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WO1995013069A1 - Piperidines, pyrrolidines et hexahydro-1h-azepines favorisant la liberation de l'hormone de croissance - Google Patents

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

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Publication number
WO1995013069A1
WO1995013069A1 PCT/US1994/012816 US9412816W WO9513069A1 WO 1995013069 A1 WO1995013069 A1 WO 1995013069A1 US 9412816 W US9412816 W US 9412816W WO 9513069 A1 WO9513069 A1 WO 9513069A1
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WIPO (PCT)
Prior art keywords
alkyl
hydrogen
aryl
cycloalkyl
phenyl
Prior art date
Application number
PCT/US1994/012816
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English (en)
Inventor
Gregori J. Morriello
Arthur A. Patchett
Lihu Yang
Meng H. Chen
Ravi Nargund
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/323,998 external-priority patent/US5492920A/en
Priority claimed from US08/323,994 external-priority patent/US5494919A/en
Priority claimed from US08/323,988 external-priority patent/US5492916A/en
Priority to SK562-96A priority Critical patent/SK56296A3/sk
Priority to AU11729/95A priority patent/AU1172995A/en
Priority to EP95902467A priority patent/EP0739204A4/fr
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to KR1019960702427A priority patent/KR960705808A/ko
Priority to BR9408019A priority patent/BR9408019A/pt
Priority to JP7513932A priority patent/JPH10506091A/ja
Publication of WO1995013069A1 publication Critical patent/WO1995013069A1/fr
Priority to BG100555A priority patent/BG100555A/bg
Priority to FI961951A priority patent/FI961951A0/fi
Priority to NO961865A priority patent/NO961865L/no
Priority to LVP-96-151A priority patent/LV11525B/en

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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
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • PIPERIDINES, PYRROLIDINES AND HEXAHYDRO-1H-AZEPINES PROMOTE RELEASE OF GROWTH HORMONE CROSS REFERENCE TO RELATED APPLICATIONS
  • 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.
  • GRF hormone releasing factor
  • an unknown endogenous growth hormone-releasing hormone or all of these.
  • 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.
  • 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
  • compositions containing the piperidine, pyrrolidine, and hexahydro-1H-azepine 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.
  • R 1 is selected from the group consisting of:
  • C 1 -C 10 alkyl, aryl, aryl(C 1 -C 6 alkyl), (C 3 -C 7 cycloalkyl)(C 1 -C 6 alkyl)- (C 1 -C 5 alkyl)-K-(C 1 -C 5 alkyl)-, aryl(C 0 -C 5 alkyl)-K-(C 1 -C 5 alkyl)-, and (C 3 -C 7 cycloalkyl)(C 0 -C 5 alkyl)-K-(C 1 -C 5 alkyl)-, where K is O, S(O)m, N(R 2 )C(O), C(O)N(R 2 ), OC(O), C(O)O, -CR 2 CR 2 -, or -C ⁇ C-.
  • aryl is selected from: phenyl, naphthyl, indolyl, azaindole, pyridyl, benzothienyl, benzofuranyl, thiazolyl, and benzimidazolyl. and R 2 and alkyl may be further substituted by 1 to 9 halogen, S(O) m R 2a. 1 to 3 of OR 2a or C(O)OR 2a , and aryl may be further substituted by 1 to 3 of C 1 -C 6 alkyl, 1 to 3 of halogen, 1 to 2 of OR 2 , methylenedioxy,
  • R 2 is selected from: hydrogen, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl, and where two C 1 -C 6 alkyl groups are present on one atom, they may be optionally joined to form a C 3 -C 8 cyclic ring, optionally including oxygen, sulfur or NR 3a ;
  • R 2a is hydrogen, or C 1 -C 6 alkyl optionally substituted by hydroxyl
  • R 3 is selected from: hydrogen, -(CH 2 ) r phenyl, -(CH 2 ) r naphthyl, -C 1 -C 10 alkyl, -C 3 -C 7 cycloalkyl, where the phenyl, naphthyl and C 3 -C 7
  • cycloalkyl rings may be substituted by 1 to 3 substituents selected from the group consisting of: C 1 -C 6 alkyl, halogen, -OR 2 , -NHSO 2 CF 3 , -(CH 2 ) r OR 6 , -(CH 2 ) r N(R 2 )(R 6 ), -(CH 2 ) r (R 6 ), -(CH 2 ) r C(O)OR 2 , -(CH 2 ) r C(O)OR 6 , -(CH 2 ) r C(O)OR 6 , -(CH 2 ) r OC(O)R 2 , -(CH 2 ) r OC(O)R 6 ,
  • R 4 and R 5 are independently hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 C 1 -C 10 alkanoyloxy, 1 to 3 C 1 -C 6 alkoxy, phenyl, phenoxy, 2-furyl, C 1 -C 6 alkoxycarbonyl, S(O) m (C 1 -C 6 alkyl); or R 4 and R 5 can be taken together to form -(CH 2 ) d L a (CH 2 ) e - where L a is C(R 2 ) 2 , O, S(O) m or N(R 2 ), d and e are independently 1 to 3 and R 2 is as defined above;
  • A is: or
  • q 0, 1, 2, 3, or 4;
  • v 0, 1, or 2 ; and pharmaceutically acceptable salts and individual diastereomers thereof.
  • alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration which may optionally contain double or triple bonds.
  • exemplary of such alkyl groups are methyl (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr), butyl (Bu), sec-butyl (s-Bu), tertiary butyl (t-Bu), pentyl, isopentyl, hexyl, isohexyl, allyl, propinyl,
  • halogen is intended to include the halogen atom fluorine, chlorine, bromine and iodine.
  • R 2 is selected from: hydrogen, C 1 -C 6 alkyl, and C3-C7 cycloalkyl, and where two C 1 -C 6 alkyl groups are present on one atom, they may be optionally joined to form a C 3 -C 8 cyclic ring, optionally including oxygen, sulfur or NR 3a ;
  • R 3 is selected from: hydrogen, -(CH 2 ) r phenyl, -(CH 2 ) r naphthyl. -C 1 -C 10 alkyl, -C 3 -C 7 cycloalkyl, where the phenyl, naphthyl and C 3 -C 7
  • R3a is hydrogen, or C 1 -C 6 alkyl optionally substituted by hydroxyl
  • W is selected from the group consisting of:
  • R 8 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted by
  • aryl is phenyl, pyridyl, or 1H-tetrazol-5-yl;
  • X is selected from: hydrogen, -C ⁇ N, -(CH 2 ) q N(R 2 )C(O)R 2 ,
  • aryl is phenyl, naphthyl, pyridyl, thiazolyl, or 1H-tetrazol-5-yl groups which may be optionally substituted by 1 to 3 halogen, 1 to 3 -OR 2 , -CON(R 2 )(R 2 ), -C(O)OR 2 , 1 to 3 C 1 -C 4 alkyl, -S(O) m R 2 , or 1H-tetrazol-5-yl;
  • R 4 and R 5 are independently hydrogen, C 1 -C 6 alkyl. substituted C 1 - C 6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 C 1 -C 10 alkanoyloxy, 1 to 3 C 1 -C 6 alkoxy, phenyl, phenoxy.
  • R4 and R5 can be taken together to form -(CH 2 )dL a (CH 2 )e- where L a is C(R 2 ) 2 , O, S(O) m or N(R 2 ), d and e are independently 1 to 3 and R 2 is as defined above;
  • x and y are independently 0, 1, 2 or 3;
  • aryl is phenyl, pyridyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolone-1-yl, benzimidazol-2-yl, triazolinone-yl optionally substituted with C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, amino, or hydroxyl;
  • R7 and R7a are independently hydrogen, C 1 -C 6 alkyl, trifluoromethyl, phenyl, substituted C 1 -C 6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR 2 , S(O) m R 2 , C(O)O(C 1 -C 6 alkyl).
  • R 7 and R 7a can independently be joined to one or both of R 4 and R 5 groups to form alkylene bridges between the terminal nitrogen and the alkyl portion of the R 7 or R 7a groups, wherein the bridge contains 1 to 5 carbons atoms: or R 7 and R 7a can be joined to one another to form a C 3 -C 7 cycloalkyl:
  • n 0, 1, or 2;
  • q 0, 1, 2, 3, or 4;
  • r 0, 1, 2, or 3;
  • t 0, 1, 2, or 3;
  • v 0, 1, or 2 ; and pharmaceutically acceptable salts and individual diastereomers thereof.
  • R 1 is selected from the group consisting of:
  • X is hydrogen, -(CH 2 ) q C(O)N(R 2 )(R 6 ), or -(CH 2 ) q C(O)OR 2 ;
  • Y is hydrogen, C 1 -C 8 alkyl, -(CH 2 ) t phenyl, -(CH 2 ) t pyridyl, or
  • R 4 and R 5 are independently hydrogen, C 1 -C 6 alkyl, or substimted C 1 -C 6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxyl, S(O) m (C 1 -C 6 alkyl) or phenyl; R 6 is hydrogen, or C 1 -C 6 alkyl; A is:
  • R 7 and R 7a are independently hydrogen C 1 -C 6 alkyl, trifluoromethyl, phenyl, substituted C 1 -C 6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR 2 , S(O)mR 2 , C(O)O(C 1 -C 6 alkyl).
