EP0900086A1 - Stimulation du sommeil avec un secretagogue d'hormone de croissance - Google Patents

Stimulation du sommeil avec un secretagogue d'hormone de croissance

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Publication number
EP0900086A1
EP0900086A1 EP97924576A EP97924576A EP0900086A1 EP 0900086 A1 EP0900086 A1 EP 0900086A1 EP 97924576 A EP97924576 A EP 97924576A EP 97924576 A EP97924576 A EP 97924576A EP 0900086 A1 EP0900086 A1 EP 0900086A1
Authority
EP
European Patent Office
Prior art keywords
aryl
alkyl
amino
carbonyl
dihydro
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Withdrawn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
EP97924576A
Other languages
German (de)
English (en)
Other versions
EP0900086A4 (fr
Inventor
Joanne Waldstreicher
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 GBGB9611002.8A external-priority patent/GB9611002D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0900086A1 publication Critical patent/EP0900086A1/fr
Publication of EP0900086A4 publication Critical patent/EP0900086A4/fr
Withdrawn legal-status Critical Current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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • NREM non rapid eye movement
  • Stage 1 sleep is drowsiness, in which the EEG displays a lower voltage, more mixed frequencies and deterioration of alpha rhythm relative to the EEG when the individual is awake.
  • stage 2 background activity similar to that of stage 1 is experienced, with bursts of slightly higher frequency "sleep spindles” and sporadic higher amplitude slow wave complexes.
  • the third and fourth stages of sleep display increasing high amplitude slow wave activity.
  • REM sleep The separate sleep stage in which the individual undergoes rapid eye movement (REM) occupies the remainder of the sleep time and occurs 5 to 6 times during a normal nights sleep.
  • REM sleep is characterized by a lower voltage, higher frequency EEG and other characteristics similar to those which occur when the individual is awake, whereas the other four sleep stages are categorized as NREM sleep.
  • Individuals vary widely in their requirements for sleep, which is influenced by a number of factors including their current emotional state. The natural aging process is associated with changes in a variety of circadian and diurnal rhythms. Age-related changes in the timing and structure of sleep are surprisingly common problems for older people, and are often associated with significant morbidity. With advancing age, the total amount of sleep tends to shorten.
  • Stage 4 can decrease or disappear and sleep may become more fragmented and interrupted. Evaluation of sleep patterns in elderly people shows that the timing of sleep is also phase advanced, especially in women. This tendency to go to sleep and wake up earlier is very frustrating to older people who feel that they are out of step with the rest of the world. In addition, the quality of sleep in the elderly is diminished with a marked reduction in slow wave sleep, a reduction in the deep stages of sleep (especially stage 4), fragmentation of REM sleep and more frequent awakenings. Similarly, non-elderly people may exhibit disturbances in the normal sleep process. These changes in the structure of sleep have been correlated to more frequent napping, decreased daytime alertness and declining intellectual function and cognitive ability.
  • REM sleep Deprivation of REM sleep has been suggested to interfere with the memory consolidation involved in learning skills through repetitive activity, and slow wave sleep has been implicated as being important in consolidation of events into long term memory. Likewise, decreases in the length of REM stages of sleep may be associated with a decrease in cognitive function and learning, especially diminished retention of memory.
  • Sleep disorders generally involve disturbances of sleep that affect a subject's ability to fall and/or stay asleep, and involve sleeping too little, too much or resulting in abnormal behavior associated with sleep.
  • Numerous compounds are employed in the art to facilitate normal sleep and to treat sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbituates, 5HT-2 antagonists, and the like.
  • sleep disorders and sleep disturbances including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbituates, 5HT-2 antagonists, and the like.
  • physical methods have been employed to treat patients with sleep disorders such as the use of light therapy or the application of modulated electrical signals to selected nerves or nerve bundles.
  • the known threapeutic regimens suffer from numerous problems, including residual effects in daytime function, impairment of memory, potential for addiction, rebound insomnia, "REM rebound” which may be associated with increased dream intensity and the occurrence of nightmares, and the like. Accordingly, a more physiological way to enhance sleep would be highly desirable.
