WO1997034604A1 - 4-spiroindoline piperidines favorisant la liberation de l'hormone de croissance - Google Patents

4-spiroindoline piperidines favorisant la liberation de l'hormone de croissance Download PDF

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WO1997034604A1
WO1997034604A1 PCT/US1997/004362 US9704362W WO9734604A1 WO 1997034604 A1 WO1997034604 A1 WO 1997034604A1 US 9704362 W US9704362 W US 9704362W WO 9734604 A1 WO9734604 A1 WO 9734604A1
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alkyl
group
phenyl
hydrogen
growth hormone
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PCT/US1997/004362
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English (en)
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Ravi Nargund
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Merck & Co., Inc.
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Priority claimed from GBGB9612276.7A external-priority patent/GB9612276D0/en
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Priority to AU23340/97A priority Critical patent/AU2334097A/en
Publication of WO1997034604A1 publication Critical patent/WO1997034604A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Growth hormone which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing.
  • growth hormone is known to have the following basic effects on the metabolic processes of the body: (1) Increased rate of protein synthesis in all cells of the body; (2) Decreased rate of carbohydrate utilization in cells of the body; (3) Increased mobilization of free fatty acids and use of fatty acids for energy.
  • a deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.
  • growth hormone Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
  • L-DOPA L-3,4-dihydroxyphenylalanine
  • GRF growth hormone releasing factor
  • the problem was generally solved by providing exogenous growth hormone or by administering GRF or a peptidal compound which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection.
  • the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone.
  • Recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.
  • Non peptidal growth hormone secretagogues with a benzolactam structure are disclosed in e.g., U.S. Patent Nos 5,206,235, 5,283,241, 5,284,841, 5,310,737 and 5,317,017.
  • Other growth hormone secretagogues are disclosed e.g., in U.S.
  • the instant compounds are low molecular weight peptide analogs for promoting the release of growth hormone which have good stability in a variety of physiological environments and which may be administered parenterally, nasally or by the oral route.
  • the instant invention is directed to 4-spiroindoline piperidine 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 production or secretion such as in humans with a deficiency of natural growth hormone or in animals used for food or wool production where the stimulation of growth hormone will result in a larger, more productive animal.
  • a still further object of this invention is to describe compositions containing the heterocyclic spiroindoline compounds for the use of treating humans and animals so as to increase the level of growth hormone secretions. Further objects will become apparent from a reading of the following description.
  • Rl is selected from the group consisting of:
  • aryl is phenyl or naphthyl, and heteroaryl is selected from indolyl, thiophenyl, furanyl, benzothiopheneyl, benzofuranyl, pyridinyl, quinolinyl, triazolyl, imidazolyl, thiazolyl, and benzimidazolyl, wherein aryl and heteroaryl are unsubstituted or substituted with phenyl, phenoxy, halophenyl, 1 to 3 of -C1-C6 alkyl, 1 to 3 of halo, 1 to 2 of -OR 2 , methylenedioxy, -S(0) m R2 1 to 2 of -CF3, -OCF3, nitro, -N(R2)(R2), -N(R2)C(0)(R2), -C(0)OR2, -C(0)N
  • R2 is selected from the group consisting of: hydrogen, -C1-C6 alkyl, -C3-C7 cycloalkyl, and -CH2- ⁇ henyl, wherein the alkyl or the cyloalkyl is unsubstituted or substituted with a substituent selected from: hydroxyl, C1-C3 alkoxy, thioalkyl, and
  • C(0)OR2a and wherein if two -C1-C6 alkyl groups are present on one atom, the groups may be optionally joined to form a C3-C8 cyclic ring selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, and thiomorpholine; R2 is hydrogen or C 1 -Cr5 alkyl;
  • R3a and R ⁇ b are independently selected from: hydrogen, phenyl, phenoxy, halophenyl, -C1-C6 alkyl, halo, -OR2, methylenedioxy, -S(0) m R 2 , -CF3, -OCF3, nitro, -N(R2)(R2), -N(R2)C(0)(R2), -C(0)OR2, -C(0)N(R2)(R2), -S ⁇ 2N(R2)(R2), -N(R2)S02-aryl, and -N(R2)S ⁇ 2R 2 ;
  • R4 is independently hydrogen, C1-C6 alkyl or substituted C1-C6 alkyl where the substituents are selected from 1 to 5 halo, 1 to 3 hydroxy, phenyl, and C1-C6 alkoxycarbonyl;
  • R5 is selected from the definitions of R ⁇ or R ⁇ and R ⁇ may be taken together to form -(CH2)d- a (CH2) e - where L a is -C(R 2 )2-, -0-, -S(0) m - or -N(R2)-, d and e are independently 1 to 3 and R is as defined above;
  • A is:
  • R 7a R 7a where Z is -N(R 6 )- or -0-, where R 6a is hydrogen or C1-C6 alkyl;
  • alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration and if two carbon atoms or more they may include a double or a triple bond.
  • exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, propargyl, and the like.
  • alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond.
  • alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.
  • halogen is intended to include the halogen atom fluorine, chlorine, bromine and iodine.
  • aryl within the present invention, unless otherwise specified, is intended to include aromatic rings, such as carbocyclic and heterocyclic aromatic rings including: phenyl, naphthyl, thiazolyl, thiadiazolvi, pyridyi, l-H-tetrazol-5-yl, isothiazolyi, oxazolyl, isoxazolyl, thienyl, oxadiazolyl, benzothienyl, benzofuranyl, benzimidazolyl, imidazolyl, indolyl, thiopheneyl, pyrimidinyi, pyrazolyl, pyrrazinyl, quinolinyl, and isoquinolinyl, which are unsubstituted or substituted with 1 to 3 of Cl-C6 alkyl, 1 to 3 of halogen, 1 to 2 of -OR 2 , methylenedioxy, -S(0) m R 2 , 1 to 2 of -OR 2
  • Rl is selected from the group consisting of: Cl-ClO alkyl, -aryl-, aryl (Cl-C6 alkyl)-, heteroaryl-, heteroaryl(Cl-C6 alkyl)-, (C3-C7 cycloalkyl)-(Cl-C6 alkyl)-, (C1-C5 alkyl)-K-(Ci-C5 alkyl)-, aryl-(C ⁇ -C5 alkyl)-K-(Ci-C5 alkyl)-, heteroaryl-(C ⁇ -C5 alkyl)-K-(Cl-C5 alkyl)-, and
  • R 2 is selected from the group consisting of: hydrogen, -C1-C6 alkyl, -C3-C7 cycloalkyl, and -CH2- ⁇ henyl, wherein the alkyl or the cyloalkyl is unsubstituted or substituted with a substituent selected from: hydroxyl, C1-C3 alkoxy, thioalkyl, and C(0)OR2a, and wherein if two -C1-C6 alkyl groups are present on one atom, the groups may be optionally joined to form a C3-C8 cyclic ring selected from the group consisting of pyrrolidine, piperidine, piperazine, mo ⁇ holine, and thiomorpholine;
  • R3a nd R3b are independently selected from: hydrogen, phenyl, phenoxy, halophenyl, -C1-C6 alkyl, halo, -OR2, methylenedioxy, -S(0) m R2, -CF3, -OCF3, nitro, -N(R2)(R2), -N(R2)C(0)(R 2 ), -C(0)OR2, -C(0)N(R2)(R2), -S ⁇ 2N(R2)(R2), -N(R2)S ⁇ 2-aryl, and -N(R2)S ⁇ 2R 2 ;
  • R ⁇ is independently hydrogen, Cl-Q) alkyl or substituted C1-C6 alkyl where the substituents are selected from 1 to 5 halo, 1 to 3 hydroxy, phenyl, and C1-C6 alkoxycarbonyl;
  • R5 is selected from the definitions of R4 or R5 and R4 may be taken together to form -(CH2)d-L a (CH2)e- where L a is -C(R 2 )2-, -0-, -S(0)m ⁇ or -N(R2)-, d and e are independently 1 to 3 and R2 is as defined above;
  • A is:
  • Z is -N(R6a). or -0-, where R ⁇ a is hydrogen or C1-C6 alkyl; R7 and R? are independently selected from: hydrogen, Cl-C6 alkyl, trifluoromethyl, phenyl, and substituted C1-C6 alkyl where the substituents are selected from: imidazolyl, naphthyl, phenyl, indolyl, p-hydroxyphenyl, -OR 2 , -S(0) m R 2 , -C(0)OR 2 , C3-C7 cycloalkyl, -N(R 2 )(R2), -C(0)N(R2)(R2), or R? and R?