  • R 7 and R 7a can independently be joined to one of R 4 or R 5 to form alkylene bridges between the terminal nitrogen and the alkyl portion of R 7 or R 7a groups to form 5 or 6 membered rings; or R 7 and R 7a can be joined to one another to form a C 3 cycloalkyl; 1 is 0 or 1 ;
  • n 0, 1, or 2;
  • r 0, 1, 2 or 3;
  • t is 0 or 1;
  • R 1 is selected from the group consisting of: C 1 -C 10 alkyl
  • R 2 is hydrogen, C 1 -C 6 alkyl, or C 3 -C 7 cycloalkyl and where two C 1-C6 alkyl groups are present on one atom they may be optionally joined to form a C 5 -C 7 cyclic ring optionally including oxygen, sulfur or NR 3a ;
  • R3 is hydrogen or phenyl optionally substimted in the ortho position by a C 1 -C 3 alkyl group, (CH 2 ) r (1H-tetrazol-5-yl) or (CH 2 ) r C(O)OR 2 ;
  • R 3a is hydrogen, or C 1 -C 4 alkyl;
  • W is -CN, -C(O)OR 2 , or -C(O)N(R 2 )R 2 );
  • Y is hydrogen, benzyl, picoyl, or thiazolylmethyl;
  • R 4 and R 5 are independently hydrogen, C 1 -C 3 alkyl, substituted C 1 -C 3 alkyl where the substituents may be 1 to 2 hydroxyl;
  • R 7 and R 7a are independently hydrogen or C 1 -C 4 alkyl; m is 0, 1, or 2;
  • R 1 is selected from the group consisting of:
  • R3 is selected from: -(CH 2 ) r phenyl, -(CH 2 ) r naphthyl, -C 1 -C 10 alkyl, -C 3 -C 7 cycloalkyl, and the phenyl, naphthyl and C 3 -C 7 cycloalkyl rings may be substituted by 1 to 3 substituents selected from the group consisting of: C 1 -C 6 alkyl, halogen, -OR 2 , -NHSO2CF 3 , -(CH 2 ) r OR 6 , -(CH 2 ) r N(R 2 )(R 6 ), -(CH 2 )r (R 6 ), -(CH 2 ) r C(O)OR 2 , -(CH 2 ) r C(O)OR 6 , -(CH 2 ) r C(O)OR 6 , -(CH 2 ) r OC(O)R 2 , -(
  • R 3a is hydrogen, or C 1 -C 6 alkyl optionally substituted by hydroxyl;
  • X is selected from: hydrogen, -C ⁇ N, -(CH 2 ) q N(R 2 )C(O)R 2 ,
  • R 2 , (CH 2 ) q and (CH 2 )t group may be optionally substimted by 1 to 2 C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 lower alkoxy, carboxyl, CONH 2 , S(O) m CH 3 ,
  • aryl is phenyl, naphthyl, pyridyl, thiazolyl, or 1H-tetrazol-5-yl groups which may be optionally substituted by 1 to 3 halogen, 1 to 3 -OR 2 , -CON(R 2 )(R 2 ), -C(O)OR 2 , 1 to 3 C 1 -C 4 alkyl, -S(O) m R 2 , or 1H-tetrazol-5-yl;
  • Y is selected from: hydrogen, C 1 -C 10 alkyl, -(CH 2 )taryl,
  • R 4 and R 5 are independently hydrogen, C 1 -C 6 alkyl, substituted C 1 - C 6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 C 1 -C 10 alkanoyloxy, 1 to 3 C 1 -C 6 alkoxy, phenyl, phenoxy, 2-furyl, C 1 -C 6 alkoxycarbonyl, S(O) m (C 1 -C 6 alkyl); or R 4 and R 5 can be taken together to form -(CH 2 )dL a (CH 2 ) e - where L a is C(R 2 ) 2 , O, S(O) m or
  • x and y are independently 0, 1, 2 or 3;
  • aryl is phenyl, pyridyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolone-1-yl, oxadiazolyl, benzimidazol-2-yl, triazolinone-yl, optionally
  • R 7 and R 7a are independently hydrogen, C 1 -C 6 alkyl, trifluoromethyl, phenyl, substituted C 1 -C 6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR 2 , S(O) m R 2 , C(O)OR 2 , C3-C7 cycloalkyl, N(R 2 )(R 2 ), C(O)N(R 2 )(R 2 ); or R 7 and R 7a can
  • q 0, 1, 2, 3 or 4;
  • r 0, 1, 2, or 3;
  • v 0, 1, or 2 ; and pharmaceutically acceptable salts and individual diastereomers thereof.
  • R 1 is selected from the group consisting of:
  • C 1 -C 10 alkyl aryl (C 1 -C 4 alkyl)-, C 3 -C 6 cycloalkyl (C 1 -C 4 alkyl)-, (C 1 -C 4 alkyl)-K-(C 1 -C 2 alkyl)-, aryl (C 0 -C 2 alkyl)-K-(C 1 -C 2 alkyl)-, and (C 3 -C 7 cycloalkyl)(C 0 -C 2 alkyl)-K-(C 1 -C 2 alkyl)-, where K is O, S(O) m , OC(O), or C(O)O, and the alkyl groups may be further substituted by 1 to 7 halogen, S(O) m R 2 , 1 to 3 OR 2 or C(O)OR 2 , and aryl is phenyl, naphthyl, indolyl, pyridyl, benzimidazoly
  • R 3a is hydrogen, or C 1 -C 4 alkyl
  • X is selected from: hydrogen, -(CH 2 ) q N(R 2 )C(O)R 2 ,
  • R 2 group may be optionally substituted by hydroxyl, carboxyl, CONH 2 , S(O) m CH 3 , carboxylate C 1 -C 4 alkyl esters, or tetrazole and the aryl which is phenyl, naphthyl, pyridyl or 1-H-tetrazolyl may be optionally substituted by 1 to 2 halogen,
  • R 4 and R 5 are independently hydrogen, C 1 -C 6 alkyl,or substituted C 1 -C 6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxyl, S(O)m (C 1 -C 6 alkyl) or phenyl;
  • R 6 is H, C 1 -C 6 alkyl, or (CH 2 )varyl, wherein the (CH 2 ) V and alkyl groups may be optionally substimted by 1-2 O(R 2 ), S(O) m R 2 , C(O)OR 2 , C(O)N(R 2 )(R 2 ) or SO 2 N(R 2 )(R 2 ), N(R 2 )C(O)N(R 2 )(R 2 ), wherein the aryl group could be phenyl, pyridyl, 1H-tetrazol-5-yl, triazolyl,
  • A is:
  • R 7 and R 7a are independently hydrogen C 1 -C 6 alkyl, trifluoromethyl, phenyl, substituted C 1 -C 6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR 2 , S(O)mR 2 , C(O)OR 2 , C 5 -C 7 cycloalkyl, N(R 2 )(R 2 ), C(O)N(R 2 )(R 2 ); or R 7 and R 7a can
  • R 4 or R 5 independently be joined to one of R 4 or R 5 to form alkylene bridges between the terminal nitrogen and the alkyl portion of R 7 or R 7a groups to form 5 or 6 membered rings; or R 7 and R 7a can be joined to one another to form a C 3 cycloalkyl; n is 2;
  • n 0, 1, or 2;
  • r 0, 1, 2, or 3;
  • q 0, 1, 2, or 3;
  • t 0, 1, 2, or 3;
  • v 0, 1, or 2
  • R 1 is selected from the group consisting of: C 1 -C 10 alkyl
  • aryl (C 0 -C 1 alkyl)-K-(C 1 -C 2 alkyl)-, where K is O or S(O) m and aryl is specifically phenyl, pyridyl, naphthyl, indolyl, azaindolyl, or
  • R 2 is hydrogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and where two C 1 -C 6 alkyl groups are present on one atom they may be optionally joined to form a C 5 -C 7 cyclic ring optionally including oxygen, sulfur or NR 3a ;
  • R 3 is phenyl optionally substituted by 1 to 2 C 1 -C 6 alkyl groups, 1 to 2 halogen or 1 to 2 OR 2 , and which may be further substituted in the ortho position by a substitutent selected from the group consisting of:
  • R 3a is hydrogen, or C 1 -C 4 alkyl
  • Y is selected from: hydrogen, C 1 -C 8 alkyl, (CH 2 )taryl, -(CH 2 ) q C 5 -C 7 cycloalkyl, -(CH 2 ) q -K-(C 1 -C 6 alkyl), -(CH 2 ) q -K-(CH 2 )taryl, and
  • R 7 and R 7a are independently hydrogen, C 1 -C 2 alkyl, phenyl, substituted C 1 -C 6 alkyl wherein the substitutent is imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR 2 , S(O)mR 2 ; or R 7 and R 7a can be independently be joined to one another to form a C3 cycloalkyl; m is 0, 1, or 2;
  • r 0, 1, 2, or 3;
  • t 0, 1, 2, or 3;
  • v 0, 1, or 2;
  • R 1 is selected from the group consisting of:
  • R 2 is hydrogen, C 1 -C 6 alkyl, or C 3 -C 7 cycloalkyl and where two C 1 -C 6 alkyl groups are present on one atom they may be optionally joined to form a C 5 -C 7 cyclic ring optionally including oxygen, sulfur or NR3a;
  • R 3 is phenyl optionally substituted in the ortho position with a
  • R 3a is hydrogen, or C 1 -C 4 alkyl
  • X is selected from the group consisting of: hydrogen,
  • Y is selected from the group consisting of:
  • A is selected from the group consisting of:
  • R 4 and R 5 are independently selected from the group consisting of:
  • R 6 is hydrogen, C 1 -C 6 alkyl or (CH 2 )varyl wherein the alkyl and (CH 2 ) v groups may be optionally substimted by halogen, OR 2 ,
  • aromatic groups are optionally substituted with C 1 -C 2 alkyl, -N(R 2 )(R 2 ). or hydroxy; mis 0, 1, or 2;
  • q is 0 or 1
  • v is 0 or 1; and pharmaceutically acceptable salts and individual diastereomers thereof.
  • All of the still more preferred compounds shown above have at least one asymmetric center. Additional asymmetric centers may be present on the molecule depending upon the nature of the substituents on the piperidine ring. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers, racemic mixtures or diastereomeric mixtures thereof, be included within the ambit of the present invention.