  • 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)).
  • Growth hormone releasing peptide-6 (GHRP-6) is believed to act via a unique pituitary and hypothalamic receptor and stimulates the release of growth hormone, cortisol and prolactin.
  • GHRP-6 Growth hormone releasing peptide-6
  • repeated intravenous boluses of GHRP-6 increased stage 2 sleep without affecting slow wave or REM sleep (Frieboes, et al.,
  • 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 or growth hormone-releasing hormone for enhancing or improving sleep quality, in particular by increasing sleep efficiency and augmenting sleep maintenance, as well as for preventing and treating sleep disorders and sleep disturbances, in a warm-blooded animal.
  • the known threapeutic regimens regarding sleep suffer from numerous problems, including residual effects in daytime function, impairment of memory, potential for addiction, rebound insomnia, "REM rebound” which may be associated with increased dream intensity and the occurrence of nightmares, and the like.
  • An advantage of the present method is that it provides a physiological-like pulsatile profile of growth hormone release from the pituitary gland and further provides for the release of growth hormone-releasing hormone. Accordingly, the present invention provides a method for enhancing or improving sleep quality and increasing sleep efficiency and sleep maintenance in a warm-blooded animal comprising the administration of a growth hormone secretagogue. The present invention further provides a pharmaceutical composition for enhancing or improving sleep quality and increasing sleep efficiency and sleep maintenance.
  • 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 or improving sleep quality as well as preventing and treating sleep disorders and sleep disturbances in a warm-blooded animal.
  • the present invention provides a method for enhancing or improving sleep quality by increasing sleep efficiency and augmenting sleep maintenance.
  • the present invention provides a method for preventing and treating sleep disorders and sleep disturbances in a warm-blooded animal which comprising the administration of a growth hormone secretagogue.
  • the present invention further provides a pharmaceutical composition for enhancing or improving sleep quality and increasing sleep efficiency and sleep maintenance
  • the following outcomes in a subject which are provided by the present invention may be correlated to enhancement in sleep quality: an increase in the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; a decrease in sleep latency (the time it takes to fall asleep); a decrease in difficulties in falling asleap; a decrease in the number of awakenings during sleep; a decrease in nocturnal arousals; a decrease in the time spent awake following the initial onset of sleep; an increase in the total amount of sleep; an increase the amount and percentage of REM sleep; an increase in the duration and occurrence of REM sleep; a reduction in the fragmentation of REM sleep; an increase in the amount and percentage of slow-wave (i.e.
  • stage 3 or 4 sleep sleep; an increase in the amount and percentage of stage 2 sleep; an enhancement of EEG-delta activity during sleep; a decrease in the number of awakenings; a decrease in nocturnal arousals, especially early morning awakenings; an increase in daytime alertness; an increased satisfaction with the intensity of sleep; and increased sleep maintenance.
  • Secondary outcomes which may be provided by the present invention include enhanced cognitive function and increased memory retention.
  • the present invention is further useful for the prevention and treatment of sleep disorders and sleep disturbances including sleep problems associated with insomnia, hypersomnia, sleep apnea, narcolepsy, nocturnal myoclonus, REM sleep interruptions, jet-lag, shift workers' sleep disturbances, dysomnias, night terror, insomnias associated with depression or with emotional/mood disorders, as well as sleep walking and enuresis, as well as sleep disorders which accompany aging. Sleep disorders and sleep disturbances are generally characterized by difficulty in initiating or maintaining sleep or in obtaining restful or enough sleep. Similarly, the present invention is useful for treating conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules.
  • certain drags may also cause reductions in REM sleep as a side effect and the present invention may be used to correct those types of sleeping disorders as well.
  • the present invention would also be of benefit in the treatment of syndromes such as f ⁇ bromyalgia which are manifested by non-restorative sleep and muscle pain or sleep apnea which is associated with respiratory disturbances during sleep.
