EP1156808A2 - Verbesserung der rückkehr zu unabhängigen lebensbedingungen mit einem wachstumshormon-sekretagog - Google Patents

Verbesserung der rückkehr zu unabhängigen lebensbedingungen mit einem wachstumshormon-sekretagog

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Publication number
EP1156808A2
EP1156808A2 EP99948091A EP99948091A EP1156808A2 EP 1156808 A2 EP1156808 A2 EP 1156808A2 EP 99948091 A EP99948091 A EP 99948091A EP 99948091 A EP99948091 A EP 99948091A EP 1156808 A2 EP1156808 A2 EP 1156808A2
Authority
EP
European Patent Office
Prior art keywords
growth hormone
alkyl
aryl
piperidin
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99948091A
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English (en)
French (fr)
Inventor
Mark Bach
Vivian Fuh
Jennifer Ng
Alice Taylor
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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Filing date
Publication date
Priority claimed from GBGB9823090.7A external-priority patent/GB9823090D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1156808A2 publication Critical patent/EP1156808A2/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4747—Quinolines; Isoquinolines spiro-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH

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.
  • 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 growth hormone 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, IGF-I or a peptidal compound which stimulated growth hormone production and/or release.
  • 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.
  • administration of exogenous growth hormone may result in side-effects, including edema, and does not correlate with the pulsitile release seen in the endogenous release of growth hormone.
  • Certain compounds have been developed which stimulate the release of endogenous growth hormone.
  • Peptides which are known to stimulate the release of endogenous growth hormone include growth hormone releasing hormone, the growth hormone releasing peptides GHRP-6 and GHRP-1 (described in U.S. Patent No. 4,411,890, PCT Patent Pub. No. WO 89/07110, and PCT Patent Pub. No. WO 89/07111) and GHRP-2 (described in PCT Patent Pub. No. WO 93/04081), as well as hexarelin (J. Endocrinol Invest.. 15(Suppl 4), 45 (1992)).
  • Other compounds possessing growth hormone secretagogue activity are disclosed in the following: U.S. Patent No.
  • the present invention is directed to the use of a compound which has the ability to stimulate or amplify the release of natural or endogenous growth hormone for enhancing the return of patients to independent living status following deconditioning, in a warm-blooded animal.
  • the advantage of this method is that in contrast to injections of growth hormone it provides a physiological-like pulsatile profile of growth hormone release from the pituitary gland.
  • the present invention provides a method for enhancing the return of patients to independent living status following deconditioning in a warm-blooded animal comprising the administration of a growth hormone secretagogue.
  • the present invention further provides a pharmaceutical composition for enhancing the return of patients to independent living status following deconditioning. DETAILED DESCRIPTION OF THE DRAWING
  • FIG. 1 depicts a summary of the data from a double-blind, placebo-controlled, parallel-group study to determine the effect of a growth hormone secretagogue on the return to independent living status in patients suffering a hip fracture. Following their hip fracture, a greater percentage of the patients receiving growth hormone secretagogue were living independently.
  • FIG. 2 depicts a summary of the data from a double-blind, placebo-controlled, parallel-group study to determine the effect of a growth hormone secretagogue on the return to independent living status in patients suffering a hip fracture. Of the patients who were living independently prior to their hip fracture, a greater percentage of the patients receiving growth hormone secretagogue returned to independence following their hip fracture.
  • the present invention is directed to the use of a compound which has the ability to stimulate or amplify the release of natural or endogenous growth hormone for enhancing the return of patients to independent living status following deconditioning.
  • the present invention provides a method for enhancing the return of a patient to independent living status following deconditioning of the patient comprising the administration of a growth hormone secretagogue.
  • the present invention provides a method for enhancing the return of a patient to independent living status following acute deconditioning of the patient comprising the administration of a growth hormone secretagogue.
  • the present invention is further directed to a method for ameliorating an acute deconditioned physiological state of in a mammal which comprises administering an effective amount of a growth hormone secretagogue.
  • the acute deconditioned physical state in the mammal may result from immobilization, surgery, major injury such as hip fracture or other bone fracture, gunshot wound or automobile accident, and the like.
  • the present invention currently has found greatest application in enhancing the return of patients to independent living status following hip fracture.
  • the subject mammal is a human.
  • the present invention is applicable both old and young people, it may find greater application in elderly people especially people aged 70 years and older.