  • R 1 is selected from the group consisting of:
  • C 1 -C 10 alkyl, aryl, aryl(C 1 -C 6 alkyl), (C 3 -C 7 cycloalkyl) (C 1 -C 6 alkyl)-, (C 1 -C 5 alkyl)-K-(C 1 -C 5 alkyl)-, aryl(C 0 -C 5 alkyl)-K-(C 1 -C 5 alkyl)-, and (C 3 -C 7 cycloalkyl)(C 0 -C 5 alkyl)-K-(C 1 -C 5 alkyl)-, where K is O, S(O)m, N(R 2 )C(O), C(O)N(R 2 ), OC(O), C(O)0, -CR 2 CR 2 -, or -C ⁇ C-, where aryl is selected from: phenyl, naphthyl, indolyl, azaindole, pyridyl,
  • R 2 is selected from: hydrogen, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl, and where two C 1 -C 6 alkyl groups are present on one atom, they may be optionally joined to form a C 3 -C 8 cyclic ring, optionally including oxygen, sulfur or NR 3a , where R 3a is hydrogen, or C 1 -C 6 alkyl, optionally substituted by hydroxyl;
  • R 2a is hydrogen, or C 1 -C 6 alkyl optionally substituted by hydroxyl;
  • X is selected from: hydrogen, -C ⁇ N, -(CH 2 ) q N(R 2 )C(O)R 2 ,
  • R 2 , (CH 2 ) q and (CH 2 ) t group may be optionally substituted by 1 to 2 C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 lower alkoxy, carboxyl, CONH 2 , S(O) m CH 3 ,
  • Y is selected from: hydrogen, C 1 -C 10 alkyl, -(CH 2 )taryl,
  • A is:
  • x and y are independently 0, 1, 2 or 3;
  • Z is N-R 6a or O, where R 6a is hydrogen or C 1 -C 6 alkyl;
  • n 1, 2, or 3;
  • t 0, 1, 2, or 3;
  • R 2 is hydrogen, C 1 -C 6 alkyl, or C 3 -C 7 cycloalkyl, and where two C 1 -C 6 alkyl groups are present on one atom they may be optionally joined to form a C 4 -C 7 cyclic ring optionally including oxygen, sulfur or NR 3a ;
  • R 3a is hydrogen, or C 1 -C 4 alkyl;
  • X is selected from: hydrogen, -(CH 2 ) q N(R 2 )C(O)R 2 ,
  • R 2 group may be optionally substituted by hydroxyl, carboxyl, CONH 2 , S(O) m CH 3 , carboxylate C 1 - C 4 alkyl esters, or tetrazole
  • aryl is phenyl, naphthyl, pyridyl or 1-H-tetrazolyl which may be optionally substituted by 1 to 2 halogen, 1 to 2 -OR 2 , -CONH 2 , -C(O)OR 2 , 1 to 3 C 1 -C 4 alkyl, -S(O) m R 2 , or 1H-tetrazole-5-yl;
  • Y is selected from: hydrogen, C 1 -C 8 alkyl, (CH 2 )taryl, -(CH 2 ) q (C 5 -C 6 cycloalkyl), -(CH 2 ) q -K-(C 1 -C 6 alkyl), -(CH 2 ) q -K-(CH 2 )taryl,
  • R4 and R5 are independently hydrogen, C 1 -C 6 alkyl, or substituted C 1 - C 6 alkyl where the substituents may be 1 to 5 halo, 1 to 3 hydroxyl, S(O)m (C 1 -C 6 alkyl) or phenyl;
  • A is:
  • R 7 and R 7a are independently hydrogen C 1 -C 6 alkyl, trifluoromethyl, phenyl, substituted C 1 -C 6 alkyl where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR 2 , S(O)mR 2 , C(O)OR 2 , C 5 -C 7 cycloalkyl, -N(R 2 )(R 2 ), -C(O)N(R 2 )(R 2 ); or R 7 and R 7a can
  • R 4 or R 5 independently be joined to one of R 4 or R 5 to form alkylene bridges between the terminal nitrogen and the alkyl portion of R 7 or R 7a groups to form 5 or 6 membered rings; or R 7 and R 7a can be joined to one another to form a C 3 cycloalkyl; n is 2;
  • n 0, 1, or 2;
  • t 0, 1, 2, or 3;
  • R 1 is selected from the group consisting of: C 1 -C 10 alkyl
  • aryl (C 0 -C 1 alkyl)-K-(C 1 -C 2 alkyl)-, where K is O or S(O) m and the aryl is phenyl, pyridyl, naphthyl, indolyl, azaindolyl, or benzimidazolyl which is optionally substimted by 1-2 C 1 -C 4 alkyl, 1 to 2 halogen, 1 to 2 OR 2 , S(O) m R 2 , or C(O)OR 2 ;
  • R 2 is hydrogen, C 1 -C 6 alkyl, or C 3 -C 7 cycloalkyl, and where two C 1 -C 6 alkyl groups are present on one atom they may be optionally joined to form a C 5 -C 7 cyclic ring optionally including oxygen, sulfur or NR3a;
  • R3a is hydrogen, or C 1 -C 4 alkyl;
  • X is selected from: hydrogen, -(CH 2 ) q N(R 2 )C(O)R 2 ,
  • R 2 group may be optionally substituted by hydroxyl, carboxyl, -CONH 2 , -S(O)mCH 3 , carboxylate C 1 -C 4 alkyl esters or tetrazole and aryl is phenyl, naphthyl or pyridyl which may be further substituted by 1-2 halogen, 1 to 2 OR 2 , C(O)OR 2 , 1 to 3 C 1 -C 4 alkyl, S(O) m R 2 , or 1H-tetrazole-5-yl;
  • Y is selected from: hydrogen, C 1 -C 8 alkyl, (CH 2 )taryl, -(CH 2 ) q C 5 -C 7 cycloalkyl, -(CH 2 ) q -K-(C 1 -C 6 alkyl), -(CH 2 ) q -K-(CH 2 )taryl, and -(CH 2 ) q -K-(CH 2 ) t (C 5 -C 6 cycloalkyl), where K is S(O) m and where the alkyl groups may be optionally substituted by hydroxyl, carboxyl, CONH 2 , carboxylate C 1 -C 4 alkyl esters or 1H-tetrazole-5-yl and aryl is phenyl, napthyl, pyridyl, thiazolyl, thiopheneyl, pyrazolyl, oxazolyl, isoxazolyl or imidazolyl which
  • R 4 and R 5 are independently hydrogen, C 1 -C 4 alkyl, or substituted C 1 -C 3 alkyl where the substiments may be 1 to 2 hydroxyl;
  • R 7 and R 7a are independently hydrogen, C 1 -C 6 alkyl, phenyl, substituted C 1 -C 6 alky wherein the substitutent is imidixolyl, phenyl, indolyl, p-hydroxyphenyl, OR 2 , S(O)mR 2 , or R 7 and R 7a may be joined to one another to form a C 3 cycloalkyl; m is 0, 1, or 2;
  • q 0, 1, 2, or 3;
  • R 1 is selected from the group consisting of:
  • A is selected from the group consisting of:
  • R 4 and R 5 are independently selected from the group consisting of: and pharmaceutically acceptable salts and individual diastereomers thereof.
  • the compounds of the instant invention all have at least one asymmetric center as noted by the asterisk in the structural Formula I above. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers, racemic mixtures or diastereomeric mixtures thereof, be included within the ambit of the instant invention.
  • the asymmetric center represented by the asterisk in Formula I it has been found that the absolute stereochemistry of the more active and thus more preferred isomer is as shown in Formula II.
  • the W group may also be present in either R- or S- configurations. Both afford active growth hormone secretagogues although, in general, the R- configuration is more active.
  • the W group may be cis- or trans- in respect to substituents X, Y or R3. In the case of the asymmetric center which bears the X and Y groups, in most cases, both the R- and S- configurations are consistent with useful levels of growth hormone secretagogue activity.
  • configurations of many of the most preferred compounds of this invention are indicated.
  • the W, X and Y groups may also be cis- or trans- to the R 3 substituent. In some of the most preferred compounds a cis- or trans- relationship is also specified in respect to the R3 substitutent. All are within the ambit of this invention and in some of the most preferred compounds these stereochemical
  • diastereomers are arbitrarily referred to a diastereomers d 1 , d 2 , d 3 , d 4 , etc. and if desired, their independent syntheses or chromatographic separations may be achieved using standard methods or as described herein.
  • Their absolute stereochemistry may be determined by the xray 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 hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methane sulfonic and the like.
  • acids hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methane sulfonic and the like.
  • 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 can 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.
  • the phrase standard peptide coupling reaction conditions is used repeatedly here, and it means coupling a carboxylic acid with an amine using an acid activating agent such as EDC, DCC, and BOP in a inert solvent such as dichloromethane in the presence of a catalyst such as HOBT.
  • an acid activating agent such as EDC, DCC, and BOP
  • a inert solvent such as dichloromethane
  • HOBT a catalyst
  • protective groups for amine and carboxylic acid to facilitate the desired reaction and minimize the undesired reaction are well documented. Conditions required to remove protecting groups which may be present and can be found in Greene, T; 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.
  • Reductive alkylation of I with an aldehyde is carried out under conditions known in the art; for example, by catalytic hydrogenation with hydrogen in the presence of platinum, palladium, or nickel catalysts or with chemical reducing agents such as sodium cyanoborohydride in a protic solvent such as methanol or ethanol in the present of catalytic amount of acid.
  • a similar transformation can be accomplished via an epoxide opening reaction.
  • Other ester protected amino acids can be prepared by classical methods familiar to those skilled in the art. Some of these methods include the reaction of the amino acid with an alcohol in the presence of an acid such as hydrochloric acid or p-toluenesulfonic acid and azeotropic removal of water. Other methods includes the reaction of a protected amino acid with a diazoalkane, or with an alcohol and an acid activating agent such as EDC, DCC in the presence of a catalyst such as DMAP and removal of the protecting group L.
  • An allyl ester can be cleaved with tetrakis-triphenylphosphine palladium catalyst in the presence of 2-ethylhexanoic acid in a variety of solvents including ethyl acetate and dichloromethane (see J. Org. Chem. , 42, 587 (1982)).
  • Acid 12 or 12a can then be elaborated to I or compound 7 as described in Scheme 8.
  • Coupling of piperidines, pyrrolidines or hexahydro-1H-azepines of formula 2 to acids of formula 12 or 12a, wherein L is a suitable protecting group is conveniently carried out under the standard peptide coupling reaction conditions. Transformation of 7 to I is achieved by removal of the protecting group L.
  • R 4 and/or R 5 is H, substituted alkyl groups may be optionally added to the nitrogen atom as described in Scheme 4.
  • the 2-substituted piperidines, pyrrolidines or hexahydro-1H-azapines are either commercially available or can be prepared by literature procedures. Illustrated herein are some, but by no means all, the methods for their preparation.
  • hydroxylaminonitrile can be hydrolyzed first, then reduced by palladium catalyzed hydrogenation to afford the amino acid of formula A15.
  • the amino acid and their derivatives prepared according to this method are racemic.
  • the carboxylic acid functionality at the 2-position of compounds of formula A15 can be converted to ester, amide, nitrile, acyl sulfonamide, and moieties as defined by W to give compound of general formula 2 according to the conventional methods well documented in the literature and known to those skilled in the art (The Practice of Peptide Synthesis, by M. Bodanszky and A. Bodanszky, Springer-Verlag, 1984).
  • L is an appropriate protecting group such as BOC, CBZ, etc.
  • the carboxylic acid can also 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. Alternatively, the ester can be directly
  • Illustrated in Scheme A11 is a general method to introduce Y wherein X is an electron withdrawing group such as -CN, -CO 2 R 8 , where R 8 is alkyl, aryl, and alkyl(C 1 -C 4 )aryl are either known
  • diastereomeric mixtures can be separated at the appropriate stage by chromatography to yield the enantiomerically pure compounds.
  • asymmetric synthesis can be carried out to synthesize optically pure piperidine, pyrrolidine and hexahydro-1H-azepine derivatives.
