Publication number
WO1998010653A1
WO1998010653A1 PCT/US1997/016103 US9716103W WO9810653A1 WO 1998010653 A1 WO1998010653 A1 WO 1998010653A1 US 9716103 W US9716103 W US 9716103W WO 9810653 A1 WO9810653 A1 WO 9810653A1
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alkyl
aryl
group
phenyl
hydrogen
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PCT/US1997/016103
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English (en)
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Ravi Nargund
Arthur A. Patchett
James Tata
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Merck & Co., Inc.
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Priority claimed from GBGB9624172.4A external-priority patent/GB9624172D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU43420/97A priority Critical patent/AU4342097A/en
Publication of WO1998010653A1 publication Critical patent/WO1998010653A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • 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
    • 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

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
  • 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. In either case the peptidyl nature of the compound necessitated that it be administered by injection.
  • the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone.
  • 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.
  • 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, 5,492,916, 5,494,919, 5,494,920, 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, WO 96/02530 and WO 96/22997.
  • 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.
  • Ri is selected from the group consisting of: Cl-ClO alkyl, -aryl-, aryl (Cl-C6 alkyl)-, heteroaryl-, heteroaryl(Cl-C6 alkyl)-,
  • -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 -OR2a 0 r -C(0)OR2a, and wherein aryl is phenyl or naphthyl, and 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 -C1-C6 alkyl, 1 to OCF3, nitro, -N(R2)(R2), -N(R2)C(0)(R2), -C(0)0R2, -C(0)N(R2)
  • Rl is hydrogen or C1-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)OR 2 a, 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 a is hydrogen or C 1 -C ⁇ alkyl
  • B is selected from:
  • R3 is selected from: hydrogen, -(CH2)rphenyl, -(CH2)rpyridyl, - (CH2)rthienyl, -(CH2)rbenzimidazolyl, -(CH2)rquinolinyl, -
  • R3a and R3b 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), -S02N(R2)(R2), -N(R2)S02-aryl, and -N(R2)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 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;
  • 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), 0 r - 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, - (CH2)qN(R2)C(0)R2, -(CH 2 ) q N(R2)C(0)(CH2)taryl, - (CH2)qN(R2)S ⁇ 2(CH2)taryl, -(CH2)qN(R2)S02R 2 , - (CH2)qN(R2)C(0)N(R2)(CH2)taryl, -(CH2)qN(R2)C(0)N(R2)(R2), - (CH2)qC(0)N(R2)(R2), -(CH2)q C(0)N(R2)(CH 2 )taryl, - (CH2)qC(0)OR 2 , -(CH2) q C(0)0(CH2)taryl, -(CH2)qOR2, - (CH2)qOC(0)R2, -(CH2) q OC(0)(CH2) t aryl, -(CH2)qOC(0)N(R2)(R2),
  • (CH2)qS(0) m (CH2)taryl where R , (CH2)q and (CH2)t group may be optionally substituted with C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, N(R )(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 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-yl;
  • Y is selected from the group consisting of: hydrogen, Cl-ClO alkyl, -(CH2)taryl,
  • D is selected from: -N(R7)-, -S(0) m -, -C(O)- and -C(H)(R7)-, wherein R? is selected from: -R 2 , -OR 2 , -(CH2) q aryl, -C(0)R 2 , - C(0)(CH2) q aryl, -SO2R 2 , -S ⁇ 2(CH2) q aryl, -C(0)N(R 2 )(R 2 ), - C(0)N(R )(CH2)qaryl, -C(0)OR 2 , l-H-tetrazol-5-yl, -S ⁇ 2N(R )aryl, - S ⁇ 2N(R 2 )(R 2 ) 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 2 a, -0(CH
  • 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) m R2, 1 to 2 of -CF3, -OCF3, nitro, - N(R2)
  • Preferred compounds of the instant invention include those of Formula la:
  • Ri is selected from the group consisting of: Cl-ClO alkyl, -aryl-, aryl (C1-C6 alkyl)-, heteroaryl-, heteroaryl(Cl-C6 alkyl)-, (C3-C7 cycloalkyl)-(Cl-C6 alkyl)-, (C1-C5 alkyl)-K-(Cl-C5 alkyl)-, aryl-(C ⁇ -C5 alkyl)-K-(Cl-C5 alkyl)-, heteroaryl-(C ⁇ -C5 alkyl)-K-(Cl-C5 alkyl)-, and (C3-C7 cycloalkyl)-(C ⁇ -C5 alkyl)-K-(C 1 -C5 alkyl)-, wherein K is -0-, -S(0) m -, -N(R2)C(0)-, -C(0)N(R2)-,-0C(0)-,
  • R2 is selected from the group consisting of: hydrogen, -C1-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)OR2a, 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:
  • R 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: Cl-C6 alkyl, halogen, -OR2, -(CH2) ⁇ OR6 -(CH2) ⁇ N(R 2 )(R6), -(CH2)r(R 6 ), - (CH2) r C(0)OR2, -(CH2) ⁇ C(0)OR6, -(CH2)rC(0)R2, -(CH2) r C(0)R°, - (CH2)rC(0)N(R2)(R2), -(CH2) ⁇ C(0)N(R2)(R6), .