  • the release of growth hormone associated with the growth hormone secretagogue may also improve respiratory function as a result of increased muscle strength and tone associated with growth hormone release.
  • the present invention is not limited to just sleep disorders and sleep disturbances, but is applicable to a wide variety of conditions which result from a diminished quality of sleep.
  • the subject mammal is a human.
  • the present invention is applicable both old and young people, it would find greater application in elderly people.
  • the invention may be employed to enhance the sleep of healthy people, it may be especially beneficial for enhancing the sleep quality of people suffering from sleep disorders or sleep disturbances.
  • growth hormone secretagogue is meant 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 non-peptidal growth hormone secretagogue is preferred. In addition, for convenience the use of an 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. It is also preferred that the growth hormone secretagogue be able to cause the release of growth hormone at night or during the sleep cycle, especially in the first half of the night or of the sleep cycle, and even more especially in the first few hours following sleep onset, or alternatively in the period immediately preceding sleep onset.
  • 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 in the enhancement of sleep efficiency.
  • 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 conjunction with other compounds which are known in the art to be useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbituates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, cloperidone, clorazepate
  • 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; l/.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.
  • a representative first class of growth hormone secretagogues is set forth in U.S. Patent No. 5,206,235 as follows:
  • Rl is selected from the group consisting of: -Cl-ClO alkyl, -aryl, -aryl-(Cl-C6 alkyl),
  • -C3-C7 cycloalkyl-(Cl-C6alkyl), -Cl-C5alkyl-K-Cl-C5 alkyl, -aryl(C ⁇ - C5alkyl)-K-(Cl-C5 alkyl), -C3-C7 cycloalkyl(Co-C5 alkyl)-K-(Cl-C5 alkyl), wherein K is O, S(0) m , N(R2>C(0), C(0)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(0)mR2a .
  • R2 is selected from the group consisting of: hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, and where two C1-C6 alkyl groups are present on one atom, they may be optionally joined to form a C3-C8 cyclic ring optionally including oxygen, sulfur or NR2a',
  • R2a is hydrogen, or C1-C6 alkyl
  • R3 a and R3b are independently selected from the group consisting of: hydrogen, halogen, -C1-C6 alkyl, -OR2, cyano, -OCF3, methylenedioxy, nitro, -S(0) m R. -CF3 or -C(0)OR2 and when R3 a and R3b are in an ortho arrangement, they may be joined to form a C5 to C8 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, -C1-C6 alkyl, substituted C1-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 C1-C6 alkoxy, phenyl, phenoxy, 2-furyl, Cl- C6 alkoxycarbonyl, -S(0) m (Cl-C6 alkyl); or R4 and R5 can be taken together to form -(CH2) r L a (CH2)s- where L a is -C(R2)2-, -O-, -S(0) m -, or -N(R2)-, where r and s are independently 1 to 3 and R2 is as defined above;
  • R6 is hydrogen or C1-C6 alkyl; A is:
  • R 7a wherein x and y are independently 0-3; Z is N-R2 or O; R ⁇ and R ⁇ a are independently selected from the group consisting of: hydrogen, -Cl-C6 alkyl, -OR2. trifluoromethyl, phenyl, substituted C1-C6 alkyl where the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, -OR2, 1 to 3 fluoro, -S(0) m R2, -C(0)OR2, -C3-C7 cycloalkyl, -N(R2)(R2), -C(0)N(R2)(R2); or 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 R7 a groups, wherein the bridge contains 1 to 5 carbons atoms;
  • R8 and Rio are independently selected from the group consisting of: hydrogen, -R2, -OR2, (-CH2)q-aryl, -(CH2)q-C(0)OR2, -(CH2)q- C(0)0(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 C1-C8 alkyl, 1 to 3 -OR2 or 1 to 2 -C(0)OR2;
  • R9 is selected from the group consisting of: -R2, -(CH2)q-aryl, -C(0)R2, -C(0)(CH2)q-aryl, -SO2R2. -S ⁇ 2(CH2)q-aryl, -C(0)N(R2)(R2), -C(0)N(R2)(CH2)q-aryl, -C(0)OR2, l-H-tetrazol-5-yl, -SO3H, -S ⁇ 2NHC ⁇ N, -S ⁇ 2N(R2)aryl,
  • (CH2)q may be optionally substituted by 1 to 2 C1-C4 alkyl
  • the R2 and aryl may be optionally further substituted by 1 to 3 -OR2a, -0(CH2)q aryl, 1 to 2 -C(0)OR2a, 1 to 2 -C(0)0(CH2)q aryl, 1 to 2 -C(0)N(R2a)(R2a).