  • a may independently be joined to one or both of R4 group to form an alkylene bridge between the terminal nitrogen and the alkyl portion of the R ⁇ or R7 groups, wherein the bridge contains 1 to 5 carbons atoms, or R7 and R7a can be joined to one another to form C3-C7 cycloalkyl;
  • n is O, l, or 2; x and y are independently 0, 1, 2 or 3;
  • Rl is selected from the group consisting of:
  • R2 is selected from the group consisting of: hydrogen, -C1-C6 alkyl, -C3-C7 cycloalkyl, and -CH2-phenyl, wherein the alkyl or the cyloalkyl is unsubstituted or substituted with a substituent selected from: hydroxyl, C1-C3 alkoxy, thioalkyl, and C(0)OR2a, and wherein if two -C1-C6 alkyl groups are present on one atom, the groups may be optionally joined to form a C3-C8 cyclic ring selected from the group consisting of pyrrolidine, piperidine, piperazine, mo ⁇ holine, and thiomo ⁇ holine;
  • R3a and R3b are independently selected from: hydrogen, -C1-C6 alkyl, halo, and -OR2;
  • R4 is independently hydrogen, C1-C6 alkyl or substituted C1-C6 alkyl where the substituents are selected from 1 to 5 halo, 1 to 3 hydroxy, phenyl, and C1-C6 alkoxycarbonyl;
  • R5 is selected from the definitions of R4 or R ⁇ and R4 may be taken together to form -(CH2)d-L (CH2) e - where L a is -C(R 2 )2-, -0-, -S(0)m- or -N(R2)-, d and e are independently 1 to 3 and R2 is as defined above;
  • A is:
  • R7 and R?a are independently selected from: hydrogen, C1-C6 alkyl, trifluoromethyl, phenyl, and substituted Cl- C6 alkyl where the substituents are selected from: imidazolyl, naphthyl, phenyl, indolyl, p-hydroxyphenyl, -OR2, -S(0) m R 2 , -C(0)OR 2 , C3-C7 cycloalkyl, -N(R 2 )(R2), -C(0)N(R2)(R2), or R and R? a may independently be joined to one or both of R 4 group to form an alkylene bridge between the terminal nitrogen and the alkyl portion of the R? or R ⁇ a groups, wherein the bridge contains 1 to 5 carbons atoms, or R? and R ⁇ a can be joined to one another to form C3-C7 cycloalkyl;
  • R8 is selected from the group consisting of:
  • the compounds of the instant invention all have at least one asymmetric center. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixture and as pure or partially purified compounds are included within the scope of the present invention.
  • the instant compounds are generally isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids.
  • acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methane sulfonic and the like.
  • certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
  • standard peptide coupling reaction conditions is used repeatedly here, and it means coupling a carboxylic acid with an amine using an acid activating agent such as EDC, DCC, and BOP in a inert solvent such as dichloromethane in the presence of a catalyst such as HOBT.
  • an acid activating agent such as EDC, DCC, and BOP
  • a inert solvent such as dichloromethane
  • HOBT a catalyst
  • protective groups for amine and carboxylic acid to facilitate the desired reaction and minimize undesired reactions are well documented. Conditions required to remove protecting groups which may be present and can be found in Greene, T, and Wuts, P. G. M., Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, NY 1991. CBZ and BOC were used extensively in the synthesis, and their removal conditions are known to those skilled in the art.
  • removal of CBZ groups can be achieved by a number of methods known in the art; for example, catalytic hydrogenation with hydrogen in the presence of a noble metal or its oxide such as palladium on activated carbon in a protic solvent such as ethanol.
  • 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 and pyrrolidines of Formula 2 are either commercially available or known in the literature and others can be prepared following literature methods described for analogous compounds. Some of these methods are illustrated in the subsequent schemes. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures includes crystallization, normal phase or reverse phase chromatography.
  • 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 reactions 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.
  • R 1 4-N-C-A-N-R 5 -N-C-A-N-R 5
  • Conversion of the ester 11 or 1 la to intermediate acids 12 or 12a may be achieved by a number of methods known in the art as described in Scheme 7.
  • methyl and ethyl esters can be hydrolyzed with lithium hydroxide in a protic solvent like aqueous methanol.
  • removal of benzyl group 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)).
  • acids of formulas 12 and 12a wherein L is a protecting group, may be coupled to piperidines of formula 2 under standard peptide-type coupling conditions to give compounds of formula 7. Removal of the protecting group L gives compounds of formula I.
  • a third approach towards synthesis of compounds of Formula I as shown in Scheme 9 involves coupling of amines of Formula 13, wherein Li is a suitable protecting group, to amino acids of Formula 1 and is conveniently carried out under standard peptide coupling conditions.
  • the preparation of amines of Formula 13 is described later if such compounds are not commercially available.
  • Conversion of 14 to intermediate 15 can be carried out as illustrated in Scheme 10 by removal of the protecting group L (CBZ, BOC, etc.).
  • the choice of the protecting group Ll is important because selective removal of L has to be carried out in the presence of Ll .
  • the protecting group Ll from the spiroindoline can be removed and the heterocycle R8 can be elaborated by methods that will be described later. Removal of the protecting group L from the amino acid by using chemistry described above provides compounds of Formula 1.
  • the spiro piperidines of formula 2 may be prepared by a number of methods, including the syntheses as described below.
  • the spiropiperidines of formula 2 may be synthesized by methods that are known in the literature (for example H. Ong et al., J. Med. Chem., 1983, 23, 981-986).
  • the indoline nitrogen of 17, wherein L is a protecting group such as methyl or benzyl can be reacted by with a variety of heterocyclic electrophiles to yield spiro piperidines of formula 18, wherein R& may be a heteroaryl group as described within the scope of the present invention.
  • Compound 17 may be reacted with, for example, with halogenated heterocycles in the presence of base is a suitable solvent like DMSO or DMF to give piperidines of Formula 18.