  • R3a and R3b 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)OR 2 , -C(0)N(R2)(R2), -S02N(R2)(R2), -N(R2)S ⁇ 2-aryl, and -N(R 2 )S0 2 R 2 ;
  • 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 alkoxy carbonyl; or R-5 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;
  • 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 R2, -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 C1-C6 alkyl, C3- C cycloalkyl, amino, or hydroxyl;
  • X is selected from the group consisting of: hydrogen, -C ⁇ N, - (CH2)qN(R2)C(0)R 2 , -(CH2)qN(R2)C(0)(CH2)taryl, -
  • Y is selected from the group consisting of: hydrogen, Cl-ClO alkyl, -(CH2)taryl, -(CH2)q(C3-C7 cycloalkyl), -(CH2)q-K-(Cl-C6 alkyl), -(CH2)q-K-
  • (CH2)taryl, -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl containing O, NR 2 S) and -(CH2)q-K-(CH2)t(C3-C7 cycloalkyl), where K is O, S(0) m , C(0)NR 2 , CH CH, C ⁇ C, N(R 2 )C(0), C(0)NR 2 , C(0)0, or OC(O), and where the alkyl, R2, (CH2)q and (CH2)t groups are optionally substituted by C1-C4 alkyl, hydroxyl, C1-C4 lower alkoxy, carboxyl, -CONH2 or a carboxylate C1-C4 alkyl ester, and aryl is phenyl, naphthyl, pyridyl, 1-H- tetrazol-5-yl, thiazolyl, imidazoly, indolyl, oxadiazoyl,
  • D is selected from: -N(R7)-, -S(0) ⁇ r, -C(O)- and -C(H)(R7)-, wherein R7 is selected from: -R 2 , -(CH2) q aryl, -C(0)R 2 , -S ⁇ 2R 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(R a)(R 2 a), halogen, -C1-C4 alkyl, and the aryl is selected from of triazolyl, oxadiazolyl, thiadiazol
  • More preferred compounds of the instant invention include those of Formula lb:
  • Ri is selected from the group consisting of:
  • 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 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;
  • R2 i 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: Cl-C6 alkyl, halogen, -OR 2 , -(CH2)rOR6, - (CH 2 )rN(R 2 )(R6), -(CH 2 )r(R 6 ), -(CH 2 ) r C(0)OR 2 , -(CH 2 ) ⁇ C(0)OR6, - (CH2)rC(0)R 2 , -(CH2) ⁇ C(0)R6, -(CH2) r C(0)N(R )(R 2 ), - (CH2)rC(0)N(R 2 )(R6), -(CH2) r S02N(R 2 )(R°X -(CH2) r S ⁇ 2N(R 2 )(R 2 ), -(CH2)rS(0) m R6, and -(CH2) r S(0) m R 2 ;
  • R3a and R3b are independently selected from: hydrogen, -Cl-C6 alkyl and halogen;
  • R4 and R5 are independently selected from hydrogen, Cl-C6 alkyl, and substituted C 1-C6 alkyl where the substituents are selected from halo, hydroxy, phenyl, and Cl-C6 alkoxy carbonyl; or R5 and R4 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 R 2 is as defined above;
  • R4 and R b are independently selected from: hydrogen, C 1 -C6 alkyl, or substituted Cl-C6 alkyl where the substituents are selected from: imidazolyl, naphthyl, phenyl, indolyl, and p-hydroxyphenyl;
  • R6 is selected from: hydrogen, -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), -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 Cl-C6 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(R 2 )(R2), -0(R 2 ), C1-C3 alkyl, halogen, and trifluoromethyl;
  • Y is selected from the group consisting of: hydrogen,
  • D is selected from: -N(R?)-, -S(0) m -, -C(O)- and -C(H)(R7)-, wherein R? is selected from: -R2, -(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: -OR2a -C(0)OR2a -C(0)N(R2a)(R2a), halogen, -C1-C4 alkyl, and the aryl is selected from of triazolyl, oxadiazoly
  • the most preferred compounds of the instant invention include compounds of the formula:
  • B is selected from the group consisting of:
  • E' is selected from:
  • -CH CH-C(CH3)2-NH2, or phenyl substituted with -CH2-NH2, -CH(CH3)-NH2, or -C(CH3)2-NH2; and pharmaceutically acceptable salts and individual diastereomers thereof.