  • 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:
  • R3 a is H, or fluoro
  • D is is selected from the group consisting of: -O-, -S-, -S(0) m -. N(R2), NS ⁇ 2(R2), NS ⁇ 2(CH2)taryl, NC(0)(R2),
  • N N ' and 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 O, 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: N-[ 1 (R)-[(l ,2-dihydro- 1 -methanesulfonylspiro[3H-indole-3,4'-piperidin]- l'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2- methylpropanamide;
  • 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. Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other. Similarly, the use of a particular variable within a noted structural formula is intended to be independent of the use of such variable within a different structural formula.
  • 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,
  • 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, -
  • 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.
  • the present invention includes within its scope the use of a growth hormone secretagogue, alone or in combination with other agents, for the prevention or treatment of sleep disorders and sleep disturbances in a warm-blooded animal.
  • a warm-blooded animal is a member of the animal kingdom which includes but is not limited to mammals and birds.
  • the preferred mammal for purposes of this invention is human.
  • the growth hormone secretagogue is useful in enhancing or improving sleep quality as well as preventing and treating sleep disorders and sleep disturbances in a warm-blooded animal.
  • the use of the growth hormone secretagogue increases sleep efficiency and augments sleep maintenance.
  • the growth hormone secretagogue may further be used in a a method for preventing and treating sleep disorders and sleep disturbances in a warm-blooded animal.
  • the present invention further provides a pharmaceutical composition for enhancing or improving sleep quality and increasing sleep efficiency and sleep maintenance.
  • the present method of using a growth hormone secretagogue further provides the following: an increase in the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; a decrease in sleep latency (the time it takes to fall asleep); a decrease in difficulties in falling asleap; a decrease in the number of awakenings during sleep; a decrease in nocturnal arousals; a decrease in the time spent awake following the initial onset of sleep; an increase in the total amount of sleep; an increase the amount and percentage of REM sleep; an increase in the duration and occurrence of REM sleep; a reduction in the fragmentation of REM sleep; an increase in the amount and percentage of slow- wave (i.e.
  • stage 3 or 4 sleep sleep; an increase in the amount and percentage of stage 2 sleep; an enhancement of EEG-delta activity during sleep; a decrease in the number of awakenings; a decrease in nocturnal arousals, especially early morning awakenings; an increase in daytime alertness; an increased satisfaction with the intensity of sleep; and increased sleep maintenance.
  • Secondary outcomes which may be provided by the present invention include enhanced cognitive function and increased memory retention.
  • the present invention is further useful for the prevention and treatment of sleep disorders and sleep disturbances including: sleep problems associated with insomnia, hypersomnia, sleep apnea, narcolepsy, nocturnal myoclonus, REM sleep interruptions, jet-lag, shift workers' sleep disturbances, dysomnias, night terror, insomnias associated with depression or with emotional/mood disorders, as well as sleep walking and enuresis, as well as sleep disorders which accompany aging, conditions associated with circadian rhythmicity, mental and physical disorders associated with travel across time zones and with rotating shift ⁇ work schedules, or syndromes such as fibromyalgia which are manifested by non-restorative sleep and muscle pain or sleep apnea which is associated with respiratory disturbances during sleep.