  • heterocyclic spiroindolines include the copper catalyzed N-arylation of amines by triarylbismuth diacetates (D.H.R. Barton et al., Tetrahedron Lett., 1986, 27, 3615 as shown in Scheme 14.
  • dealkylation can be carried out by a number methods familiar those skilled in the art.
  • dealkylation of 18 be accomplished by reacting it with cyanogen bromide and potassium carbonate in an inert solvent solvent such as dichloromethane to yield a cyanamide which can reduced to give 2 by treatment with lithium aluminum hydride in refluxing tetrahydrofuran, refluxing strong acid like aqueous hydrochloric acid, or with Grignard reagents like methyl magnesium bromide.
  • dealkylation of 18 can be effected with the ACE-C1 method as described in R. Olofson et al, J. Org. Chem. 1984, 49, 2795 and references therein.
  • the compounds of the present invention may also be prepared from a variety of substituted natural and unnatural amino acids of formulas 20. The preparation of many of these acids is described in US Patent No. 5,206,237. The preparation of these intermediates in racemic form is accomplished by classical methods familiar to those skilled in the art (Williams, R. M. "Synthesis of Optically Active a-Amino Acids" Pergamon Press: Oxford, 1989; Vol. 7) Several methods exist to resolve (DL)-
  • amino acids 20 amino acids.
  • One of the common methods is to resolve amino or carboxyl protected intermediates by crystallization of salts derived from optically active acids or amines.
  • the amino group of carboxyl protected intermediates may be coupled to optically active acids by using chemistry described earlier. Separation of the individual diastereomers either by chromatographic techniques or by crystallization followed by hydrolysis of the chiral amide furnishes resolved amino acids.
  • amino protected intermediates may be converted to a mixture of chiral diastereomeric esters and amides. Separation of the mixture using methods described above and hydrolysis of the individual diastereomers provides (D) and (L) amino acids.
  • an enzymatic method to resolve N-acetyl derivatives of (DL)-amino acids has been reported by Whitesides and coworkers in J. Am. Chem. Soc, 1989, 111, 6354-6364.
  • Intermediates of formula 20 which are 0-benzyl-(D)-serine derivatives 25 are conveniently prepared from suitably substituted benzyl halides and N-protected-(D)-serine 24.
  • the protecting group L is conveniently a BOC or a CBZ group.
  • Benzylation of 24 can be achieved by a number of methods well known in the literature including deprotonation with two equivalents of sodium hydride in an inert solvent such as DMF followed by treatment with one equivalent of a variety of benzyl halides (Synthesis 1989, 36) as shown in Scheme 17.
  • the 0-alkyl-(D)-serine derivatives may also be prepared using an alkylation protocol.
  • D,L-0-aryl(alkyl)serines may be prepared and resolved by methods described above.
  • ⁇ -Alkyl amino acids can be synthesized well established methods. Some of these methods are documented in J. Samanen et al, J. Med. Chem., 1989, 32, 466, K. Kover et al, J. Org. chem., 1994, 59, 991, V. Hruby et al, J. Med. Chem., 1991, 34, 1823, Y-B. He et al, J. Am. Chem. Soc, 1993, 115, 8066, Z. Huang et al, J. Am. Chem. Soc, 1992, 114, 9390, and D. M. Birney et al, J. Med. Chem., 1995, 38, 24 '8.
  • the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • the utility of the compounds of the present invention as growth hormone secretagogues may be demonstrated by methodology known in the art, such as an assay described by Smith, et al., Science, 260, 1640-1643 (1993) (see text of Figure 2 therein).
  • the intrinsic growth horomone secretagogue activities of the compounds of the present invention may be demonstrated by this assay.
  • the compounds of the following examples have activity in the aforementioned assay in the range of 0.1 nm to 5 ⁇ m.
  • the growth hormone releasing compounds of Formula I are useful in vitro as unique tools for understanding how growth hormone secretion is regulated at the pituitary level. This includes use in the evaluation of many factors thought or known to influence growth hormone secretion such as age, sex, nutritional factors, glucose, amino acids, fatty acids, as well as fasting and non-fasting states. In addition, the compounds of this invention can be used in the evaluation of how other hormones modify growth hormone releasing activity. For example, it has already been established that somatostatin inhibits growth hormone release.
  • hormones that are important and in need of study as to their effect on growth hormone release include the gonadal hormones, e.g., testosterone, estradiol, and progesterone; the adrenal hormones, e.g., cortisol and other corticoids, epinephrine and norepinephrine; the pancreatic and gastrointestinal hormones, e.g., insulin, glucagon, gastrin, secretin; the vasoactive peptides, e.g., bombesin, the neurokinins; and the thyroid hormones, e.g., thyroxine and triiodothyronine.