  • 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 £ . - 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 carboxyiic 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 carboxyiic 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.
  • 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.
  • 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.
  • 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 - Amino Acids, Pergamon Press: Oxford, 1989).
  • Many of the piperidines, pyrrolidines, and hexahydro-lH-azepines of Formula 2 are either commercially available or known in the literature and others can be prepared following literature methods described for analogous compounds. Some of these methods .are illustrated in the subsequent schemes.
  • the skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures includes crystallization, normal phase or reverse phase chromatography.
  • Intermediates of Formula I may be prepared as shown in Scheme 3 by coupling intermediates of Formula 4 to protected amino acids of Formula 5 under the standard peptide-type coupling reaction conditions.
  • the amino acids 5 are either commercially available or can be synthesized by routine methods.
  • the compounds of general Formula I of the present invention may also be prepared in a convergent manner as described in Scheme 6.
  • Intermediates of Formula 7 can be synthesized by well documented methods in the literature.
  • Elaboration of 7 to compounds of Formula 1 can be accomplished as shown in Scheme 6 by coupling intermediates of Formula 7 to amino acids of Formula 6 under standard peptide coupling reaction conditions. SCHEME 6
  • amines BH of Formula 2 can be coupled to the corresponding acid under standard peptide-type coupling conditions to give compounds of Formula I.
  • R4 and/or R-5 is H
  • substituted alkyl groups may be option-ally added to the nitrogen atom as described in Scheme 5.
  • Schemes preparations of amines BH of Formula 3 are described.
  • 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 8 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- carboxyiic 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 (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 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 aery late 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 carboxyiic acid, which can be further derivatized to amides or other esters.
  • the carboxyiic 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.
  • 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" 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.
  • 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.
  • D,L-0-aryl(alkyl)serines may be prepared and resolved by methods described above.
  • 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 R9 is ⁇ -hydroxy-substituted alkyl or arylalkyl groups.
  • This chemistry is detailed by H. Ong et al J. Med. Chem. 1983, 23, 981-986. 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-Cl 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 ⁇ -methylbenzylamine.
  • the absolute stereochemistry can be determined in a number of ways including X-ray crystallography of a suitable crystalline derivative.
  • Spiroindane intermediates for incorporation 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-ct- 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 DIB ALH. 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.
  • benzoic acids esters of formula 86 are reduced with Raney nickel in ethanol in the presence of ammonia to provide the corresponding benzylamine derivative 87.
  • the amino group is protected as its Boc or CBZ derivative and the ester group is hydrolyzed to give protected amino acids of formula 85.