  • sleep disorders and sleep disturbances including: sleep problems associated with insomnia, hypersomnia, sleep apnea, narcolepsy, nocturnal myoclonus, REM sleep interruptions, jet-lag, shift workers' sleep disturbances, dys
  • 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 or growth hormone-releasing 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 growth hormone secretagogue not only stimulates the production of growth hormone which provides remedial outcomes in sleep, but it also acts to increase the levels of growth hormone-releasing hormone and/or somatostatin which then directly enhance the quality of sleep.
  • the present invention includes within its scope a pharmaceutical composition for enhancing and improving the quality of sleep 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 growth hormone secretagogue may be administered with somatomedin-C for the treatment of disorders characterized by non-restorative sleep, such as fibromyalgia (U.S. Patent No. 5,378,686).
  • the present invention further includes the use of a growth hormone secretagogue in the manufacture of a medicament for enhancing and improving the quality of sleep and for the treatement of sleep disorders and sleep disturbances.
  • the present invention contemplates the use of a growth hormone secretagogue for enhancing and improving the quality of sleep 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.
  • hexarelin or growth hormone releasing hormone GHRH, also designated GRF
  • GHRH hexarelin or growth hormone releasing hormone
  • ⁇ -adrenergic agonists such as clonidine or serotonin 5HTD agonists such as sumatriptan, or agents which inhibit somatostatin or its release such as physostigmine and pyridostigmine.
  • a growth hormone secretagogue may be used in combination with IGF-1 for enhancing and improving the quality of sleep.
  • 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.
  • the growth hormone secretagogue may be administered in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbituates, 5HT-2 antagonists, and the like, or the growth hormone secretagogue may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.
  • a growth hormone secretagogue may be given in combination with such compounds as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, cloperidone, clorazepate, clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazep
  • 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: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, cloperidone, clorazepate, clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvyno
  • 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, Testosterone and stanozolol.
  • anabolic steroids such as dehydroepiandrosterone, oxymetholone, methyltesterone, fluoxymesterone, Testosterone 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 inco ⁇ orated 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 inco ⁇ orating 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. Perferably, 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.
  • Pharmaceutical 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.
  • Step A 3-Amino-2.3.4.5-tetrahvdro- 1 H- 1 -benzazepin-2-one
  • the material was isolated by filtration and dried under vacuum to afford 4.18 g (23.7 mmol, 52%) of the product.
  • the mother liquors were diluted to 100 mL with methanol, treated with 2 g of charcoal, filtered through Celite and the filtrate concentrated under vacuum to approximatley 15 mL.
  • a second crop formed yielding 2.02 g of product (11.5 mmol, 25%).
  • Another recycling of the mother liquors afforded a third crop of 0.88 g (5.0, 11%).
  • a total of 7.08 g (40.2 mmol, 88%) of the product was thus obtained.
  • Step B 3(RV Amino-2.3.4.5-tetrahydro- 1 H- 1 -benzazepin-2-one 2.37 g (13.5 mmol) of 3-amino-2,3,4,5-tetrahydro-lH-l- benzazepin-2-one (Step A) and 2.02 g (13.5 mmol) of L-tartaric acid were suspended in 40 mL of ethanol. The mixture was gently heated and complete dissolution achieved by dropwise addition of 5 mL of distilled water. The solution was cooled to room temperature and aged overnight. The solid that formed was removed by filtration, washed with ethanol/diethyl ether (1:1) and dried under vacuum to afford 1.75 g of crude L-tartrate salt.
  • the purified L-tartrate salt was dissolved in 20 mL of water and the pH adjusted to 10-11 by the addition of solid potassium carbonate.
  • Step C 2.2-DimethyIbutanedioic acid.
  • 4-methyl ester 2,2-dimethylsuccinic acid (20 g, 137 mmol) dissolved in 200 mL absolute methanol at 0°C was treated dropwise with 2 mL concentrated sulfuric acid. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was concentrated in vacuo to 50 mL and slowly treated with 200 mL of saturated aqueous sodium bicarbonate. The mixture was washed with hexane (3x) and the aqueous layer removed and cooled in an ice bath. The mixture was acidified to pH 2 by slow addition of 6N HCl then extracted with ether (8x).