  • gonadal hormones e.g., testosterone, estradiol, and progesterone
  • the adrenal hormones e.g., cortisol and other corticoids, epinephrine and norepinephrine
  • the pancreatic and gastrointestinal hormones e.g., insulin, glucagon,
  • the compounds of Formula I can also be employed to investigate the possible negative or positive feedback effects of some of the pituitary hormones, e.g., growth hormone and endorphin peptides, on the pituitary to modify growth hormone release.
  • some of the pituitary hormones e.g., growth hormone and endorphin peptides
  • endorphin peptides e.g., endorphin peptides
  • the compounds of Formula I can be administered to animals, including man, to release growth hormone in vivo.
  • the compounds can be administered to commercially important animals such as swine, cattle, sheep and the like to accelerate and increase their rate and extent of growth, to improve feed efficiency and to increase milk production in such animals.
  • these compounds can be administered to humans in vivo as a diagnostic tool to directly determine whether the pituitary is capable of releasing growth hormone.
  • the compounds of Formula I can be administered in vivo to children. Serum samples taken before and after such administration can be assayed for growth hormone. Comparison of the amounts of growth hormone in each of these samples would be a means for directly determining the ability of the patient's pituitary to release growth hormone.
  • the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of Formula I in association with a pharmaceutical carrier or diluent.
  • the active ingredient of the pharma ⁇ ceutical compositions can comprise an anabolic agent in addition to at least one of the compounds of Formula I or another composition which exhibits a different activity, e.g., an antibiotic growth permittant or an agent to treat osteoporosis or in combination with a corticosteroid to minimize the latter's catabolic side effects or with other pharmaceutically active materials wherein the combination enhances efficacy and minimizes side effects.
  • Growth promoting and anabolic agents include, but are not limited to, TRH, diethylstilbesterol, amino acids, estrogens, ⁇ -agonists, theophylline, anabolic steroids, enkephalins, E series prostaglandins, retinoic acid, compounds disclosed in U.S. Patent No. 3,239,345, e.g., zeranol, and compounds disclosed in U.S. Patent No. 4,036,979, e.g., sulbenox. or peptides disclosed in U.S. Patent No. 4,411,890.
  • a still further use of the compounds of this invention is in combination with other growth hormone secretagogues such as the growth hormone releasing peptides GHRP-6, GHRP-1 as described in U.S. Patent Nos. 4,411,890 and publications WO 89/07110, WO 89/07111 and B-HT920 as well as hexarelin and GHRP-2 as described in WO 93/04081 or growth hormone releasing hormone (GHRH, also designated GRF) and its analogs or growth hormone and its analogs or somatomedins including IGF-1 and IGF-2 or ⁇ -adrenergic agonists such as clonidine or serotonin 5HTID agonists such as sumitriptan or agents which inhibit somatostatin or its release such as physostigmine and pyridostigmine.
  • growth hormone secretagogues such as the growth hormone releasing peptides GHRP-6, GHRP-1 as described in U.S. Patent Nos. 4,411,890 and
  • the compounds of this invention may be used in combination with growth hormone releasing factor, an analog of growth hormone releasing factor, IGF- 1, or IGF-2.
  • a compound of the present invention may be used in combination with IGF-1 for the treatment or prevention of obesity.
  • a compound of this invention may be employed in conjunction with retinoic acid to improve the condition of musculature and skin that results from intrinsic aging.
  • the present invention is further directed to a method for the manufacture of a medicament for stimulating the release of growth hormone in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
  • a pharmaceutical carrier or diluent As is well known to those skilled in the art, the known and potential uses of growth hormone are varied and multitudinous. Thus, 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.
  • the instant compounds are useful for increasing feed efficiency, promoting growth, increasing milk production and improving the carcass quality of livestock.
  • the instant compounds are useful in a method of treatment of diseases or conditions which are benefited by the anabolic effects of enhanced growth hormone levels that comprises the administration of an instant compound.
  • the instant compounds are useful in the prevention or treatment of a condition selected from the group consisting of: osteoporosis; catabolic illness; immune deficiency, including that in individuals with a depressed T4/T8 cell ratio; bone fracture, including hip fracture; musculoskeletal impairment in the elderly; growth hormone deficiency in adults or in children; short stature in children; obesity; sleep disorders; cachexia and protein loss due to chronic illness such as AIDS or cancer; and treating patients recovering from major surgery, wounds or burns, in a patient in need thereof.
  • a condition selected from the group consisting of: osteoporosis; catabolic illness; immune deficiency, including that in individuals with a depressed T4/T8 cell ratio; bone fracture, including hip fracture; musculoskeletal impairment in the elderly; growth hormone deficiency in adults or in children; short stature in children; obesity; sleep disorders; cachexia and protein loss due to chronic illness such as AIDS or cancer; and treating patients recovering from major surgery, wounds or burns, in a
  • the instant compounds may be useful in the treatment of illnesses induced or facilitated by corticotropin releasing factor or stress- and anxiety-related disorders, including stress-induced depression and headache, abdominal bowel syndrome, immune suppression, HIV infections, Alzheimer's disease, gastrointestinal disease, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, and fertility problems.