  • Olefinic amino acids of formula 89 may be prepared as shown in Scheme 36.
  • the Boc-aminoisobutyric acid methyl ester 90 is reduced to the corresponding aldehyde derivative 91 with the use of diisobutylaluminum hydride in a aprotic solvent such as THF or dichloromethane.
  • the commercially available acid of 90 may be reduced with diborane to the alcohol and reduced up to the aldehyde 91 by using Swern oxidation protocol.
  • a Homer- Emmons condensation of 91 with triethylphosphonoacetate by using a base like potassium t-butoxide in an aprotic solvent provides the corresponding unsaturated aester that can be hydrolyzed under standard conditions to protected amino acid of formula 89.
  • 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 endorphin peptides, on the pituitary to modify growth hormone release.
  • some of the pituitary hormones e.g., growth hormone and endorphin peptides
  • endorphin peptides e.g., endorphin peptides
  • the compounds of Formula I can be administered to animals, including man, to release growth hormone in vivo.
  • the compounds can be administered to commercially important animals such as swine, cattle, sheep and the like to accelerate and increase their rate and extent of growth, 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 pharmaceutical 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 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 ⁇ -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. 4,411,8
  • 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 neuropathies; replacement of growth hormone in stressed patients; treatment of osteochondrody- splasias, Noonans syndrome, sleep disorders, schizophrenia, depression, Alzheimer's disease, delayed wound healing, and psychosocial deprivation; treatment of pulmonary dysfunction and ventilator dependency; prevention or treatment of congestive heart failure, improving pulmonary function, restoring systolic and diastolic function, increasing myocardial contractility, decreasing peripheral total vascular resistance, diminishing or preventing loss of body weight and enhancing recovery following congestive heart failure; increasing appetite; attenuation of protein catabolic response after a major operation; treating malabsorption syndromes; reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; accelerating weight gain and protein accretion in patients on TPN (total parenteral nutrition); treatment of hyperinsulinemia including nesidioblastosis; adjuvant treatment for ovulation induction and to prevent and treat gastric .and duodenal ulcers; stimulation of th
  • 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 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.
  • 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 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 incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions.
  • 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.
  • 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.
  • 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 N-Acetyl-77 ⁇ reo-(2R,3S)- ⁇ -methyltryptophan R-(+)- ⁇ - methylbenzyl amine salt Racemic ⁇ -methyltryptophan was prepared by the method of
  • Step B N- Acetyl- r/ ⁇ reo-(2S,3R)- ⁇ -methyltryptophan S-(-)- ⁇ - methylbenzyl amine salt
  • 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-(-)- ⁇ - 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-Acety ⁇ -Erythro (2R,3R)- ⁇ -methyltryptophan R-(+)- ⁇ - methylbenzyl amine salt 170g of Isomer B ( see ref. in Step A) which was a brittle foam containing ethyl acetate was dissolved in 2.5 L of ethyl acetate containing 100 mL of ethanol. To this was added 60 mL of R-(+)- ⁇ - methylbenzylamine. After 10 min, an additional 2L of ethyl acetate was added and the resulting thick suspension was aged at 20°C for 3 days. The product was collected by filtration, washed with ethyl acetate and and sucked to a damp cake.
  • the mother liquors from the Step C 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 overnight. The product was collected by filtration washed with ethyl acetate and and sucked to a damp cake.
  • the salt was suspended in 6 L of ethyl acetate and suspension was heated to boiling.