  • optically active piperidine-2-carboxylic acid derivatives A15a, A15b can be prepared by the aza-Diels-Alder reaction as described by Bailey et al (J. Chem. Soc. Perkin Trans I, 1337-1340 (1991)). Reaction between the chiral imine A23 and the diene A24 in the presence of TFA (1 equivalent) and water (catalytic) gives the adducts A25 and A26 with good diastereoselectivity. The two
  • hydrogenation of the olefin can be accomplished by use of platinum or palladium catalysts in a protic solvent like methanol.
  • Compounds B18 can be transformed to B19 or B20 as described above.
  • the 3,4-disubstituted piperidines, pyrrolidines and hexahydro-1H-azepines of formula B21 wherein X is an electron withdrawing group like an ester, ketone, nitrile, etc., can be further alkylated, hydroxylated, halogenated by using methods familiar to those skilled in the art.
  • deprotection of the protecting group L can be carried out by methods familiar to those skilled in the art.
  • the piperidine B27 can be elaborated to compounds of Formula I by using chemistry detailed in Schemes 1-8.
  • the acid intermediate B28 can be used to prepare compounds bearing a variety of highly functionalized piperidines that can be transformed to compoundsof formula I.
  • the piperidine B26 may also serve as a key intermediate for the synthesis of a variety of piperidines of formula B22a, wherein R 10 may be alkyl and aryl amides, alkyl and aryl acylsulfonamides, alkyl and aryl ureas, alkyl and aryl carbamates, etc.
  • the piperidine nitrogen of B26 can be protected with a protecting group L (commonly used groups include BOC, CBZ, FMOC) by well documented methods and the ester unit can now be hydrolyzed with sodium or potassium hydroxide in aqueous or alcoholic media to give B29.
  • the protecting group L can be removed and elaborated to compounds of Formula I using chemistry presented in Schemes 1-8.
  • the protecting group L may be removed and elaborated to compounds of formula I by using chemistry detailed in Schemes 1-8.
  • acids, acid chlorides, nitriles, and imino-ethers serve as key intermediates in the preparation of a number of other alkyl, phenyl, hydroxy, and amino-substituted heterocycles.
  • Many of the methods are documented in A.R. Katrizky, Handbook of Heterocyclic Chemistry, Pergamon Press, 1985, New York, New York, and may be used to synthesize a variety of heterocycle bearing compounds.
  • NC(O)NR 2 R 2 , NC(O)OR 2 by the Curtius rearrangement (Smith, Org. React., 3, 337 (1946)) followed by trapping of the isocyanate
  • the cis 3,4-disubstituted piperidines B38 can be converted to trans 3,4-disubstituted piperidines B40 as shown in Scheme B19 by treating B38 with a catalytic amount of base such as sodium ethoxide in protic solvent.
  • a catalytic amount of base such as sodium ethoxide in protic solvent.
  • the ester functional group of B40 can be further modified by methods familiar to those skilled in the art, including the procedures described in Scheme B18.
  • the protecting group L from compounds of formulas B39 and B41 can be removed through conventional chemistry and elaborated to compounds of formula I by using chemistry described above.
  • cis 3,4-disubstituted piperidines of formula B43 can be prepared by the addition of B42 to ethyl nicotinate by the procedure of G.T. Borrett (U.S. Patent No.
  • the acetal protecting group can be removed by a number of methods familiar to those skilled in the art.
  • the resulting aldehyde B44 serves as a key intermediate for the synthesis of highly functionalized 3,4-disubstituted piperidines.
  • the aldehyde B44 can be oxidized to the corresponding carboxylic acid B45 and then further elaborated to a variety of functional groups such as amides, ureas, carbamates, acylsulfonamides and etc. Some examples of these transformations are discussed in connection with Scheme B14.
  • Compound B44 can also be converted to an ⁇ , ⁇ -unsamrated ester or nitrile by an Emmons reaction.
  • the resulting unsamrated ester or nitrile can be hydrogenated using a catalytic amount of palladium or platinum under hydrogen atmosphere.
  • the 3,4-disubstituted compounds 2 generated by these synthetic protocols are racemic.
  • Mono and disubstituted pyrrolidines and hexahydro-1H-azepines 2 generated by these synthetic protocols are also racemic.
  • Chiral intermediates of formula 2 are available by numerous methods including by the classical resolution of racemates. For example resolution can be achieved by the formation of diastereomeric salts of racemic amines with optically active acids such as D- and L- tartaric acid.
  • the determination of the absolute stereochemistry can be accomplished in a number of ways including X-ray crystallography of a suitable crystalline derivative such as a D- or L- tartaric acid salt. Alternatively, asymmetric synthesis can be carried out to synthesize optically pure compounds.
  • 3-Monosubstituted piperidines of formula C13 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 may also be prepared by catalytic hydrogenation of 3-substituted pyrroles.
  • Introduction of the Y substitution can be achieved by first reacting compounds of Formula C14 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 C15 may be removed with conventional chemistry to give compounds of Formula 2.
  • the cyanoacetates of general formula C16 may be alkylated with an ethoxycarbonylalkyl bromide or reacted with ethyl acrylate to give compounds of Formula C18.
  • Reduction of the nitriles C18 by borane or by hydrogenation using Raney Ni as a catalyst gives the corresponding primary amines, which upon refluxing in ethanol gives lactam C19.
  • Reduction of the lactam C19 by borane gives compounds of Formula C2a.
  • a malonate of general formula C20 may be alkylated with cyanoalkyl bromide or can be reacted with acrylonitrile to form compounds of formula C21.
  • Reduction of the nitriles C21 by borane or by hydrogenation using Raney Ni as a catalyst gives the corresponding primary amines, which upon refluxing in ethanol gives lactam C22.
  • Reduction of the lactam C22 by borane gives compounds of formula C2a.
  • the X, Y functionalities in compounds of general structure C15 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 C15a may be reduced to an alcohol C18 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 C19 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 C18 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 C20 to an amine C21 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 C21 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 C28, 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 C2b. Shown in Scheme C16 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 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 formula D46. The preparation of many of these acids is described in
  • 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.
  • the O-alkyl-(D)-serine derivatives may also be prepared using an alkylation protocol.
  • alkylation of the chiral gylcine enolates J. Am. Chem. Soc. 1991, 113, 9276; J. Org. Chem.
  • D,L-O-aryl(alkyl)serines may be prepared and resolved by methods described above.
  • 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,
  • 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
  • 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.
  • compositions comprising, as an active
  • 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 catabolic side effects or with other pharmaceutically active materials wherein the combination enhances efficacy and minimizes side effects.
  • an antibiotic growth permittant or an agent to treat osteoporosis or in combination with a corticosteroid to minimize the 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, estrogens, ⁇ -agonists,
  • GRF GRF
  • GRF GRF-1 and IGF-2 or a- adrenergic aginists
  • clonidine or serotonin 5HTID agonists such as sumitriptan or agents which inhibit somatostatin or its release such as physostigmine and pyridostigmine.
  • growth hormone As is well known to those skilled in the art, 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 of the present compounds thus 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
  • hyperinsulinemia including nesidioblastosis; adjuvant treatment for ovulation induction and to prevent and treat gastric and duodenal ulcers; to stimulate thymic development and prevent the age-related decline of thymic function; adjunctive therapy for patients on chronic hemodialysis; treatment of immunosuppressed patients and to enhance antibody response following vaccination; increasing the total lymphocyte count of a human, in particular, increasing the T4/T8-cell ratio in a human with a depressed T4/T8-cell ratio resulting, for example, from physical trauma, such as closed head injury, or from infection, such as bacterial or viral infection, especially infection with the human immunodeficiency virus; improvement in muscle strength, mobility, maintenance of skin thiclcness, metabolic homeostasis, renal hemeostasis in the frail elderly; stimulation of osteoblasts, bone remodelling, and cartilage growth; stimulation of the immune system in companion animals and treatment of disorders of aging in companion animals; growth promotant in livestock; and stimulation of wool growth in sheep.
  • the 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 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; hip fracture;
  • 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
  • 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.
  • the compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated in dosage forms appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant
  • nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated in dosage forms appropriate for each route of administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch.
  • Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the
  • compositions 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
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. Generally, dosage levels of between 0.0001 to 100 mg/kg. of body weight daily are administered to patients and animals, e.g., mammals, to obtain effective release of growth hormone.
  • Step C (D)-N-t-Boc-2-amino-5-phenylpentanoic acid
  • step B The intermediate from step B (4.2 g, 17.8 mmol) was suspended in 2 N HCl (100 mL) and refluxed for two hours. The reaction mixture was evaporated in vacuo to remove water and hydrochloric acid to yield a white solid. To a solution of this solid in 50 mL of water, was added 3 N NaOH until the pH 11, then di-t-butyl dicarbonate (4.66 g, 21.4 mmol) was added with vigorous stirring. After four hours, the reaction mixture was acidified to pH 2 with 3 N HCl and it was extracted with ethyl acetate (100 mLX3). The orgamc extracts were combined and evaporated to give a white solid (6.56 g, crude) which was used without purification.
  • Step A (d1)-Pipecolinic acid, benzyl ester
  • step B A suspension of the product from Example A4, step B (5.30 g) and 10% palladium on carbon (270 mg) in ethanol (100 mL) was stirred under a hydrogen balloon for 3 hours. The reaction mixmre was filtered through celite, evaporated to give the acid ( 4.48g).
  • Step B using products from the previous step and HCl gas in ethyl acetate at 0°C gave the desired products.
  • Example A9 step A Prepared according to the procedure in Example A9 step A from the intermediate from the previous step (27 g).
  • the crude reaction product was purified by a SiO 2 flash column eluting with 20-40% ethyl acetate in hexane to give 5-benzyl-2-cyanopyridine (3.0g, 10%) and 3-benzyl-2-cyanopyridine (24.2 g, 85%).
  • Step F A suspension of the product from the previous step (1.0 g) and platinum dioxide (100 mg) in ethanol was stirred under a hydrogen balloon for five hours. The reaction mixture was then filtered through celite and evaporated to give the desired compound.
  • the compound was prepared according to the procedure of the previous step from the intermediate d2 from Step F (130 mg).
  • Step A Diethyl N-Boc-piperidine-(cis)-2,3-dicarboxylate
  • the reaction was quenched with 75 mL of water and oxygen gas was bubbled in for 3h.
  • the organic layer was washed with water, brine (200 mL), dried over Na2S ⁇ 4, filtered, and evaporated.
  • Example B1 The PtO 2 reduction of the phenyl-piperidine intermediate prepared in Step A, Example B1 was attempted in different solvents like ethanol and methanol in the presence and absence of cone. HCl.