  • corticotropin releasing factor or stress- and anxiety-related disorders including stress-induced depression and headache, abdominal bowel syndrome, immune suppression, HIV infections, Alzheimer's disease, gastrointestinal disease, anorexia nervosa, hemorrhagic stress, drug and alcohol withdrawal symptoms, drug addiction, and fertility problems.
  • the therapeutic agents and the growth hormone secretagogues of this invention may be independently present in dose ranges from one one-hundredth to one times the dose levels which are effective when these compounds and secretagogues are used singly.
  • Combined therapy to inhibit bone reso ⁇ tion, prevent osteoporosis and enhance the healing of bone fractures can be illustrated by combinations of bisphosphonates and the growth hormone secretagogues of this invention.
  • the use of bisphosphonates for these utilities has been reviewed, for example, by Hamdy, N.A.T. Role of Bisphosphonates in Metabolic Bone Diseases. Trends in Endocrinol. Metab., , 4, 19-25 (1993).
  • Bisphosphonates with these utilities include alendronate, tiludronate, dimethyl - APD, risedronate, etidronate, YM- 175, clodronate, pamidronate, and BM-210995.
  • oral daily dosage levels of the bisphosphonate of between 0.1 mg and 5 g and daily dosage levels of the growth hormone secretagogues of this invention of between 0.01 mg/kg to 20 mg/kg of body weight are administered to patients to obtain effective treatment of osteoporosis.
  • Osteoporosis and other bone disorders may also be treated with compounds of this invention in combination with calcitonin, estrogens, raloxifene and calcium supplements such as calcium citrate or calcium carbonate.
  • Anabolic effects especially in the treatment of geriatric male patients are obtained with compounds of this invention in combination with anabolic steroids such as oxymetholone, methyltesterone, fluoxymesterone and stanozolol.
  • the compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated in dosage forms appropriate for each route of administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch.
  • Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • additional substances other than inert diluents e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and com oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.
  • compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
  • the dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.
  • dosage levels of between 0.0001 to 10 mg/kg. of body weight daily are administered to patients and animals, e.g., mammals, to obtain effective release of growth hormone.
  • the dosage level will be about 0.001 to about 25 mg/kg per day; more preferably about 0.01 to about 10 mg/kg per day.
  • Step A (DLVN-Acetyl-2-amino-5-phenylpentanoic acid To a solution of sodium (2.3 g, 0.1 mol) in ethanol (60 mL) under nitrogen at room temperature, was added diethyl acetamidomalonate. The mixture was stirred at room temperature for one hour, and then l-bromo-3-phenylpropane was added dropwisely. After the addition, the mixture was stirred at room temperature for two hours, then refluxed overnight. It was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with sodium bicarbonate in water, dried over MgS04 and evaporated to give an intermediate (32.5 g, 97%).
  • the product above was suspended in 190 mL of 2.5 N NaOH in water and refluxed for two hours. The mixture was cooled to 0°C, and it was carefully neutralized with 6 N HCl to pH2. The precipitate was collected using a glass sinter funnel and washed with a small amount of cold water and air dried. The solid was then suspended in 300 mL of water and refluxed for four hours. The solution was cooled and acidified to pHl and the solid was collected by filtration (15.3 g, 67%).
  • Step g ( DVN-Acetyl-2-amino-5-phenylpentanoic acid
  • the racemic intermediate from the previous step (10 g, 42.5 mmol) and CoC13-6H2 ⁇ were dissolved in 21 ml of 2 N KOH and 200 mL of water at 40°C, and the pH of the solution was adjusted to 8 by the addition of the several drops of 2 N KOH.
  • acylase I (Aspergillus sp, 0.5 u mg, from Sigma; 0.9 g) was added with vigorous stirring. The reaction mixture was stirred for one day at 40°C and the pH was kept at 8 by the addition of a few drops of KOH. The solid which formed was filtered off.
  • Step C (DVN-t-Boc-2-amino-5-phenylpentanoic acid
  • 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.

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Abstract

L'invention concerne quelques composés nouveaux appelés 4-spiroindoline pipéridines et ayant la formule structurale générale (I), où R?1, R1a, R2a, R3a, R3b, R4, R5, R8¿, et A sont tels qu'ils sont définis dans le texte. Ces composés favorisent la libération de l'hormone de croissance chez l'homme et les animaux. Cette propriété peut être utilisée pour favoriser la croissance des animaux destinés à l'alimentation afin d'augmenter l'efficacité de la production de produits carnés comestibles et, chez l'homme, pour traiter des troubles physiologiques ou médicaux caractérisés par une sécrétion insuffisante de l'hormone de croissance tels que la petite taille chez les enfants manquant d'hormone de croissance, ainsi que pour traiter des troubles médicaux atténués par les effets anaboliques de l'hormone de croissance. De même, invention de compositions libérant l'hormone de croissance et contenant ces composés en tant qu'ingrédient actif.