  • therapy with the growth hormone secretagogue is supplemented or employed in conjunction with physical rehabilitation.
  • the patient be living independently prior to their acute deconditioning.
  • the present invention may also be applicable in helping patients who were not living independently prior to their acute deconditioning to achieve independent living status.
  • growth hormone secretagogue any exogenously administered compound or agent that directly or indirectly stimulates or increases the endogenous release of growth hormone, growth hormone-releasing hormone or somatostatin in an animal, in particular, a human.
  • the growth hormone secretagogue may be peptidal or non- peptidal in nature, however, the use of a orally active growth hormone secretagogue is preferred. In addition, it is preferred that the growth hormone secretagogue induce or amplify a pulsatile release of endogenous growth hormone.
  • the growth hormone secretagogue may be used alone or in combination with other growth hormone secretagogues or with other agents which are known to be beneficial for enhancing the return of patients to independent living status following deconditioning.
  • the growth hormone secretagogue and the other agent may be coadministered, either in concomitant therapy or in a fixed combination.
  • the growth hormone secretagogue may be administered in combination with other compounds which are known in the art to be useful for enhancing the return of patients to independent living status following deconditioning.
  • Representative growth hormone secretagogues are disclosed in: U.S. Patent No. 3,239,345; U.S. Patent No. 4,036,979; U.S. Patent No. 4,411,890; U.S. Patent No. 5,206,235; U.S. Patent No. 5,283,241; U.S. Patent No. 5,284,841; U.S. Patent No. 5,310,737; U.S. Patent No. 5,317,017; U.S. Patent No. 5,374,721; U.S. Patent No. 5,430,144; U.S. Patent No. 5,434,261; U.S. Patent No. 5,438,136; U.S. Patent No. 5,494,919; U.S. Patent No. 5,494,920; U.S. Patent No. 5,492,916; U.S. Patent No. 5,536,716; EPO Patent Pub. No. 0,144,230; EPO Patent Pub. No. 0,513,974;
  • a representative first class of growth hormone secretagogues is set forth in U.S. Patent No. 5,206,235 as follows: wherein the various substituents are as defined in U.S. Patent 5,206,235.
  • Rl is selected from the group consisting of:
  • K is O, S(O) m , N(R2 C(O), C(O)N(R2), OC(O), C(0)0, or
  • -CR2 CR2-, or -C ⁇ C-, and wherein the aryl groups are as defined below and the R2 and alkyl groups may be futher substituted by 1 to 9 halogen, S(O)mR2a, 1 to 3
  • OR2a, or C(O)OR2a > an ⁇ " tne ar yl groups may be further substituted by phenyl, phenoxy, halophenyl, 1-3 C1-C6 alkyl, 1 to 3 halogen, 1 to 2 -OR2, methylenedioxy, -S(O) m R2, 1 to 2 -CF3, -OCF3, nitro, -N(R2)(R2), -N(R 2 )C(O)R 2 , -C(O)OR2, -C(0)N(R2)(R2), -SO2N(R2)(R2), -N(R 2 )S(O) 2 aryl, and -N(R2)SO2R2;
  • R2 is selected from the group consisting of: hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, and where two Cl-C ⁇ alkyl groups are present on one atom, they may be optionally joined to form a C3-C8 cyclic ring optionally including oxygen, sulfur or NR2aJ
  • R2a is hydrogen, or Cl-C ⁇ alkyl
  • R3a and R3 are independently selected from the group consisting of: hydrogen, halogen, -Cl-C ⁇ alkyl, -OR2, cyano, -OCF3, methylenedioxy, nitro, -S(O) R, -CF3 or -C(O)OR2 and when R3 a and R3 D are in an ortho arrangement, they may be joined to form a C5 to Cs aliphatic or aromatic ring optionally including 1 or 2 heteroatoms selected from oxygen, sulfur or nitrogen;
  • R4 and R5 are independently selected from the group consisting of: hydrogen, -Cl-C ⁇ alkyl, substituted C ⁇ -C6 alkyl wherein the substituents are selected from 1 to 5 halo, 1 to 3 hydroxy, 1 to 3 Cl-Cio alkanoyloxy, 1 to 3 Cl-C ⁇ alkoxy, phenyl, phenoxy, 2-furyl, Cl-C ⁇ alkoxycarbonyl, -S(O) m (C ⁇ -C6 alkyl); or R4 and R5 can be taken together to form -(CH2)rL a (CH s- where L a is -C(R2)2-, -0-, -S(0) m -, or -N(R2)-, where r and s are independently 1 to 3 and R2 is as defined above; R ⁇ is hydrogen or C ⁇ -C6 alkyl; A is:
  • x and y are independently 0-3;
  • Z is N-R2 or O;
  • R7 and R7 a are independently selected from the group consisting of: hydrogen, -Cl-C ⁇ alkyl, -OR2, trifluoromethyl, phenyl, substituted
  • R7 and R7 a can independently be joined to one or both of R4 and R5 groups to form alkylene bridges between the terminal nitrogen and the alkyl portion of the R7 or R7a groups, wherein the bridge contains 1 to 5 carbons atoms;
  • R8 and Rlfj are independently selected from the group consisting of: hydrogen, -R2, -OR2, (-CH2)q-aryl, -(CH2)q-C(O)OR2, -(CH2)q- C(O)O(CH2)q-aryl, or -(CH2)q-(lH-tetrazol-5-yl), where the aryl may be optionally substituted by 1 to 3 halo, 1 to 2 Ci-C ⁇ alkyl, 1 to 3 -OR2 or 1 to 2 -C(O)OR2;
  • R9 is selected from the group consisting of: -R2, -(CH2)q-aryl, -C(0)R2, -C(O)(CH 2 )q-aryl, -SO R2,
  • G, H, I and J are carbon, nitrogen, sulfur or oxygen atoms, such that at least one is a heteroatom and one of G, H, I or J may be optionally missing to afford a 5 or 6 membered heterocyclic aromatic ring; and pharmaceutically acceptable salts and individual diastereomers thereof.
  • Rl is selected from the group consisting of:
  • R3a is H, or fluoro
  • D is selected from the group consisting of:
  • the aryl is phenyl or pyridyl and the phenyl may be substituted by 1-2 halogen;
  • R2 is H, or C1-C4 alkyl; m is 1, 2; t is 0, 1, or 2; q is 1, 2, or 3; w is 2, 3, 4, 5, or 6; and the pharmaceutically acceptable salts and individual diastereomers thereof.