  • Step D 3-[Benzyloxycarbonylamino]-3-methylbutanoic acid, methyl ester
  • Step C 2,2-dimethylbutanedioic acid-4- methyl ester
  • Step C containing 15% of the isomeric 1-methyl ester compound
  • 150 mL benzene was added 13 mL of triethylamine (9.4 g, 93 mmol, 1.01 eq) followed by 21.8 mL diphenylphosphoryl azide (27.8 g, 101 mmol, 1.1 eq).
  • Step E 3-Benzyloxycarbonylamino-3-methylbutanoic acid
  • a solution of 18.27 g (68.9 mmol) of methyl 3- benzyloxycarbonylamino-3-methylbutanoate (Step D) in 20 mL of methanol at room temperature was treated dropwise with 51 mL of 2N_ NaOH (102 mmol, 1.5 eq).
  • the mixture was stirred at room temperature for 16 hours then transferred to a separatory funnel and washed with hexane (3x).
  • the aqueous layer was removed, cooled to 0°C and slowly acidified to pH 2 (paper) by dropwise addition of 6N HCl.
  • Zinc chloride (3.3 g, 24.3 mmol, 0.5 eq) was added to 15 mL of N,N-dimethylformamide in small portions while maintaining the temperature below 60°C.
  • the suspension of zinc chloride was cooled to room temperature and treated with 5.0 g of benzonitrile (48.5 mmol, 1.0 eq) followed by 3.2 g of sodium azide (48.5 mmol, 1.0 eq).
  • the heterogeneous mixture was heated at 115°C with agitation for 18 hours.
  • the mixture was cooled to room temperature, water (30 mL) was added and the mixture acidified by the addition of 5.1 mL of concentrated hydrochloric acid.
  • Step I N-Triphenylmethyl-5-f2-(4'-methylbiphen-4-vDl tetrazole
  • the solution was warmed to room temperature and added, under nitrogen purge, to the arylzinc solution.
  • the reaction mixture was stirred vigorously for 8 hours at room temperature then quenched by the slow addition of a solution of 10 mL of glacial acetic acid (1.6 mmol, 0.02 eq) in 60 mL of tetrahydrofuran at a rate so that the temperature was maintained below 40°C.
  • the mixture was stirred for 30 minutes and 150 mL of 80% saturated aqueous sodium chloride was added; the reaction mixture was extracted for 30 minutes and the layers allowed to separate.
  • the organic layer was removed and washed with 150 mL of 80% saturated aqueous sodium chloride buffered to pH>10 by the addition of ammonium hydroxide.
  • Step J N-Tri ⁇ henylmethyl-5-[2-(4'-bromomethylbiphen-4-yl)] tetrazole
  • Step K 3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro- 2-oxo- l-[[2'-(N-triphenylmethyl)-tetrazol-5-yl][ 1 , 1 '- biphenyl]-4-yl]methyl- IH- 1 -benzazepin-3(R)-yl]- butanamide
  • Step L 3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-l-[[2'-(lH- tetrazol-5-yl] [1,1 '-biphenyl]-4-yl]methyl- 1 H- 1 -benzazepin-
  • Step A 3-[(2-(R)-Benzyloxypropyl)amino]-3-methyl-N-[2,3,4,5- tetrahydro-2-oxo- 1 -[[2'-( 1 H-tetrazol-5-yl)[ 1 , 1 '-biphenyl] -4- yl] methyl] - 1 H- 1 -benzazepin-3 (R)-y l]butanamide, trifluoroacetate
  • Step B 3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5- tetrahydro-2-oxo- 1 -[[2'-( 1 H-tetrazol-5-yl)[ 1 , 1 '-biphenyl]-4- yl]methyl]- 1 H- 1 -benzazepin-3(R)-yl]butanamide, trifluoroacetate
  • Step A l,2-Dihydro-l-methanesulfonylspiro[3H-indole-3,4'- piperdinelhydrochloride To a solution of 1.20 g (5.8mmol) of 1 '-methyl- 1,2-dihydro- spiro[3H-indole-3,4'-piperdine] (prepared as described by H. Ong, et al., J. Med. Chem..