PCT/US1997/004362 1996-03-21 1997-03-18 4-spiroindoline piperidines favorisant la liberation de l'hormone de croissance WO1997034604A1 (fr)

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WO1998051687A1 (fr) * 1997-05-14 1998-11-19 Fujisawa Pharmaceutical Co., Ltd. Derives piperidino favorisant la liberation de l'hormone de croissance
WO1998058947A1 (fr) * 1997-06-25 1998-12-30 Pfizer Inc. Derives dipeptides secretagogues de l'hormone de croissance
EP0900086A1 (fr) * 1996-05-07 1999-03-10 Merck & Co., Inc. Stimulation du sommeil avec un secretagogue d'hormone de croissance
US6294534B1 (en) 1998-06-11 2001-09-25 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
EP1149583A2 (fr) * 2000-04-13 2001-10-31 Pfizer Products Inc. Combinaison des antagonistes de la facteur de la liberation de la corticotropin et des secrétagogues de l hormone de croissance
EP1159964A2 (fr) 2000-05-31 2001-12-05 Pfizer Products Inc. Compositions et methodes pour stimuler la motilité gastrointestinale
US6329342B1 (en) 1997-08-19 2001-12-11 Eli Lilly And Company Treatment of congestive heart failure with growth hormone secretagogues
EP1166778A2 (fr) * 2000-06-19 2002-01-02 Pfizer Products Inc. Utilisation d'un sécrétagogue d'hormone de croissance pour traiter le lupus érythémateux systémique et les maladies intestinales inflammatoires
KR20020002279A (ko) * 2000-06-29 2002-01-09 실버스타인 아써 에이. 신체적 기능 감퇴를 치료하기 위한 성장호르몬분비촉진제를 포함하는 약학 조성물
KR20020010527A (ko) * 2000-07-27 2002-02-04 실버스타인 아써 에이. 기능적 건강 상태를 향상시키기 위한 성장 호르몬분비촉진물질을 포함하는 약학 조성물
US6350760B1 (en) 1999-06-04 2002-02-26 Merck & Co., Inc. Substituted piperidines as melanocortin-4 receptor agonists
EP1181933A3 (fr) * 2000-06-29 2002-04-10 Pfizer Products Inc. Utilisation d'un secretagogue de l'hormone de croissance comme comme inducteur de la faim
US6458790B2 (en) 2000-03-23 2002-10-01 Merck & Co., Inc. Substituted piperidines as melanocortin receptor agonists
US6472398B1 (en) 2000-03-23 2002-10-29 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
US6541634B2 (en) 1999-02-26 2003-04-01 Pfizer Inc. Process for preparing growth hormone secretagogues
US6639076B1 (en) 1998-08-18 2003-10-28 Eli Lilly And Company Growth hormone secretagogues
US6767915B2 (en) 2000-08-23 2004-07-27 Merck & Co., Inc. Substituted piperidines as melanocortin receptor agonists
US6828331B1 (en) 1999-02-19 2004-12-07 Eli Lilly And Company Growth hormone secretagogues
EP1506969A1 (fr) 1998-01-16 2005-02-16 Novo Nordisk A/S Composés présentant des propriétés de libération d'hormone de croissance
US7125840B2 (en) 2001-10-09 2006-10-24 Eli Lilly And Company Substituted dipeptides as growth hormone secretagogues
WO2007098716A1 (fr) 2006-02-28 2007-09-07 Centro De Ingeniería Genética Y Biotecnología Composés analogues aux sécrétagogues peptidiques de l'hormone de croissance et préparations contenant ceux-ci
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
US7396846B2 (en) 2002-04-09 2008-07-08 Eli Lilly And Company Growth hormone secretagogues
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
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury

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Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0900086A1 (fr) * 1996-05-07 1999-03-10 Merck & Co., Inc. Stimulation du sommeil avec un secretagogue d'hormone de croissance
EP0900086A4 (fr) * 1996-05-07 2000-01-12 Merck & Co Inc Stimulation du sommeil avec un secretagogue d'hormone de croissance
WO1998051687A1 (fr) * 1997-05-14 1998-11-19 Fujisawa Pharmaceutical Co., Ltd. Derives piperidino favorisant la liberation de l'hormone de croissance
WO1998058947A1 (fr) * 1997-06-25 1998-12-30 Pfizer Inc. Derives dipeptides secretagogues de l'hormone de croissance
US6251902B1 (en) * 1997-06-25 2001-06-26 Pfizer Inc. Dipeptide derivatives as growth hormone secretagogues
US6525047B2 (en) 1997-06-25 2003-02-25 Pfizer Inc. Dipeptide derivatives
US6429313B2 (en) 1997-06-25 2002-08-06 Pfizer Inc. Dipeptide derivatives
US6433171B1 (en) 1997-06-25 2002-08-13 Pfizer Inc. Dipeptide derivatives
US6953791B2 (en) 1997-06-25 2005-10-11 Pfizer, Inc. Dipeptide derivatives