  • Representative most preferred growth hormone secretagoues within this third class which may be employed in the present invention include the following:
  • Expecially preferred growth hormone secretagogues within this third class which may be employed in the present invention include:
  • 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.
  • alkyl groups are methyl, ethyl, propyl, ethinyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, allyl, propenyl, butenyl, butadienyl and the like.
  • the alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration which may optionally contain double or triple bonds.
  • alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propinyloxy, isobutenyloxy, 2-hexenyloxy, and the like.
  • halogen is intended to include the halogen atom fluorine, chlorine, bromine and iodine.
  • aryl is intended to include phenyl and naphthyl and aromatic residues of 5- and 6- membered rings with 1 to 3 heteroatoms or fused 5 or 6 membered bicyclic rings with 1 to 3 heteroatoms of nitrogen, sulfur or oxygen.
  • heterocyclic aromatic rings examples include pyridine, thiophene, benzothiophene, tetrazole, indole, N-methylindole, dihydroindole, indazole, N-formylindole, benzimidazole, thiazole, furan, pyrimidine, and thiadiazole.
  • salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts.”
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
  • Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Representative salts include the following: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Oxalate, Pamoate (Embonate),
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., quaternary ammonium salts.
  • the compounds employed in the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers.
  • GHRP-6 and GHRP-1 are described in U.S. Patent Nos. 4,411,890 and PCT Patent Publications WO 89/07110, WO 89/07111, methods to obtain the growth hormone releasing peptide GHRP-2 are described in PCT Patent Publication WO 93/04081, and methods to obtain hexarelin are described in J. Endocrinol Invest.. 15(Suppl 4), 45 (1992).
  • terapéuticaally effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
  • acute deconditioning is meant to indicate the presence of a diminished physical state in a patient characterized by muscle atrophy and muscle loss which results from specific insult such as immobilization or inactivity brought on by acute illness or injury.
  • chronic deconditioning refers to long-term muscle loss or wasting, i.e. sarcopenia.
  • independent living is meant to indicate that the patient is able to handle the physical demands of daily living with a minimal level of physical assistance from other persons.
  • Patients living independently include, for example, patients who live in a private home or apartment and who do not receive formal or nonformal home health care services.
  • the present invention includes within its scope the use of a growth hormone secretagogue for enhancing the return of patients to independent living status following deconditioning, alone or in combination with other agents such as growth promoting and anabolic agents including 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.
  • the growth hormone secretagogue may be used in combination with growth hormone releasing factor, an analog of growth hormone releasing factor, IGF-1, or IGF-2.
  • growth hormone secretagogues provides unexpected benefit relative to the administration of exogenous growth hormone.
  • the growth hormone secretagogue enhances the normal pulsatile releases of endogenous growth hormone and thus is more likely to reproduce the natural pattern of endogenous growth hormone release, especially with regard to increasing the level of endogenous growth hormone prior to or in during the initial onset of sleep.
  • Growth hormone secregagogues which are orally active also have the benefit being able to be administered orally, rather than just intravenously, intraperitoneally or subcutaneously.
  • the present invention includes within its scope a pharmaceutical composition for enhancing the return of patients to independent living status following acute deconditioning comprising, as an active ingredient, at least one growth hormone secretagogues in association with a pharmaceutical carrier or diluent.
  • the active ingredient of the pharmaceutical compositions can comprise an anabolic agent in addition to at least one growth hormone secretagogue or another composition which exhibits a different activity, e.g., an antibiotic growth promoting agent 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, theophylline, anabolic steroids, dehydroepiandrosterone, 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.
  • the present invention further includes the use of a growth hormone secretagogue, alone or in combination with another agent, in the manufacture of a medicament for enhancing the return of patients to independent living status following acute deconditioning.
  • the present invention contemplates the use of a growth hormone secretagogue for enhancing the return of patients to independent living status following deconditioning in combination with another growth hormone secretagogues such as those referenced herein, including the growth hormone releasing peptides GHRP-6 and GHRP-1 (described in U.S. Patent No.