  • Step B N-[ 1 (R)-[( 1 ,2-Dihydro- l-methanesulfonylspiro[3H-indole- 3,4'-pi ⁇ erdin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2- [(l,l-dimethylethoxy)carbonyl]amino-2-methyl- propanamide
  • Step C N- [ 1 (R)-[( 1 ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole- 3,4'-piperidin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2- amino-2-methylpropanamide hydrochloride
  • Step A (2R)-[[[-2-(l,l-dimethylethoxy)carbonyl]amino]-2,2- dimethyl- 1 -oxoethyl]amino-2-(phenylmethoxy)ethyl]- 1 - propanoic acid allyl ester
  • Step B (2R)-[[[-2-(l,l-dimethylethoxy)carbonyl]amino]-2,2- dimethyl- l-oxoethyl]amino-2-(phenylmethyloxy)ethyl)- 1 - propanoic acid
  • Step C N- [ 1 (R)- [( 1 ,2-Dihydro- 1 -methanesulfonylspiro[3H-indole- 3,4'-piperdin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2- [(1,1 -dimethyl-ethoxy)carbonyl]amino-2-methyl- propanamide
  • 1-methanesulfonyl- spiro[indoline-3,4'-piperidine] hydrochloride 1.44 g (3.78 mmol) of (2R)-[[-2-( 1 , l-dimethylethoxy)carbonyl)amino]-2,2-dimethyl- 1-oxo- ethyl]-amino-2-(phenylmethyloxy)ethyl)- 1 -propanoic acid, N-methyl mo ⁇ hol
  • reaction mixture was diluted with an additional 50 mL of dichloromethane and washed with aqueous sodium bicarbonate solution (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. Flash chromatography (50 g silica gel) of the crude oily residue gave 2.148 g (90%) of the desired material as a colorless foam.
  • Step D N-[l(R)-[(l,2-Dihydro-l-methanesulfonylspiro[3H-indole- 3,4'-piperdin]- 1 '-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2 ⁇ amino-2-methylpropanamide hydrochloride
  • the active ingredient (equivalent to 5.0 mg anhydrous free base per tablet) was mixed with the calcium phosphate dibasic, the starch pregelatinized NF 1000, the microcrystalline cellulose NF, and half of the croscarmellose sodium NF in a high Fielder 10/25 mixer for about 6 minutes.
  • the 25% ethanol/water granulating solution was slowly added to the powder mixture with the mixer running over a period of about 1.5 minutes then granulated for about 8 minutes to form granules.
  • the wet granules were dried at about 47°C (range 46 to 48°C) in a tray dryer or a fluid bed dryer for approximately 3.0 hours.
  • the dried granules were then milled using a Quadro Comill to achieve fine granules. After milling, the remainder of the croscarmellose sodium NFS was added to the fine granules and mixed in a V blender for about 10 minutes. Magnesium stearate impalpable powder NF was added to this blend through a 60 mesh stainless steel screen and blended in the V blender for about 1 minute. The lubricated mixture was compressed to provide tablets of 5.0 mg active ingredient (free base equivalent).
  • Titanium Dioxide USP 1.28 mg 32.0 g
  • the titanium dioxide and talc, USP were mixed and passed through a 60 mesh stainless steel screen. This mixture was mixed with HPMC and HPC to form a dry blend.
  • the dry blend was added to water (20 ml) which was previously heated to 90°C with mild agitation to ensure that the blend is wetted to form a slurry.
  • the remainder of the water (up to 32 ml) was added to the slurry at ambient temperature with gentle agitation to form a suspension.
  • the suspension was then applied to the tablets from the previous Example using the following guidelines to provide the coated tablets.