US6951850B2 (en) 1997-06-25 2005-10-04 Pfizer, Inc. Dipeptide derivatives
US6924280B2 (en) 1997-06-25 2005-08-02 Pfizer Inc. Dipeptide derivatives
US6432945B1 (en) 1997-06-25 2002-08-13 Pfizer Inc. Dipeptide derivatives
USRE38524E1 (en) 1997-06-25 2004-06-01 Pfizer Inc. Dipeptide derivatives as growth hormone secretagogues
US6329342B1 (en) 1997-08-19 2001-12-11 Eli Lilly And Company Treatment of congestive heart failure with growth hormone secretagogues
EP1506969A1 (fr) 1998-01-16 2005-02-16 Novo Nordisk A/S Composés présentant des propriétés de libération d'hormone de croissance
US6294534B1 (en) 1998-06-11 2001-09-25 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
US6410548B2 (en) 1998-06-11 2002-06-25 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
US6992097B2 (en) 1998-08-18 2006-01-31 Eli Lilly And Company Growth hormone secretagogues
US6639076B1 (en) 1998-08-18 2003-10-28 Eli Lilly And Company Growth hormone secretagogues
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
US6828331B1 (en) 1999-02-19 2004-12-07 Eli Lilly And Company Growth hormone secretagogues
US6541634B2 (en) 1999-02-26 2003-04-01 Pfizer Inc. Process for preparing growth hormone secretagogues
US6673929B2 (en) 1999-02-26 2004-01-06 Pfizer Inc. Process for preparing growth hormone secretagogues
US6350760B1 (en) 1999-06-04 2002-02-26 Merck & Co., Inc. Substituted piperidines as melanocortin-4 receptor agonists
US6458790B2 (en) 2000-03-23 2002-10-01 Merck & Co., Inc. Substituted piperidines as melanocortin receptor agonists
US6472398B1 (en) 2000-03-23 2002-10-29 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
EP1149583A2 (fr) * 2000-04-13 2001-10-31 Pfizer Products Inc. Combinaison des antagonistes de la facteur de la liberation de la corticotropin et des secrétagogues de l hormone de croissance
EP1149583A3 (fr) * 2000-04-13 2001-11-14 Pfizer Products Inc. Combinaison des antagonistes de la facteur de la liberation de la corticotropin et des secrétagogues de l hormone de croissance
EP1159964A2 (fr) 2000-05-31 2001-12-05 Pfizer Products Inc. Compositions et methodes pour stimuler la motilité gastrointestinale
EP1166778A3 (fr) * 2000-06-19 2003-09-17 Pfizer Products Inc. Utilisation d'un sécrétagogue d'hormone de croissance pour traiter le lupus érythémateux systémique et les maladies intestinales inflammatoires
EP1166778A2 (fr) * 2000-06-19 2002-01-02 Pfizer Products Inc. Utilisation d'un sécrétagogue d'hormone de croissance pour traiter le lupus érythémateux systémique et les maladies intestinales inflammatoires
EP1181933A3 (fr) * 2000-06-29 2002-04-10 Pfizer Products Inc. Utilisation d'un secretagogue de l'hormone de croissance comme comme inducteur de la faim
KR20020002279A (ko) * 2000-06-29 2002-01-09 실버스타인 아써 에이. 신체적 기능 감퇴를 치료하기 위한 성장호르몬분비촉진제를 포함하는 약학 조성물
KR20020010527A (ko) * 2000-07-27 2002-02-04 실버스타인 아써 에이. 기능적 건강 상태를 향상시키기 위한 성장 호르몬분비촉진물질을 포함하는 약학 조성물
US6767915B2 (en) 2000-08-23 2004-07-27 Merck & Co., Inc. Substituted piperidines as melanocortin receptor agonists
US7125840B2 (en) 2001-10-09 2006-10-24 Eli Lilly And Company Substituted dipeptides as growth hormone secretagogues
US7396846B2 (en) 2002-04-09 2008-07-08 Eli Lilly And Company Growth hormone secretagogues
EP2457893A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Intermédiaires pour des modulateurs macrocycliques du récepteur de ghréline
EP2457925A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Procédé pour la préparation d'un modulateur macrocyclique du récepteur de ghréline et intermédiaires
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
EP2644618A1 (fr) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. Intermédaires dans la synthese de modulateurs macrocycliques du récepteur de la ghréline
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury
US10617740B2 (en) 2014-02-05 2020-04-14 The Regents Of The University Of California Methods of treating mild brain injury
US11241483B2 (en) 2014-02-05 2022-02-08 The Regents Of The University Of California Methods of treating mild brain injury
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs

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