  • a growth hormone secretagogue may be used in combination with IGF-1 for enhancing the return of patients to independent living status following deconditioning. It will be known to those skilled in the art that other compounds may be used in an effort to enhance the return of patients to independent living status following deconditioning. Combinations of these therapeutic agents some of which have also been mentioned herein with a growth hormone secretagogue will bring additional, complementary, and often synergistic properties to enhance the desirable properties of these various therapeutic agents. In these combinations, the growth hormone secretagogue and the therapeutic agents 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. Typically, the individual daily dosages for these combinations may range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly.
  • a growth hormone secretagogue effective clinically effective clinically at a given daily dose range may be effectively combined, at levels which are equal or less than the daily dose range, with the following compounds at the indicated per day dose range: and salts thereof, and combinations thereof, and the like.
  • these dose ranges may be adjusted on a unit basis as necessary to permit divided daily dosage and, as noted above, the dose will vary depending on the nature and severity of the disease, weight of patient, special diets and other factors.
  • Anabolic effects especially in the treatment of geriatric male patients are obtained with compounds of this invention in combination with anabolic steroids such as dehydroepiandrosterone, oxymetholone, methyltesterone, fluoxymesterone, restosterone and stanozolol.
  • anabolic steroids such as dehydroepiandrosterone, oxymetholone, methyltesterone, fluoxymesterone, restosterone and stanozolol.
  • a growth hormone secretagogue may be administered alone or in combination 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.
  • Illustrative of the adjuvants which may be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry.
  • the dosage forms may also comprise buffering agents.
  • the dosage unitform When the dosage unitform is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. Tablets and pills can additionally be prepared with enteric coatings and tablets may be coated with shellac, sugar or both.
  • 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.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • Sterile compositions for injection may be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like may be incorporated as required.
  • non-aqueous solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.
  • Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
  • the dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
  • the active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.
  • the dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize.
  • 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 range will generally be about 0.5 mg to 1.0 g. per patient per day which may be administered in single or multiple doses.
  • the dosage range will be about 0.5 mg to 500 mg per patient per day; more preferably about 0.5 mg to 200 mg per patient per day; and even more preferably about 5 mg to 50 mg per patient per day.
  • compositions of the present invention may be provided in a solid dosage formulation preferably comprising about 0.5 mg to 500 mg active ingredient, more preferably comprising about 1 mg to 250 mg active ingredient.
  • the pharmaceutical composition is preferably provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient.
  • hip fracture is a model state of acute deconditioning in the elderly for determining the effect of a growth hormone secretagogue in return of patients to independent living status.
  • Approximately 168 postoperative hip fracture patients were enrolled in this study. Patients were betweeen 3 and 14 days postoperative hip repair. Patients included both males and females over 65 years of age who have ambulatory prefracture (with or without assistance), with need for assistance and level of premorbid ambulation documented. Their fracture was of nonpathological origin, e.g., it resulted from a fall or accident rather than from neoplasm.
  • the questionnaires compared the subject's pre-fracture status and post-fracture status with respect to housing and degree of care which they received.
  • the questionnaire for pre-fracture status determined where the particular subject was living before their hip fracture (i.e. in a private home/apartment, an assisted living center, a nursing home, or other living situation) and whether they received home health care services.
  • the questionnaire for post-fracture status determined where the particular subject was living and had lived after their hip fracture (i.e.
  • FIG. 1 depicts a summary of the data regarding living independence from a double-blind, placebo-controlled, parallel-group study to determine the effect of a growth hormone secretagogue on the return to independent living status in patients suffering a hip fracture.
  • the percentage of patients living independently is presented with respect to the number of weeks since the patient initiated the study.
  • FIG. 2 depicts a summary of the data regarding the return to independent living status from a double-blind, placebo-controlled, parallel-group study to determine the effect of a growth hormone secretagogue on the return to independent living status in patients suffering a hip fracture.
  • the percentage of patients living independently is presented with respect to the number of weeks since the patient initiated the study.
  • Compound growth hormone secretagogue

