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  • 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
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
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  • 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
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  • 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
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  • 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
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  • 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
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• • 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.
• growth hormone Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth
• 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
• the instant invention is directed to certain piperidine, pyrrolidine, and hexahydro-1H-azepine compounds which have the ability to stimulate the release of natural or endogenous growth hormone.
• the compounds thus have the ability to be used to treat conditions which require the stimulation of growth hormone
• a still further object is to describe the use of such compounds to increase the secretion of growth
• 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 ,
• R3a is hydrogen, or C 1 -C 6 alkyl optionally substituted by hydroxyl
• W is selected from the group consisting of: hydrogen
• R 8 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted by OR 2 , C(O)OR 2 , CON(R 2 )(R 2 ), N(R 2 )C(O)R 2 ,
• aryl is phenyl, pyridyl, or 1H-tetrazol-5-yl
• X is selected from the group consisting of: hydrogen, -C ⁇ N,
• 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 , carboxylate C 1 -C 4 alkyl esters, or 1H-tetrazol-5-yl, and aryl is phenyl, naphthyl, pyridyl, thiazolyl, or 1H-tetrazol-5-yl groups which may be optionally substimted 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
• 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
• 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; R 6 is hydrogen, C 1 -C 6 alkyl, or (CH 2 )varyl, wherein the alkyl and (CH 2 )v groups may be optionally substituted by 1-2 O(R 2 ), S(O) m R 2 , 1H-tetrazol-5-yl, C(O)OR 2 , C(O)N(R 2 )(R 2 ) or SO 2 N(R 2 )(R 2 ),
• 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)O(C 1 -C 6 alkyl), C 3 -
• n 0, 1, or 2;
• n 1, 2, or 3;
• 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.
• n 1, a pyrrolidine ring is formed, when n is 2 a piperidine ring is formed and when n is 3 the ring is designated as a hexahydro-1H-azepine.
• 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,
• alkoxy groups of the designated length in either a straight or branched configuration which may optionally contain double or triple bonds.
• alkoxy groups of the designated length in either a straight or branched configuration which may optionally contain double or triple bonds.
• alkoxy groups are those alkoxy groups of the designated length in either a straight or branched configuration which may optionally contain double or triple bonds.
• halogen is intended to include the halogen atom fluorine, chlorine, bromine and iodine.
• aryl within the present invention, unless otherwise specified, is intended to include aromatic rings, such as carbocyclic and heterocyclic aromatic rings selected the group consisting of: phenyl, naphthyl, pyridyl, 1-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrrazinyl, or isothiazolyl, which may be optionally substimted by 1 to 3 of C 1 -C 6 alkyl, 1 to 3 of halogen, 1 to 2 of -OR 2 , methylenedioxy, -S(O) m R 2 , 1 to 2 of -CF 3 , -OCF 3 , nitro, -N(R 2 )C(O)(R 2 ), -C(O)
• a first embodiment of the present invention is directed to the compounds of the structural formula AI:
• 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-, where aryl is selected from: phenyl, naphthyl, indolyl, azaindole, pyridy
• 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 2a is hydrogen, or C 1 -C 6 alkyl optionally substimted 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 , -NHSO2CF 3 , -(CH 2 ) r OR 6 , -(CH 2 ) r N(R 2 )(R6), -(CH 2 ) r (R 6 ), -(CH 2 ) r C(O)OR 2 , -(CH 2 ) r C(O)OR 6 , -(CH 2 ) r OC(O)R 2 , -(CH 2 ) r OC(O)R 6 ,
• 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 ,
• 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.
• 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;
• A is: or
• 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; R 6 is hydrogen, C 1 -C 6 alkyl, or (CH 2 )varyl, wherein the alkyl and (CH 2 )v groups may be optionally substituted by 1-2 O(R 2 ), S(O) m R 2 , 1H-tetrazol-5-yl, C(O)OR 2 , C(O)N(R 2 )(R 2 ) or SO 2 N(R 2 )(R 2 ),
• 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:
• R 3a is hydrogen, or C 1 -C 4 alkyl
• W is -CN, -C(O)OR 2 , -C(O)N(R 2 )(R 2 ), -C(O)N(R 2 )(CH 2 ) l phenyl, 1H-tetrazol-5-yl, or -(CH 2 ) r OR 2 ;
• 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 2;
• 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 );
• X is hydrogen or C(O)OR 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 is 0, 1, or 2; and pharmaceutically acceptable salts and individual diastereomers thereof.