  • Example B7 To a solution of 0.19 g of the intermediate from Step C, Example B7 in 3 mL of dioxane was added 50 mg of 10% Pd/C and hydrogenated under H 2 balloon for 3h. The reaction was slow so about 50 mg of 20% Pd(OH) 2 /C was added and hydrogenated overnight. The catalyst was filtered off through a pad of celite and washed with dioxane. Evaporation of the filtrate gave the title compound as a pink solid.
  • Step A- 1
  • Step A-1 Prepared from the intermediate obtained from Step A-1 (3.2 g, 9.66 mmole) which was dissolved in 100 ml of methanol,
  • Step C The intermediate obtained from Step C was dissolved in 3 ml of methanol and hydrogenated over Pd(OH) 2 /C at one atmosphere for an hour (monitored by TLC). The mixmre was filtered through Celite and the filtrate concentrated under vacuum. The residue was acidified with HCl in ether to give a white precipitate (d1, 40 mg).
  • Step A-1 1.0 g, 3.02 mmole
  • 4N sodium hydroxide 4 ml
  • the reaction was stirred at room temperature for 16 hours and evaporated in vacuo.
  • the residue was diluted with water and acidified with 0.5N hydrochloric acid and then exacted with ether.
  • the orgamc layer was dried over sodium sulfate, filtered and concentrated.
  • the crude residue was dissolved in methanol and hydrogenated over Pd(OH) 2 at one atmosphere for 16 hours. The mixture was filtered through Celite and the filtrate concentrated under vacuum.

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Abstract

L'invention concerne certains composés de pipéridine, de pyrrolidine, et d'hexahydro-1H-azépine de formule structurale (I) dans laquelle R1, R3, R4, R5, A, W, X, Y et n sont définis dans la description. Ces composés favorisent la libération de l'hormone de croissance chez les humains et les animaux. Cette propriété peut être utilisée pour favoriser la croissance d'animaux destinés à l'alimentation et augmenter la production de produits de viande comestibles, et, chez les humains, pour traiter des états physiologiques ou médicaux caractérisés par une insuffisance de sécrétion de l'hormone de croissance telle que l'insuffisance staturale chez l'enfant, et traiter des états médicaux pouvant être améliorés par les effets anabolisants de l'hormone de croissance. L'invention porte également sur des compositions libérant l'hormone de croissance dans lesquelles lesdits composés sont utilisés comme principes actifs.
PCT/US1994/012816 1993-11-09 1994-11-07 Piperidines, pyrrolidines et hexahydro-1h-azepines favorisant la liberation de l'hormone de croissance WO1995013069A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
JP7513932A JPH10506091A (ja) 1993-11-09 1994-11-07 成長ホルモン放出促進性のピペリジン、ピロリジンおよびヘキサヒドロ−１ｈ−アゼピン類
BR9408019A BR9408019A (pt) 1993-11-09 1994-11-07 Composto composição util para aumentar a produção endógena ou a liberaçao de hormonio do crescimento em ser humano ou um animal e para o tratamento da osteoporose processos para aumentar os niveis de hormônio do crescimento em um ser humano ou um animal e a eficácia de alimentação promover o crescimento aumentar a produçao de leite e melhorar a qualidade da carcaça de gado para tratar ou previnir uma condição selecionada para tratar osteoporose e para preparar um composto
KR1019960702427A KR960705808A (ko) 1993-11-09 1994-11-07 성장 호르몬의 방출을 촉진시키는 피페리딘, 피롤리딘 및 헥사하이드로-1H-아제핀(Piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone)
AU11729/95A AU1172995A (en) 1993-11-09 1994-11-07 Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone
EP95902467A EP0739204A4 (fr) 1993-11-09 1994-11-07 Piperidines, pyrrolidines et hexahydro-1h-azepines favorisant la liberation de l'hormone de croissance
SK562-96A SK56296A3 (en) 1993-11-09 1994-11-07 Piperidinal, pyrrolidinal and hexahydro-1h-azepinal derivatives, manufacturing process thereof and pharmaceutical compositions containing them
BG100555A BG100555A (bg) 1993-11-09 1996-05-02 Пиперидини, пиролидини и хексахидро-1н-азепини, стимулиращи освобождаването на хормон на растежа
FI961951A FI961951A0 (fi) 1993-11-09 1996-05-08 Piperidiinit, pyrrolidiinit ja heksahydro-1H-atsepiinit edistävät kasvuhormonin vapautumista
NO961865A NO961865L (no) 1993-11-09 1996-05-08 Piperidiner, pyrrolidiner og heksahydro-1H-azepiner fremmer frigjörelse av veksthormon
LVP-96-151A LV11525B (en) 1993-11-09 1996-05-22 Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
US14944193A 1993-11-09 1993-11-09
US149,441 1993-11-09
US16514993A 1993-12-10 1993-12-10
US165,149 1993-12-10
US17344993A 1993-12-23 1993-12-23
US173,449 1993-12-23
US323,988 1994-10-17
US08/323,998 US5492920A (en) 1993-12-10 1994-10-17 Piperidine, pyrrolidine and hexahydro-1H-azepines promote release of growth hormone
US08/323,988 US5492916A (en) 1993-12-23 1994-10-17 Di- and tri-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone
US323,998 1994-10-17
US323,994 1994-10-17
US08/323,994 US5494919A (en) 1993-11-09 1994-10-17 2-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone

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JP (1) JPH10506091A (fr)
KR (1) KR960705808A (fr)
CN (1) CN1174504A (fr)
AU (1) AU1172995A (fr)
BG (1) BG100555A (fr)
BR (1) BR9408019A (fr)
CA (1) CA2175218A1 (fr)
CZ (1) CZ134296A3 (fr)
FI (1) FI961951A0 (fr)
HU (1) HUT74733A (fr)
LV (1) LV11525B (fr)
NO (1) NO961865L (fr)
PL (1) PL322706A1 (fr)
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Cited By (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5559128A (en) * 1995-04-18 1996-09-24 Merck & Co., Inc. 3-substituted piperidines promote release of growth hormone
WO1996015148A3 (fr) * 1994-11-16 1996-11-14 Genentech Inc Secretagogues peptidomimetiques de faible poids moleculaire liberant de la somatotrophine
WO1996035713A1 (fr) * 1995-05-08 1996-11-14 Pfizer, Inc. Dipeptides stimulant la liberation de l'hormone de croissance
US5622973A (en) * 1993-12-23 1997-04-22 Merck & Co., Inc. Treatment of osteoporosis with substituted piperidines, pyrrolidines and hexahydro-1H-azepines in combination with bisphosphonates
WO1997024369A1 (fr) * 1995-12-28 1997-07-10 Pfizer Inc. Composes secretagogues d'hormone de croissance
WO1997024323A1 (fr) * 1995-12-28 1997-07-10 Chirotech Technology Procede de preparation de piperidines a substitution 4-aryl-3-hydromethyle, optiquement enrichies destinees a etre utilisees comme intermediaires dans la synthese de la paroxetine
US5721250A (en) * 1993-12-23 1998-02-24 Merck & Co. Inc. Di-and tri-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone
US5721251A (en) * 1993-12-10 1998-02-24 Merck & Co., Inc. Piperidine, pyrrolidine and hexahydro-1H-azepines promote release of growth hormone
EP0785784A4 (fr) * 1994-10-26 1998-03-11 Merck & Co Inc Piperidines heterocycliques en position 4 favorisant la liberation de l'hormone de croissance
US5731317A (en) * 1995-03-10 1998-03-24 Merck & Co., Inc. Bridged piperidines promote release of growth hormone
EP0831823A4 (fr) * 1995-06-07 1998-10-21 Merck & Co Inc ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a
WO1998058948A1 (fr) * 1997-06-25 1998-12-30 Pfizer Products Inc. Tartrate de dipeptide substitue intervenant comme secretagogue d'hormone de croissance
WO1998058947A1 (fr) * 1997-06-25 1998-12-30 Pfizer Inc. Derives dipeptides secretagogues de l'hormone de croissance
WO1999058501A1 (fr) * 1998-05-11 1999-11-18 Novo Nordisk A/S Composes possedant des proprietes de liberation d'hormone de croissance
US6011155A (en) * 1996-11-07 2000-01-04 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6110949A (en) * 1999-06-24 2000-08-29 Novartis Ag N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6166063A (en) * 1998-12-10 2000-12-26 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6172081B1 (en) 1999-06-24 2001-01-09 Novartis Ag Tetrahydroisoquinoline 3-carboxamide derivatives
JP3133073B2 (ja) 1995-05-29 2001-02-05 ファイザー・インコーポレーテッド 成長ホルモンの放出を促進するジペプチド類
WO2000055126A3 (fr) * 1999-03-15 2001-02-22 Axys Pharm Inc Nouveaux composes et compositions utiles comme inhibiteurs de protease
US6242199B1 (en) 1995-12-13 2001-06-05 Merck & Co., Inc. Assays for growth hormone secretagogue receptors
EP1086083A4 (fr) * 1998-06-12 2001-09-26 Smithkline Beecham Corp Inhibiteurs de proteases
US6303620B1 (en) 1998-05-11 2001-10-16 Novo Nordisk A/S Compounds with growth hormone releasing properties
WO2001085695A1 (fr) * 2000-05-11 2001-11-15 Bristol-Myers Squibb Co. Analogues de tetrahydroisoquinoline servant de secretagogues d'hormones de croissance
US6323223B1 (en) 1997-08-18 2001-11-27 Syntex (U.S.A.) Llc Cyclic amine derivatives- CCR-3 receptor antagonists
EP1159964A2 (fr) 2000-05-31 2001-12-05 Pfizer Products Inc. Compositions et methodes pour stimuler la motilité gastrointestinale
US6339087B1 (en) 1997-08-18 2002-01-15 Syntex (U.S.A.) Llc Cyclic amine derivatives-CCR-3 receptor antagonists
WO2001098268A3 (fr) * 2000-06-21 2002-08-08 Bristol Myers Squibb Pharma Co Amides de piperidine utilises comme modulateurs de l'activite des recepteurs des chimiokines