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EP99948091A 1998-09-02 1999-08-31 Verbesserung der rückkehr zu unabhängigen lebensbedingungen mit einem wachstumshormon-sekretagog Withdrawn EP1156808A2 (de)

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US9886998P 1998-09-02 1998-09-02
US98869P 1998-09-02
GBGB9823090.7A GB9823090D0 (en) 1998-10-21 1998-10-21 Enhancement of return to independent living status with a growth hormone secretaogue
GB9823090 1998-10-21
PCT/US1999/019996 WO2000012047A2 (en) 1998-09-02 1999-08-31 Enhancement of return to independent living status with a growth hormone secretagogue

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US6329342B1 (en) 1997-08-19 2001-12-11 Eli Lilly And Company Treatment of congestive heart failure with growth hormone secretagogues
US6639076B1 (en) 1998-08-18 2003-10-28 Eli Lilly And Company Growth hormone secretagogues
US6828331B1 (en) 1999-02-19 2004-12-07 Eli Lilly And Company Growth hormone secretagogues
BR0113626A (pt) 2000-08-30 2003-06-17 Pfizer Prod Inc Formulações de liberação sustentada para secretores de hormÈnio do crescimento
EP1192943A3 (de) * 2000-09-28 2002-11-27 Pfizer Products Inc. Verwendung von Sekretionsfördermitteln für Wachstumshormone in Verbindung mit Körpertraining
CU23157A1 (es) * 2001-01-03 2006-07-18 Ct Ingenieria Genetica Biotech COMPOSICION FARMACéUTICA PARA EL TRATAMIENTO DEL DANO TISULAR DEBIDO A FALTA DE IRRIGACION SANGUINEA ARTERIAL
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
WO2005097174A2 (en) * 2004-04-07 2005-10-20 Gastrotech Pharma A/S Uses of a combination of ghrelin and somatotropin for the treatment of cachexia
JP5336349B2 (ja) * 2006-03-15 2013-11-06 マイケル・オー・ソーナー 成長ホルモン分泌促進物質による筋肉減少症の処置方法

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AU6772996A (en) * 1995-08-21 1997-03-12 Eli Lilly And Company 2-acylaminopropanamides as growth hormone secretagogues
US5723616A (en) * 1995-10-27 1998-03-03 Merck & Co., Inc. Process for the preparation of a growth hormone secretagogue
US5767124A (en) * 1995-10-27 1998-06-16 Merck & Co., Inc. Polymorphic forms of a growth hormone secretagogue
CA2240427C (en) * 1995-12-13 2007-08-14 Merck & Co., Inc. Growth hormone secretagogue receptor family
TW432073B (en) * 1995-12-28 2001-05-01 Pfizer Pyrazolopyridine compounds

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CA2341649A1 (en) 2000-03-09

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