  • Pan suitable size
  • the active ingredient (equivalent to 25 mg anhydrous free base per tablet) was mixed with the calcium phosphate dibasic, the starch pregelatinized NF 1000, the microcrystalline cellulose NF, and half of the croscarmellose sodium NF in a high shear granulator Fielder 10/25 mixer for about 6 minutes.
  • the 25% ethanol/water granulating solution was slowly added to the powder mixture with the mixer running over a period of about 1.5 minutes then granulated for about 8 minutes to form granules.
  • the wet granules were dried at about 47°C (range 46 to 48°C) in a tray dryer or a fluid bed dryer for approximately 3.0 hours.
  • the dried granules were then milled using a Quadro Comill to achieve fine granules. After milling, the remainder of the croscarmellose sodium NFS was added to the fine granules and mixed in a V blender for about 10 minutes. Magnesium stearate impalpable powder NF was added to this blend through a 60 mesh stainless steel screen and blended in the V blender for about 1 minute. The lubricated mixture was compressed to provide tablets of 25 mg active ingredient (free base equivalent).
  • Titanium Dioxide USP 1.28 mg 32.0 g
  • Talc USP Purified 0.32 mg 8.0 g

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Abstract

Un sécrétagogue d'hormone de croissance est utile, seul ou en association avec d'autres agents, pour stimuler et améliorer la qualité du sommeil, notamment par augmentation de l'efficacité du sommeil et augmentation du maintien du sommeil.
EP97924576A 1996-05-07 1997-05-05 Stimulation du sommeil avec un secretagogue d'hormone de croissance Withdrawn EP0900086A4 (fr)

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US1678796P 1996-05-07 1996-05-07
US16787P 1996-05-07
GB9611002 1996-05-24
GBGB9611002.8A GB9611002D0 (en) 1996-05-24 1996-05-24 Enhancement of sleep with a growth hormone secreragogue
PCT/US1997/007516 WO1997041879A1 (fr) 1996-05-07 1997-05-05 Stimulation du sommeil avec un secretagogue d'hormone de croissance

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WO2004080459A1 (fr) * 2003-03-14 2004-09-23 Merck Sharp & Dohme Limited Methode permettant de traiter une deficience cognitive legere et de prevenir ou de retarder l'apparition la maladie d'alzheimer
WO2004108120A1 (fr) * 2003-06-11 2004-12-16 Pfizer Products Inc. Utilisation de sécrétagogues de l'hormone de croissance pour le traitement de la fibromyalgie
US7476653B2 (en) 2003-06-18 2009-01-13 Tranzyme Pharma, Inc. Macrocyclic modulators of the ghrelin receptor
NZ553202A (en) 2004-08-19 2010-12-24 Vertex Pharma Modulators of muscarinic receptors
US7786141B2 (en) 2004-08-19 2010-08-31 Vertex Pharmaceuticals Incorporated Dihydrospiroindene modulators of muscarinic receptors
AU2005309365B2 (en) 2004-11-29 2011-10-06 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
AU2006330866A1 (en) 2005-12-22 2007-07-05 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
KR20080094964A (ko) 2006-02-22 2008-10-27 버텍스 파마슈티칼스 인코포레이티드 무스카린성 수용체의 조절제
NZ570497A (en) 2006-02-22 2011-09-30 Vertex Pharma Spiro condensed 4,4'-quinilino-piperidines derivatives as modulators of muscarinic receptors
CU23558A1 (es) 2006-02-28 2010-07-20 Ct Ingenieria Genetica Biotech Compuestos análogos a los secretagogos peptidicos de la hormona de crecimiento
US7858790B2 (en) 2006-06-29 2010-12-28 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
WO2008021375A2 (fr) 2006-08-15 2008-02-21 Vertex Pharmaceuticals Incorporated Modulateurs de récepteurs muscariniques
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CA2253390A1 (fr) 1997-11-13
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JP2000511885A (ja) 2000-09-12
AU711884B2 (en) 1999-10-21
AU2996397A (en) 1997-11-26

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