US6448263B1 (en) 1997-06-25 2002-09-10 Pfizer Inc. Treatment of insulin resistance with growth hormone secretagogues
US6468974B1 (en) 1998-08-14 2002-10-22 The Administrators Of The Tulane Educational Fund Compounds having growth hormone releasing activity
US6531314B1 (en) 1996-12-10 2003-03-11 Merck & Co., Inc. Growth hormone secretagogue receptor family
US6541634B2 (en) 1999-02-26 2003-04-01 Pfizer Inc. Process for preparing growth hormone secretagogues
WO2003026649A1 (fr) * 2001-09-27 2003-04-03 Applied Research Systems Ars Holding N.V. Methodes pouvant augmenter des concentrations en testosterone endogene
US6586446B1 (en) 1999-10-15 2003-07-01 Bristol-Myers Squibb Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
US6599718B1 (en) 1998-07-13 2003-07-29 Merck & Co., Inc. Growth hormone secretagogue related receptors and nucleic acids
US6608227B1 (en) 1999-10-15 2003-08-19 Bristol-Myers Squibb Pharma Benzylcycloalkyl amines as modulators of chemokine receptor activity
US6617340B1 (en) 1999-07-29 2003-09-09 Novartis Ag N-(substituted glycyl)-pyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6645726B1 (en) 1998-08-10 2003-11-11 Merck & Co., Inc. Canine growth hormone secretagogue receptor
US6649657B2 (en) 1996-12-20 2003-11-18 Pfizer Inc. Prevention of loss and restoration of bone mass by certain prostaglandin agonists
US6649606B1 (en) 2001-11-09 2003-11-18 Bristol-Myers Squibb Co. Tetrahydroisoquinoline analogs as modulators of chemokine receptor activity
US6682908B1 (en) 1998-07-10 2004-01-27 Merck & Co., Inc. Mouse growth hormone secretagogue receptor
US6784200B2 (en) 2000-10-13 2004-08-31 Bristol-Myers Squibb Pharma Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
US6919356B2 (en) 2002-09-26 2005-07-19 Bristol Myers Squibb Company N-substituted heterocyclic amines as modulators of chemokine receptor activity
US6974869B2 (en) 2001-09-18 2005-12-13 Bristol-Myers Squibb Pharma Company Piperizinones as modulators of chemokine receptor activity
US6977256B2 (en) 2001-11-14 2005-12-20 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin S inhibitors
WO2005120477A2 (fr) 2004-06-07 2005-12-22 Merck & Co., Inc. N- (2-benzyl) -2-phenylbutanamides modulant le recepteur d'androgene
US6992091B2 (en) 2002-09-12 2006-01-31 Bristol-Myers Squibb Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US7030116B2 (en) 2000-12-22 2006-04-18 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US7064123B1 (en) 2000-12-22 2006-06-20 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
WO2006069788A1 (fr) * 2004-12-30 2006-07-06 Novartis Ag Composes organiques
US7094869B2 (en) 1994-11-16 2006-08-22 Genentech, Inc. Low molecular weight peptidomimetic growth hormone secretagogues
US7153822B2 (en) 2002-01-29 2006-12-26 Wyeth Compositions and methods for modulating connexin hemichannels
US7196099B2 (en) 2001-09-14 2007-03-27 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
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
WO2008028654A1 (fr) * 2006-09-06 2008-03-13 Lonza Ag PROCÉDÉ DE PRÉPARATION DE 3-AMINOPYRROLIDINE N-PROTÉGÉE OPTIQUEMENT ACTIVE OU DE 3-AMINOPIPÉRIDINE N-PROTÉGÉE OPTIQUEMENT ACTIVE ET DES CÉTONES CORRESPONDANTES PAR RÉSOLUTION OPTIQUE DES MÉLANGES RACÉMIQUES D'AMINES, AU MOYEN D'UNE OM&Eacute
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
EP1932543A2 (fr) 1996-02-28 2008-06-18 Pfizer, Inc. Thérapie combinée pour l'ostéoporose basée sur un agoniste/antagoniste d'estrogène et un sécrétagogue d'hormone de croissance
WO2008134828A2 (fr) 2007-05-04 2008-11-13 Katholieke Universiteit Leuven Protection contre la dégénérescence tissulaire
JP2009062369A (ja) * 1999-11-10 2009-03-26 Novo Nordisk As 成長ホルモン放出特性を有する化合物
US7622496B2 (en) 2005-12-23 2009-11-24 Zealand Pharma A/S Modified lysine-mimetic compounds
US7659305B2 (en) 2002-10-31 2010-02-09 Pfizer Inc. Therapeutic proline derivatives
EP2269986A4 (fr) * 2008-03-26 2011-07-13 Sumitomo Chemical Co Procédé de fabrication d un composé pipéridin-3-ylcarbamate et procédé de résolution optique de celui-ci
US8183280B2 (en) 2005-09-02 2012-05-22 Vantia Limited FAP inhibitors
EP2457893A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Intermédiaires pour des modulateurs macrocycliques du récepteur de ghréline
EP2644618A1 (fr) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. Intermédaires dans la synthese de modulateurs macrocycliques du récepteur de la ghréline
WO2013190520A2 (fr) 2012-06-22 2013-12-27 The General Hospital Corporation Agents de libération de gh dans le traitement d'une sténose vasculaire et d'états associés
US8927590B2 (en) 2006-12-21 2015-01-06 Zealand Pharma A/S Synthesis of pyrrolidine compounds
WO2015181676A1 (fr) 2014-05-30 2015-12-03 Pfizer Inc. Dérivés carbonitriles en tant que modulateurs sélectifs du récepteur des androgènes
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs
WO2018167631A1 (fr) 2017-03-13 2018-09-20 Richter Gedeon Nyrt. Procédé de séparation d'isomères optiques d'esters éthyliques de l'acide 3-alkylpipéridine-carboxylique racémique
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury
RU2695649C2 (ru) * 2014-08-05 2019-07-25 Раквалиа Фарма Инк. Производные серина в качестве агонистов грелиновых рецепторов
CN112204007A (zh) * 2018-06-01 2021-01-08 施万生物制药研发Ip有限责任公司 制备2-(1-(叔丁氧基羰基)哌啶-4-基)苯甲酸的方法
US11324799B2 (en) 2017-05-05 2022-05-10 Zealand Pharma A/S Gap junction intercellular communication modulators and their use for the treatment of diabetic eye disease
CN114805305A (zh) * 2022-04-20 2022-07-29 成都诺和晟泰生物科技有限公司 一种化合物及其应用
US11439649B2 (en) 2018-02-21 2022-09-13 AI Therapeutics, Inc. Combination therapy with apilimod and glutamatergic agents
WO2023275715A1 (fr) 2021-06-30 2023-01-05 Pfizer Inc. Métabolites de modulateurs sélectifs du récepteur des androgènes

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002523368A (ja) * 1999-02-19 2002-07-30 イーライ・リリー・アンド・カンパニー 成長ホルモン分泌促進薬
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Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4299821A (en) * 1979-06-28 1981-11-10 Richter Gedeon Vegyeszeti Gyar Rt. Tripeptides acting on the central nervous system and a process for the preparation thereof
US4411890A (en) * 1981-04-14 1983-10-25 Beckman Instruments, Inc. Synthetic peptides having pituitary growth hormone releasing activity
US4782139A (en) * 1985-10-28 1988-11-01 Eli Lilly And Company Selective chemical removal of a protein amino-terminal residue
US4997825A (en) * 1986-12-22 1991-03-05 Eli Lilly And Company Synergistic treatment method
US5036045A (en) * 1985-09-12 1991-07-30 The University Of Virginia Alumni Patents Foundation Method for increasing growth hormone secretion
US5084442A (en) * 1988-09-06 1992-01-28 Hoffmann-La Roche Inc. Cyclic growth hormone releasing factor analogs and method for the manufacture thereof
US5137872A (en) * 1989-09-18 1992-08-11 Pitman-Moore, Inc. Growth hormone-releasing factor analogs
US5162302A (en) * 1988-03-18 1992-11-10 University Of Delaware Endocrine manipulation to improve body composition of poultry
US5164368A (en) * 1990-11-26 1992-11-17 Recker Robert R Treatment for osteoporosis using growth hormone releasing factor (grf) in combination with parathyroid hormone (pth)
JPH05163224A (ja) * 1991-12-12 1993-06-29 Mitsui Petrochem Ind Ltd アミノ基含有化合物の製造方法
US5276014A (en) * 1990-08-03 1994-01-04 Kabi Pharmacia Ab Treatment of human lactation failure
US5284841A (en) * 1993-02-04 1994-02-08 Merck & Co., Inc. Benzo-fused lactams promote release of growth hormone
US5366965A (en) * 1993-01-29 1994-11-22 Boehringer Mannheim Gmbh Regimen for treatment or prophylaxis of osteoporosis

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8332704D0 (en) * 1983-12-07 1984-01-11 Pfizer Ltd Growth promotants for animals
US5206235A (en) * 1991-03-20 1993-04-27 Merck & Co., Inc. Benzo-fused lactams that promote the release of growth hormone

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4299821A (en) * 1979-06-28 1981-11-10 Richter Gedeon Vegyeszeti Gyar Rt. Tripeptides acting on the central nervous system and a process for the preparation thereof
US4411890A (en) * 1981-04-14 1983-10-25 Beckman Instruments, Inc. Synthetic peptides having pituitary growth hormone releasing activity
US5036045A (en) * 1985-09-12 1991-07-30 The University Of Virginia Alumni Patents Foundation Method for increasing growth hormone secretion
US4782139A (en) * 1985-10-28 1988-11-01 Eli Lilly And Company Selective chemical removal of a protein amino-terminal residue
US4997825A (en) * 1986-12-22 1991-03-05 Eli Lilly And Company Synergistic treatment method
US5162302A (en) * 1988-03-18 1992-11-10 University Of Delaware Endocrine manipulation to improve body composition of poultry
US5084442A (en) * 1988-09-06 1992-01-28 Hoffmann-La Roche Inc. Cyclic growth hormone releasing factor analogs and method for the manufacture thereof
US5137872A (en) * 1989-09-18 1992-08-11 Pitman-Moore, Inc. Growth hormone-releasing factor analogs