  • Step E N-acetyl- /zrgo-(2S.3R)- ⁇ -Methyltryptophan
  • Step F ⁇ re ⁇ ?-(2S.3RV ⁇ -Methyltrvptophan
  • Step G N-?-BOC---/trgo-(2S.3R)- ⁇ -methyltrvptophan
  • 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
  • Step H N-Acetyl-fftreo-(2R.3SV ⁇ -methyltrvptophan
  • Step I fftreo-(2R.3SV ⁇ -Methyltryptophan
  • Step J N-r-BOC-r/ ⁇ rgo-(2R.3S)- ⁇ -Methyltrvptophan
  • Step K N- Acetyl-Ervthro (2S .3SV ⁇ -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-f-BOC-Jgrvf ⁇ ro (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 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. 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 O ;/ ⁇ rgo-(2R.3R)- ⁇ -methyltryptophan
  • the title compound was prepared following the procedure of
  • Step P N ⁇ BOC-/ftrgo-(2R.3RV ⁇ -methvItrvpto ⁇ han
  • Step AA

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Abstract

La présente invention se rapporte à certaines pipéridines, pyrrolidines et hexahydro-1h-azépines représentées par la formule générale (I) dans laquelle B est sélectionné parmi les composés représentés par les formules (A) et (B) et où R?1, R1a, R2a, R3a, R3b, R4, R4a, R4b, R5¿, D, E, X, Y, n, x et y sont définis dans le descriptif de l'invention. Ces composés favorisent la sécrétion d'hormone de croissance chez les humains et les animaux. Cette propriété peut permettre de stimuler la croissance des animaux destinés à l'alimentation de façon à augmenter la production de produits carnés comestibles. Chez les humains, ces composés peuvent permettre de traiter des états médicaux ou physiologiques caractérisés par une anomalie de sécrétion de l'hormone de croissance, tels que la petite taille chez les enfants présentant une carence en hormone de croissance, et de traiter des troubles pouvant bénéficier des effets anaboliques de l'hormone de croissance. L'invention se rapporte également à des compositions qui contiennent de tels composés et qui favorisent la sécrétion d'hormone de croissance.
PCT/US1997/016103 1996-09-13 1997-09-10 Piperidines, pyrrolidines et hexahydro-1h-azepines favorisant la secretion d'hormone de croissance WO1998010653A1 (fr)

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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998051687A1 (fr) * 1997-05-14 1998-11-19 Fujisawa Pharmaceutical Co., Ltd. Derives piperidino favorisant la liberation de l'hormone de croissance
US6294534B1 (en) 1998-06-11 2001-09-25 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
EP1159964A2 (fr) 2000-05-31 2001-12-05 Pfizer Products Inc. Compositions et methodes pour stimuler la motilité gastrointestinale
US6350760B1 (en) 1999-06-04 2002-02-26 Merck & Co., Inc. Substituted piperidines as melanocortin-4 receptor agonists
US6358951B1 (en) 1998-08-21 2002-03-19 Pfizer Inc. Growth hormone secretagogues
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
US6458790B2 (en) 2000-03-23 2002-10-01 Merck & Co., Inc. Substituted piperidines as melanocortin receptor agonists
US6472398B1 (en) 2000-03-23 2002-10-29 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin 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
US6767915B2 (en) 2000-08-23 2004-07-27 Merck & Co., Inc. Substituted piperidines as melanocortin receptor agonists
US6911447B2 (en) 2001-04-25 2005-06-28 The Procter & Gamble Company Melanocortin receptor ligands
US6919315B1 (en) 1998-06-30 2005-07-19 Novo Nordisk A/S Compounds with growth hormone releasing properties
US7026335B2 (en) 2002-04-30 2006-04-11 The Procter & Gamble Co. Melanocortin receptor ligands
US7132539B2 (en) 2002-10-23 2006-11-07 The Procter & Gamble Company Melanocortin receptor ligands
US7153822B2 (en) 2002-01-29 2006-12-26 Wyeth Compositions and methods for modulating connexin hemichannels
US7189755B2 (en) 2001-08-10 2007-03-13 Palatin Technologies, Inc. Pyrrolidine melanocortin-specific 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
US7354923B2 (en) 2001-08-10 2008-04-08 Palatin Technologies, Inc. Piperazine melanocortin-specific compounds
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
US7456184B2 (en) 2003-05-01 2008-11-25 Palatin Technologies Inc. Melanocortin receptor-specific compounds