• R 1 is selected from the group consisting of:
• R 2 and alkyl may be further substimted by 1 to 9 halogen, S(O)mR 2a , 1 to 3 of OR 2a or C(O)OR 2a , and aryl may be further substimted by 1 to 3 of C 1 -C 6 alkyl, 1 to 3 of halogen, 1 to 2 of OR 2 , methylenedioxy, -S(O) m R 2 , 1 to 2 of -CF 3 , -OCF 3 , nitro, -
• R 2a is hydrogen, or C 1 -C 6 alkyl optionally substituted by hydroxyl
• 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
• A is: or
• 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; R 6 is hydrogen, C 1 -C 6 alkyl, or (CH 2 )varyl, wherein the alkyl and (CH 2 ) v groups may be optionally substituted by 1-2 O(R 2 ), S(O) m R 2 , 1H-tetrazol-5-yl, C(O)OR 2 , C(O)N(R 2 )(R 2 ) or SO 2 N(R 2 )(R 2 ),
• 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
• R 4 and R 5 groups 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; m is 0, 1, or 2;
• n 1, 2, or 3;
• 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:
• 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,
• Y is selected from: hydrogen, C 1 -C 8 alkyl, (CH 2 ) t aryl, -(CH 2 ) q (C 5 -C 6 cycloalkyl), -(CH 2 ) q -K-(C 1 -C 6 alkyl), -(CH 2 ) q -K-(CH 2 )ta ⁇ yl,
• 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
• X is selected from: hydrogen, -(CH 2 ) q N(R 2 )C(O)R 2 ,
• R 2 group may be optionally substimted by hydroxyl, carboxyl, -CONH 2 , -S(O) m CH 3 , carboxylate C 1 -C 4 alkyl esters or tetrazole and aryl is phenyl, napthyl 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
• R 4 and R 5 are independently hydrogen, C 1 -C 4 alkyl, substituted C 1 -C 3 alkyl where the substituents may be 1 to 2 hydroxyl;
• R 6 is hydrogen, C 1 -C 6 alkyl or (CH 2 )varyl, wherein the C 1 -C 6 alky
• aryl is specifically phenyl, pyridyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, oxadiazolyl, pyrazolyl, thiadiazolyl, benzimidazol-2-yl, optionally substituted with C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, amino, or hydroxyl;
• 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;
• 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:
• 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 ,
• 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, or substituted C 1 -C 6 alkyl where the substiments 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, phenyloxy, 2-furyl, C 1 -C 6 alkoxycarbonyl, S(O) m (C 1 -C 6 alkyl), or R 4 and R 5 may 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:
• 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;
• R 7 and R 7a are independently hydrogen, C 1 -C 6 alkyl, trifluoromethyl, phenyl, or substimted C 1 -C 6 alkyl where the substiments are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR 2 , S(O) m R 2 , C(O)OR 2 , C 3 -C 7 cycloalkyl, N(R 2 )(R 2 ), C(O)N(R 2 )(R 2 ), or R 7 and R 7a may
• R 4 and R 5 groups independently be joined to one or both of R 4 and R 5 groups to form an alkylene bridge 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 C 3 -C 7 cycloalkyl; m is 0, 1, or 2;
• n 1, 2, or 3;
• q 0, 1, 2, 3, or 4;
• t 0, 1, 2, or 3;
• Preferred compounds within this third embodiment include those of Formula CIa:
• 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 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;
• q 0, 1, 2, or 3;
• 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;
• t 0, 1, 2, or 3;
• R 1 is selected from the group consisting of:
• X is selected from the group consisting of: hydrogen,
• Y is selected from the group consisting of: hydrogen,
• 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.
• the protected amino acid derivatives 1 are, in many cases, commercially available, where the protecting group L is, for example, BOC or CBZ groups.
• Other protected amino acid derivatives 1 can be prepared by literature methods (Williams, R. M. Synthesis of Optically Active ⁇ -Amino Acids. Pergamon Press: Oxford, 1989).
• Many of the piperidines, pyrrolidines and hexahydro-1H-azepines of formula 2 are either commercially available or known in the literature and others can be prepared following literature methods desribed for known compounds, some of which are described here.
• the skills required in carrying out the reaction and purification of the resulting reaction products are known to those skilled in the art. Purification procedures includes crystallization, and normal phase or reverse phase chromatography.
• 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.
• the compounds of general formula I of the present invention may also be prepared in a convergent manner as described in Reaction Schemes 6, 7 and 8.
• 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.
• Conversion of the ester 11 or 11a to intermediate acids 12 or 12a can be achieved by a number of methods known in the art as described in Scheme 7; for example, methyl and ethyl esters can be hydrolyzed with lithium hydroxide in a protic solvent like aqueous methanol.
• removal of benzyl groups can be accomplished by a number of reductive methods including hydrogenation in the presence of palladium catalyst in a protic solvent such as methanol.
• 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 nitrile A2a can be prepared by oxidation of the compound A13 to the imine as described in the literature (Goti and Romani in Tetrahedron Letters, 35, 6567-6570 (1994)) followed by reaction with cyanide.