US5276014A (en) * 1990-08-03 1994-01-04 Kabi Pharmacia Ab Treatment of human lactation failure
US5164368A (en) * 1990-11-26 1992-11-17 Recker Robert R Treatment for osteoporosis using growth hormone releasing factor (grf) in combination with parathyroid hormone (pth)
JPH05163224A (ja) * 1991-12-12 1993-06-29 Mitsui Petrochem Ind Ltd アミノ基含有化合物の製造方法
US5366965A (en) * 1993-01-29 1994-11-22 Boehringer Mannheim Gmbh Regimen for treatment or prophylaxis of osteoporosis
US5284841A (en) * 1993-02-04 1994-02-08 Merck & Co., Inc. Benzo-fused lactams promote release of growth hormone

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 113, No. 15, issued 08 October 1990, HORWELL et al., "Alpha-Methyl Tryptophanyl Phenyl Alanines and their Arylathylamine 'Dipeptoid' Analogs of the Tetrapeptide Cholecystokinin", see p. 715, column 2, Abstract No. 132771p; & EUR. J. MED. CHEM., 25(1), 53-60. *
CHEMICAL ABSTRACTS, Volume 113, No. 9, issued 27 August 1990, SAKAMOTO et al., "Chymotrypsin Inhibition by Dipeptide Esters, Phnylpiperidide and Phenyl Piparazides", see page 322, column 1, Abstract No. 73560u; & PEPT. CHEM., 1989, 27th, 375-8. *
See also references of EP0739204A4 *

Cited By (143)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5721251A (en) * 1993-12-10 1998-02-24 Merck & Co., Inc. Piperidine, pyrrolidine and hexahydro-1H-azepines promote release of growth hormone
US5622973A (en) * 1993-12-23 1997-04-22 Merck & Co., Inc. Treatment of osteoporosis with substituted piperidines, pyrrolidines and hexahydro-1H-azepines in combination with bisphosphonates
US5721250A (en) * 1993-12-23 1998-02-24 Merck & Co. Inc. Di-and tri-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone
EP0785784A4 (fr) * 1994-10-26 1998-03-11 Merck & Co Inc Piperidines heterocycliques en position 4 favorisant la liberation de l'hormone de croissance
US5798337A (en) * 1994-11-16 1998-08-25 Genentech, Inc. Low molecular weight peptidomimetic growth hormone secretagogues
WO1996015148A3 (fr) * 1994-11-16 1996-11-14 Genentech Inc Secretagogues peptidomimetiques de faible poids moleculaire liberant de la somatotrophine
US7094869B2 (en) 1994-11-16 2006-08-22 Genentech, Inc. Low molecular weight peptidomimetic growth hormone secretagogues
US6034216A (en) * 1994-11-16 2000-03-07 Genentech Inc. Low molecular weight peptidomimetic growth hormone secretagogues
EP0999220A3 (fr) * 1994-11-16 2000-09-20 Genentech, Inc. Secretagogues peptidmimetiques de faible poids moleculaire liberant de la somatotrophine
US5731317A (en) * 1995-03-10 1998-03-24 Merck & Co., Inc. Bridged piperidines promote release of growth hormone
US5559128A (en) * 1995-04-18 1996-09-24 Merck & Co., Inc. 3-substituted piperidines promote release of growth hormone
WO1996035713A1 (fr) * 1995-05-08 1996-11-14 Pfizer, Inc. Dipeptides stimulant la liberation de l'hormone de croissance
JP3133073B2 (ja) 1995-05-29 2001-02-05 ファイザー・インコーポレーテッド 成長ホルモンの放出を促進するジペプチド類
EP0831823A4 (fr) * 1995-06-07 1998-10-21 Merck & Co Inc ANTAGONISTES DU RECEPTEUR ADRENERGIQUE ALPHA 1a
US6075038A (en) * 1995-06-07 2000-06-13 Merck & Co., Inc. Alpha 1a adrenergic receptor antagonists
US6242199B1 (en) 1995-12-13 2001-06-05 Merck & Co., Inc. Assays for growth hormone secretagogue receptors
US6124264A (en) * 1995-12-28 2000-09-26 Pfizer Inc. Heterocyclic compounds
US6313140B1 (en) 1995-12-28 2001-11-06 Pfizer Inc. Method of treatment using certain growth-hormone secret agogues
WO1997024369A1 (fr) * 1995-12-28 1997-07-10 Pfizer Inc. Composes secretagogues d'hormone de croissance
AP860A (en) * 1995-12-28 1999-08-06 Pfizer Dipeptide compounds which are growth hormone secretegoques.
US6107306A (en) * 1995-12-28 2000-08-22 Pfizer Inc. Heterocyclic compounds
US6110932A (en) * 1995-12-28 2000-08-29 Pfizer Inc. Growth hormone secretagogues
AP756A (en) * 1995-12-28 1999-08-06 Pfizer Dipeptide compounds which are growth hormone secretagoques.
US6482825B2 (en) 1995-12-28 2002-11-19 Pfizer Inc. Growth-hormone secretagogues
US6278000B1 (en) 1995-12-28 2001-08-21 Pfizer Inc. Growth-hormone secretagogues
US6306875B1 (en) 1995-12-28 2001-10-23 Pfizer Inc. Growth-hormone secretagogues
WO1997024323A1 (fr) * 1995-12-28 1997-07-10 Chirotech Technology Procede de preparation de piperidines a substitution 4-aryl-3-hydromethyle, optiquement enrichies destinees a etre utilisees comme intermediaires dans la synthese de la paroxetine
EP1932543A2 (fr) 1996-02-28 2008-06-18 Pfizer, Inc. Thérapie combinée pour l'ostéoporose basée sur un agoniste/antagoniste d'estrogène et un sécrétagogue d'hormone de croissance
US6011155A (en) * 1996-11-07 2000-01-04 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6124305A (en) * 1996-11-07 2000-09-26 Novartis Ag Use of N-(substituted glycyl)-2-cyanopyrrolidines in inhibiting dipeptidyl peptidase-IV
US6531314B1 (en) 1996-12-10 2003-03-11 Merck & Co., Inc. Growth hormone secretagogue receptor family
US6649657B2 (en) 1996-12-20 2003-11-18 Pfizer Inc. Prevention of loss and restoration of bone mass by certain prostaglandin agonists
US6998423B2 (en) 1996-12-20 2006-02-14 Pfizer Inc. Prevention of loss and restoration of bone mass by certain prostaglandin agonists
WO1998058948A1 (fr) * 1997-06-25 1998-12-30 Pfizer Products Inc. Tartrate de dipeptide substitue intervenant comme secretagogue d'hormone de croissance
AP1043A (en) * 1997-06-25 2002-02-04 Pfizer Prod Inc Tartrate salt of a substituted dipeptide.
US6251902B1 (en) * 1997-06-25 2001-06-26 Pfizer Inc. Dipeptide derivatives as growth hormone secretagogues
US6248717B1 (en) 1997-06-25 2001-06-19 Pfizer Inc. Tartrate salt of a substituted dipeptide as growth hormone secretagogue
US6953791B2 (en) 1997-06-25 2005-10-11 Pfizer, Inc. Dipeptide derivatives
US6924280B2 (en) 1997-06-25 2005-08-02 Pfizer Inc. Dipeptide derivatives
US6596867B2 (en) 1997-06-25 2003-07-22 Pfizer Inc. Tartrate salt of a substituted dipeptide as growth hormone secretagogue
US6867202B1 (en) 1997-06-25 2005-03-15 Pfizer Inc. Treatment of insulin resistance
US6525047B2 (en) 1997-06-25 2003-02-25 Pfizer Inc. Dipeptide derivatives
US6630487B2 (en) 1997-06-25 2003-10-07 Pfizer Inc. Treatment of insulin resistance with growth hormone secretagogues
US6429313B2 (en) 1997-06-25 2002-08-06 Pfizer Inc. Dipeptide derivatives
US6951850B2 (en) 1997-06-25 2005-10-04 Pfizer, Inc. Dipeptide derivatives
US6432945B1 (en) 1997-06-25 2002-08-13 Pfizer Inc. Dipeptide derivatives
US6433171B1 (en) 1997-06-25 2002-08-13 Pfizer Inc. Dipeptide derivatives
US6448263B1 (en) 1997-06-25 2002-09-10 Pfizer Inc. Treatment of insulin resistance with growth hormone secretagogues
USRE38524E1 (en) 1997-06-25 2004-06-01 Pfizer Inc. Dipeptide derivatives as growth hormone secretagogues
WO1998058947A1 (fr) * 1997-06-25 1998-12-30 Pfizer Inc. Derives dipeptides secretagogues de l'hormone de croissance
US6770650B2 (en) 1997-08-18 2004-08-03 Syntex (U.S.A.) Llc Cyclic amine derivatives-CCR-3 receptor antagonists
US6984637B2 (en) 1997-08-18 2006-01-10 Syntex (U.S.A.) Llc Cyclic amine derivatives-CCR-3 receptor antagonists
US6683074B1 (en) 1997-08-18 2004-01-27 Syntex (U.S.A.) Llc Cyclic amine derivatives-CCR-3 receptor antagonists
US6339087B1 (en) 1997-08-18 2002-01-15 Syntex (U.S.A.) Llc Cyclic amine derivatives-CCR-3 receptor antagonists
US6323223B1 (en) 1997-08-18 2001-11-27 Syntex (U.S.A.) Llc Cyclic amine derivatives- CCR-3 receptor antagonists
US6303620B1 (en) 1998-05-11 2001-10-16 Novo Nordisk A/S Compounds with growth hormone releasing properties
KR100593601B1 (ko) * 1998-05-11 2006-06-28 노보 노르디스크 에이/에스 성장호르몬 방출성을 가진 화합물
JP2008156372A (ja) * 1998-05-11 2008-07-10 Novo Nordisk As 成長ホルモン放出特性を有する化合物
CZ301276B6 (cs) * 1998-05-11 2009-12-30 Novo Nordisk A/S Piperidinový derivát vykazující schopnost uvolnování rustového hormonu
RU2243215C2 (ru) * 1998-05-11 2004-12-27 Ново Нордиск А/С Производные пиперидинкарбоновых кислот, фармацевтические композиции, содержащие их, способ стимуляции секреции гормона роста
WO1999058501A1 (fr) * 1998-05-11 1999-11-18 Novo Nordisk A/S Composes possedant des proprietes de liberation d'hormone de croissance
EP1086083A4 (fr) * 1998-06-12 2001-09-26 Smithkline Beecham Corp Inhibiteurs de proteases
US6682908B1 (en) 1998-07-10 2004-01-27 Merck & Co., Inc. Mouse growth hormone secretagogue receptor
US6599718B1 (en) 1998-07-13 2003-07-29 Merck & Co., Inc. Growth hormone secretagogue related receptors and nucleic acids
US6645726B1 (en) 1998-08-10 2003-11-11 Merck & Co., Inc. Canine growth hormone secretagogue receptor
US6468974B1 (en) 1998-08-14 2002-10-22 The Administrators Of The Tulane Educational Fund Compounds having growth hormone releasing activity
US7250399B2 (en) 1998-08-14 2007-07-31 The Administrators Of The Tulane Educational Fund Compounds having growth hormone releasing activity
US6166063A (en) * 1998-12-10 2000-12-26 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
US6673929B2 (en) 1999-02-26 2004-01-06 Pfizer Inc. Process for preparing growth hormone secretagogues