US7618959B2 (en) 2002-11-05 2009-11-17 Smithklinebeecham Corp Antibacterial agents
US7622496B2 (en) 2005-12-23 2009-11-24 Zealand Pharma A/S Modified lysine-mimetic compounds
CZ301276B6 (cs) * 1998-05-11 2009-12-30 Novo Nordisk A/S Piperidinový derivát vykazující schopnost uvolnování rustového hormonu
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
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
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury
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

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5492920A (en) * 1993-12-10 1996-02-20 Merck & Co., Inc. Piperidine, pyrrolidine and hexahydro-1H-azepines promote release of growth hormone
US5536716A (en) * 1992-12-11 1996-07-16 Merck & Co., Inc. Spiro piperidines and homologs which promote release of growth hormone

Patent Citations (2)

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US5536716A (en) * 1992-12-11 1996-07-16 Merck & Co., Inc. Spiro piperidines and homologs which promote release of growth hormone
US5492920A (en) * 1993-12-10 1996-02-20 Merck & Co., Inc. Piperidine, pyrrolidine and hexahydro-1H-azepines promote release of growth hormone

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998051687A1 (fr) * 1997-05-14 1998-11-19 Fujisawa Pharmaceutical Co., Ltd. Derives piperidino favorisant la liberation de l'hormone de croissance
CZ301276B6 (cs) * 1998-05-11 2009-12-30 Novo Nordisk A/S Piperidinový derivát vykazující schopnost uvolnování rustového hormonu
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
US6919315B1 (en) 1998-06-30 2005-07-19 Novo Nordisk A/S Compounds with growth hormone releasing properties
US7576062B2 (en) 1998-06-30 2009-08-18 Novo Nordisk A/S Compounds with growth hormone releasing properties
US6358951B1 (en) 1998-08-21 2002-03-19 Pfizer Inc. Growth hormone secretagogues
US6559150B2 (en) 1998-08-21 2003-05-06 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
US6458790B2 (en) 2000-03-23 2002-10-01 Merck & Co., Inc. Substituted piperidines as melanocortin receptor agonists
US6472398B1 (en) 2000-03-23 2002-10-29 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
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
US6767915B2 (en) 2000-08-23 2004-07-27 Merck & Co., Inc. Substituted piperidines as melanocortin receptor agonists
US6911447B2 (en) 2001-04-25 2005-06-28 The Procter & Gamble Company Melanocortin receptor ligands
US7087759B2 (en) 2001-04-25 2006-08-08 The Procter & Gamble Company Melanocortin receptor ligands
US7189755B2 (en) 2001-08-10 2007-03-13 Palatin Technologies, Inc. Pyrrolidine melanocortin-specific compounds
US7326707B2 (en) 2001-08-10 2008-02-05 Palatin Technologies Incorporated Bicyclic melanocortin-specific compounds
US7354923B2 (en) 2001-08-10 2008-04-08 Palatin Technologies, Inc. Piperazine melanocortin-specific compounds
US7601753B2 (en) 2001-08-10 2009-10-13 Palatin Technologies, Inc. Pyrrolidine melanocortin-specific compounds
US7153822B2 (en) 2002-01-29 2006-12-26 Wyeth Compositions and methods for modulating connexin hemichannels
US7026335B2 (en) 2002-04-30 2006-04-11 The Procter & Gamble Co. Melanocortin receptor ligands
US7132539B2 (en) 2002-10-23 2006-11-07 The Procter & Gamble Company Melanocortin receptor ligands
US7618959B2 (en) 2002-11-05 2009-11-17 Smithklinebeecham Corp Antibacterial agents
US7456184B2 (en) 2003-05-01 2008-11-25 Palatin Technologies Inc. Melanocortin receptor-specific compounds
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
EP2457893A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Intermédiaires pour des modulateurs macrocycliques du récepteur de ghréline
US7622496B2 (en) 2005-12-23 2009-11-24 Zealand Pharma A/S Modified lysine-mimetic compounds
US8431540B2 (en) 2005-12-23 2013-04-30 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
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
EP2644618A1 (fr) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. Intermédaires dans la synthese de modulateurs macrocycliques du récepteur de la ghréline
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
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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