• W can also be introduced by direct alkylation of the Boc protected compound A13 by butyl lithium followed by addition of electrophiles known as the Beak alkylation (Beak and Lee J. Org.
• 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
• Y substitution can be achieved by first reacting compounds of formula A 18 with a strong base such as potassium bis(trimethylsilyl)amide, lithium diisopropylamide following by addition of alkylating 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.
• alkylating 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 can be prepared by methods analogous to those used for the preparation of known compounds.
• 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
• diastereoisomers can be separated, and each can be hydrogenated to reduce the double bond and to remove the chiral auxiliary. All four possible isomers can be achieved by this methodology. Illustrated here (Scheme A13) is the preparation of the two isomers A15a and A15b which have an S-configuration at the chiral center adjacent to the COOH. The two R- isomers at this center can be prepared similarly using compound A26.
• hydrogenation of the olefin can be accomplished by use of platinum or palladium catalysts in a protic solvent like methanol.
• McMurry Ace. Chem. Res., 21, 47 (1988) to give in their examples tetrahydropiperidines B18 (L protecting group).
• B19 can be transformed to compounds of formula B20 by hydrogenating the olefin in the presence of platinum or palladium catalysts in a protic solvent such as 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.
• racemic intermediates of formula 2 can be derivatized with chiral reagents and these products may be separated by chromatography and chiral compounds of formula 2 may be regenerated from them by hydrolysis, or as stated earlier, racemic intermediates of formula 2 can be converted directly to growth hormone secretagogues, and the resulting diastereomeric mixtures can be separated by
• 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 are commercially available or can be conveniently prepared by literature procedures. Shown in Scheme C9A is an example of the preparation of these compounds via pyrrolidine-3-carboxylic acid ester.
• the commercially available compound methyl 1-benzyl-4-oxo-3-pyrrolidinecarboxylate is reduced by borane (J. Chem. Soc., 24, 1618-1619). Removal of the benzyl group by catalytic hydrogenolysis followed by ester exchange in an appropriate alcohol medium such as ethyl alcohol in the presence of acid gave the compound C13b.
• the ester functionality may be further modified through conventional chemistry to other groups as defined by X.
• 3-Monosubstituted pyrrolidines may also be prepared by catalytic hydrogenation of 3-substituted pyrroles.
• Hexahydro-1H-azepines are commercially available or may be prepared by the literature procedure.
• Hexahydro-1H-azepine-3-carboxylic acid (Krogsgaard-Larsen, P. et al., Acta. Chem. Scand., B32, 327, (1978)) is esterified in an alcohol solvent in the presence of acid.
• the ester functionality may be further modified through conventional chemistry to other groups within the definition of X.
• Compounds of Formula C13 wherein X is an electron withdrawing group such as -CN, -CO 2 R 8 , where R 8 is alkyl, aryl, and (C 1 -C 4 alkyl)aryl are known compounds or may be prepared by methods analogous to those used for the preparation of such known compounds.
• the secondary amine of compounds of Formula C13 may be first protected by a protecting group L such as BOC and CBZ using the conventional techniques.
• Introduction of the Y substitution can be achieved by first reacting compounds of Formula 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
• the compounds of Formula I may be administered to animals, including man, to release growth hormone in vivo.
• the compounds can be administered to commercially important animals such as swine, cattle, sheep and the like to accelerate and increase their rate and extent of growth, to improve feed efficiency and to increase milk production in such animals.
• these compounds can be administered to humans in vivo as a diagnostic tool to directly determine whether the pituitary is capable of releasing growth hormone.
• 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,
• a still further use of the growth hormone secretagogues of this invention is in combination with other growth hormone
• GHRH growth hormone releasing hormone
• 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
• Bisphosphonates for these utilities have been reviewed, for example, by Hamdy, N.A.T., Role of Bisphosphonates in Metabolic Bone Diseases, Trends in Endocrinol. Metab ., 4, 19-25 (1993).
• Bisphosphonates with these utilities include alendronate, tiludronate, dimethyl-APD, risedronate, etidronate, YM-175, clodronate, pamidronate, and BM-210995.
• oral daily dosage levels of the bisphosphonate of between 0.1 mg and 5 g and daily dosage levels of the growth hormone secretagogues of this invention of between 0.01 mg/kg to 20 mg/kg of body weight are administered to patients to obtain effective treatment of osteoporosis.
• 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 by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
• compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.
• Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
• the dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is
• 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 A (DL)-N-acetyl-2-amino-5-phenylpentanoic acid
• 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.
• Step B 4-Phenylpyridine-2-carboxylic acid
• 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).
• the title compound was prepared from the compound made in Step A by treating it with a saturated solution of HCl(gas) in ethyl acetate for 30min. at RT. Ether was added and the precipitate was filtered and dried.
• 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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