US6541634B2 (en) 1999-02-26 2003-04-01 Pfizer Inc. Process for preparing growth hormone secretagogues
US6455502B1 (en) 1999-03-15 2002-09-24 Axys Pharmaceuticals, Inc. Compounds and compositions as protease inhibitors
US6476026B1 (en) 1999-03-15 2002-11-05 Axys Pharmaceuticals, Inc. Compounds and compositions as protease inhibitors
WO2000055126A3 (fr) * 1999-03-15 2001-02-22 Axys Pharm Inc Nouveaux composes et compositions utiles comme inhibiteurs de protease
US6593327B2 (en) 1999-03-15 2003-07-15 Axys Pharmaceuticals, Inc. Compounds and compositions as protease inhibitors
US6110949A (en) * 1999-06-24 2000-08-29 Novartis Ag N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6172081B1 (en) 1999-06-24 2001-01-09 Novartis Ag Tetrahydroisoquinoline 3-carboxamide derivatives
US6617340B1 (en) 1999-07-29 2003-09-09 Novartis Ag N-(substituted glycyl)-pyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US7550500B2 (en) 1999-10-15 2009-06-23 Bristol-Myers Squibb Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
US6864380B2 (en) 1999-10-15 2005-03-08 Bristol-Myers Squibb Pharma Company Benzylcycloalkyl amines as modulators of chemokine receptor activity
US6960666B2 (en) 1999-10-15 2005-11-01 Bristol-Myers Squibb Pharma Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
US7126010B2 (en) 1999-10-15 2006-10-24 Bristol-Myers Squibb Pharma Company Benzylcycloalkyl amines as modulators of chemokine receptor activity
US6608227B1 (en) 1999-10-15 2003-08-19 Bristol-Myers Squibb Pharma Benzylcycloalkyl amines as modulators of chemokine receptor activity
US6586446B1 (en) 1999-10-15 2003-07-01 Bristol-Myers Squibb Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
JP2009062369A (ja) * 1999-11-10 2009-03-26 Novo Nordisk As 成長ホルモン放出特性を有する化合物
WO2001085695A1 (fr) * 2000-05-11 2001-11-15 Bristol-Myers Squibb Co. Analogues de tetrahydroisoquinoline servant de secretagogues d'hormones de croissance
US6469024B2 (en) 2000-05-11 2002-10-22 Bristol-Myers Squibb Company Tetrahydroisoquinoline analogs useful as growth hormone secretagogues
EP1159964A2 (fr) 2000-05-31 2001-12-05 Pfizer Products Inc. Compositions et methodes pour stimuler la motilité gastrointestinale
US6984651B2 (en) 2000-06-21 2006-01-10 Bristol-Myers Squibb Pharma, Company Piperidine amides as modulators of chemokine receptor activity
WO2001098268A3 (fr) * 2000-06-21 2002-08-08 Bristol Myers Squibb Pharma Co Amides de piperidine utilises comme modulateurs de l'activite des recepteurs des chimiokines
US6638950B2 (en) 2000-06-21 2003-10-28 Bristol-Myers Squibb Pharma Company Piperidine amides as modulators of chemokine receptor activity
US6784200B2 (en) 2000-10-13 2004-08-31 Bristol-Myers Squibb Pharma Company Bicyclic and tricyclic amines as modulators of chemokine receptor activity
US7030116B2 (en) 2000-12-22 2006-04-18 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US7064123B1 (en) 2000-12-22 2006-06-20 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US7196099B2 (en) 2001-09-14 2007-03-27 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US7514430B2 (en) 2001-09-18 2009-04-07 Bristol-Myers Squibb Pharma Company Piperizinones as modulators of chemokine receptor activity
US6974869B2 (en) 2001-09-18 2005-12-13 Bristol-Myers Squibb Pharma Company Piperizinones as modulators of chemokine receptor activity
WO2003026649A1 (fr) * 2001-09-27 2003-04-03 Applied Research Systems Ars Holding N.V. Methodes pouvant augmenter des concentrations en testosterone endogene
US6649606B1 (en) 2001-11-09 2003-11-18 Bristol-Myers Squibb Co. Tetrahydroisoquinoline analogs as modulators of chemokine receptor activity
US6977256B2 (en) 2001-11-14 2005-12-20 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin S inhibitors
US7153822B2 (en) 2002-01-29 2006-12-26 Wyeth Compositions and methods for modulating connexin hemichannels
US6992091B2 (en) 2002-09-12 2006-01-31 Bristol-Myers Squibb Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6919356B2 (en) 2002-09-26 2005-07-19 Bristol Myers Squibb Company N-substituted heterocyclic amines as modulators of chemokine receptor activity
US7659305B2 (en) 2002-10-31 2010-02-09 Pfizer Inc. Therapeutic proline derivatives
WO2005120477A2 (fr) 2004-06-07 2005-12-22 Merck & Co., Inc. N- (2-benzyl) -2-phenylbutanamides modulant le recepteur d'androgene
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
WO2006069788A1 (fr) * 2004-12-30 2006-07-06 Novartis Ag Composes organiques
US8178559B2 (en) 2004-12-30 2012-05-15 Novartis Ag Organic compounds
RU2411239C2 (ru) * 2004-12-30 2011-02-10 Новартис Аг Органические соединения
US8084450B2 (en) 2004-12-30 2011-12-27 Novartis Ag Organic compounds
US8183280B2 (en) 2005-09-02 2012-05-22 Vantia Limited FAP inhibitors
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
EA016471B1 (ru) * 2006-09-06 2012-05-30 Лонца Аг Способ получения оптически активного n-защищенного 3-аминопирролидина или оптически активного n-защищенного 3-аминопиперидина и соответствующих кетонов путем оптического разделения рацемических смесей аминов с использованием бактериальной омега-трансаминазы
CN101512005B (zh) * 2006-09-06 2013-01-02 龙沙股份有限公司 通过使用细菌ω-转氨酶光学拆分外消旋胺混合物制备光学活性N-保护的3-氨基吡咯烷或光学活性N-保护的3-氨基哌啶以及相应的酮
WO2008028654A1 (fr) * 2006-09-06 2008-03-13 Lonza Ag PROCÉDÉ DE PRÉPARATION DE 3-AMINOPYRROLIDINE N-PROTÉGÉE OPTIQUEMENT ACTIVE OU DE 3-AMINOPIPÉRIDINE N-PROTÉGÉE OPTIQUEMENT ACTIVE ET DES CÉTONES CORRESPONDANTES PAR RÉSOLUTION OPTIQUE DES MÉLANGES RACÉMIQUES D'AMINES, AU MOYEN D'UNE OM&Eacute
US8728750B2 (en) 2006-09-06 2014-05-20 Lonza Ag Process for preparation of optically active N-protected 3-aminopyrrolidine or optically active N-protected 3-aminopiperidine and the corresponding ketones by optical resolution of the racemic amine mixtures employing a bacterial omega-transaminase
KR101119501B1 (ko) 2006-09-06 2012-02-28 론자 아게 박테리아 오메가-아미노기 전이효소를 이용한 라세미 아민 혼합물의 광학 분할에 의한 광학 활성 ｎ-보호된 3-아미노피롤리딘 또는 광학 활성 ｎ-보호된 3-아미노피페리딘 및 대응 케톤의 제조 방법
US9469609B2 (en) 2006-12-21 2016-10-18 Zealand Pharma A/S Synthesis of pyrrolidine compounds
US8927590B2 (en) 2006-12-21 2015-01-06 Zealand Pharma A/S Synthesis of pyrrolidine compounds
EP2644618A1 (fr) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. Intermédaires dans la synthese de modulateurs macrocycliques du récepteur de la ghréline
WO2008134828A2 (fr) 2007-05-04 2008-11-13 Katholieke Universiteit Leuven Protection contre la dégénérescence tissulaire
EP2269986A4 (fr) * 2008-03-26 2011-07-13 Sumitomo Chemical Co Procédé de fabrication d un composé pipéridin-3-ylcarbamate et procédé de résolution optique de celui-ci
WO2013190520A2 (fr) 2012-06-22 2013-12-27 The General Hospital Corporation Agents de libération de gh dans le traitement d'une sténose vasculaire et d'états associés
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury
US10617740B2 (en) 2014-02-05 2020-04-14 The Regents Of The University Of California Methods of treating mild brain injury
US11241483B2 (en) 2014-02-05 2022-02-08 The Regents Of The University Of California Methods of treating mild brain injury
WO2015181676A1 (fr) 2014-05-30 2015-12-03 Pfizer Inc. Dérivés carbonitriles en tant que modulateurs sélectifs du récepteur des androgènes
US10328082B2 (en) 2014-05-30 2019-06-25 Pfizer Inc. Methods of use and combinations
RU2695649C2 (ru) * 2014-08-05 2019-07-25 Раквалиа Фарма Инк. Производные серина в качестве агонистов грелиновых рецепторов
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs
US11091436B2 (en) 2017-03-13 2021-08-17 Richter Gedeon Nyrt. Process for the separation of optical isomers of racemic 3-alkylpiperidine-carboxylic acid ethyl esters
WO2018167631A1 (fr) 2017-03-13 2018-09-20 Richter Gedeon Nyrt. Procédé de séparation d'isomères optiques d'esters éthyliques de l'acide 3-alkylpipéridine-carboxylique racémique
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
US11439649B2 (en) 2018-02-21 2022-09-13 AI Therapeutics, Inc. Combination therapy with apilimod and glutamatergic agents
US11957688B2 (en) 2018-02-21 2024-04-16 OrphAl Therapeutics Inc. Combination therapy with apilimod and glutamatergic agents
CN112204007A (zh) * 2018-06-01 2021-01-08 施万生物制药研发Ip有限责任公司 制备2-(1-(叔丁氧基羰基)哌啶-4-基)苯甲酸的方法
CN112204007B (zh) * 2018-06-01 2023-06-20 施万生物制药研发Ip有限责任公司 制备2-(1-(叔丁氧基羰基)哌啶-4-基)苯甲酸的方法
WO2023275715A1 (fr) 2021-06-30 2023-01-05 Pfizer Inc. Métabolites de modulateurs sélectifs du récepteur des androgènes
CN114805305A (zh) * 2022-04-20 2022-07-29 成都诺和晟泰生物科技有限公司 一种化合物及其应用
CN114805305B (zh) * 2022-04-20 2024-04-26 成都诺和晟泰生物科技有限公司 一种化合物及其应用

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CZ134296A3 (en) 1996-12-11
NO961865L (no) 1996-07-08
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NO961865D0 (no) 1996-05-08
HUT74733A (en) 1997-02-28
AU1172995A (en) 1995-05-29
HU9601230D0 (en) 1996-07-29
SK56296A3 (en) 1997-02-05
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BR9408019A (pt) 1997-08-26
EP0739204A1 (fr) 1996-10-30

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