WO2002057241A1 - 8-(aminoalcoxymino)-8h-dibenzo[a,e]triazolo[4,5-c]cycloheptenes en tant que secretagogues de l'hormone de croissance - Google Patents

8-(aminoalcoxymino)-8h-dibenzo[a,e]triazolo[4,5-c]cycloheptenes en tant que secretagogues de l'hormone de croissance Download PDF

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WO2002057241A1
WO2002057241A1 PCT/US2001/048259 US0148259W WO02057241A1 WO 2002057241 A1 WO2002057241 A1 WO 2002057241A1 US 0148259 W US0148259 W US 0148259W WO 02057241 A1 WO02057241 A1 WO 02057241A1
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carbon atoms
alkyl
growth hormone
hydrogen
formula
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PCT/US2001/048259
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English (en)
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Brian R. Dixon
Cedo M. Bagi
William J. Scott
Gerald Ranges
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Bayer Pharmaceuticals Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders

Definitions

  • the invention relates to the use of 8-(aminoalkoxyimino)-8H- dibenzo[a,e]triazolo[4,5-c]cycloheptenes as growth hormone secretagogues. More particularly, the invention relates to methods of treating or preventing diseases or conditions caused by deficiencies in growth hormone by administering to a mammal a 8-
  • Growth hormone a hormone that is both produced by and secreted from the pituitary gland, stimulates growth of all tissues in the body that are capable of growing.
  • Deficiencies in growth hormone can result in various diseases and conditions, such as osteoporosis, obesity, growth retardation, skeletal displasia, etc. In children, it causes growth retardation or dwarfism. In adults, the consequences of growth hormone deficiency can include reduction of lean body mass and concomitant increase in total body fat. The consequences of growth hormone deficiency in adults can further include decreased skeletal and muscle mass and decreased bone density. Administration of exogenous growth hormone has been shown to reduce or reverse the effects of such metabolic disturbances.
  • exogenous growth hormone has historically been administered.
  • the peptidyl nature of the compound required that it be administered by injection.
  • early sources of growth hormone included the pituitary glands of cadavers. This resulted in an expensive product that carried with it the risk of disease transmission (e.g., Creutzfel- acob disease).
  • Most deficiencies of growth hormone result from defects in release of growth hormone from the pituitary gland, however, and not from defects in the synthesis of growth hormone.
  • the release of growth hormone is controlled by a number of hormones and neurotransmitter systems in the brain, particularly the hypothalamus.
  • the release of growth hormone can be stimulated by growth hormone releasing factor (GHRF) and inhibited by somatostatin. In both the cases, the hormones are released from the hypothalamus, but the release of growth hormone itself is mediated primarily by specific receptors in the pituitary gland.
  • GHRF growth hormone releasing factor
  • Methods of treating or preventing diseases or conditions caused by growth hormone deficiencies therefore involve stimulating release of growth hormone, such as by administration of a growth hormone secretagogue.
  • Compounds that stimulate the release of growth hormone include arginine, L,-3.4-dihydroxyphenylalanine (L-Dopa), glucagon, vasopressin, pituitary adenylyl cyclase activating peptide (PACAP), and growth hormone releasing peptide (GHRP).
  • PACAP pituitary adenylyl cyclase activating peptide
  • GHRP growth hormone releasing peptide
  • n is a number from 2 to 4;
  • R 3 and R 4 join together with the nitrogen atom to which they are attached to form a 5-8 membered ring, which may contain an additional heteroatom selected from O and NR 6 ;
  • R 1 and R 2 are independently selected from hydrogen and alkyl of 1-3 carbon atoms; or
  • R 3 and R 1 join together with the nitrogen atom to which they are attached when n is 2 or 3 to form a 5-6 membered ring;
  • R 6 is selected from hydrogen and alkyl of 1-3 carbon atoms
  • R and R are independently selected from hydrogen and alkyl of 1-3 carbon atoms;
  • R 4 is selected from hydrogen and alkyl of 1-6 carbon atoms
  • R 13 is alkyl of 1-4 carbon atoms
  • R 14 is selected from H and OH; and pharmaceutically acceptable salts thereof.
  • R 4 is selected from hydrogen and alkyl of 1-6 carbon atoms
  • R 5 is alkyl of 1-6 carbon atoms
  • R 6 is selected from hydrogen and alkyl of 1-3 carbon atoms
  • R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently selected from hydrogen, halogen, alkyl of 1-3 carbon atoms, alkoxy of 1-3 carbon atoms, NO 2 , CN and CF 3 ;
  • R 14 is selected from H and OH; and pharmaceutically acceptable salts thereof.
  • n is a number from 2 to 4.
  • R 1 and R 2 join to form a 3-7 membered ring, wherein the R 1 and R 2 that form the ring can be on the same carbon atom, adjacent carbon atoms, or carbon atoms that are 2-3 carbon atoms away from one another;
  • R 4 is selected from hydrogen and alkyl of 1-6 carbon atoms
  • R 3 and R 4 join together with the nitrogen atom to which they are attached to form a 5-8 membered ring, which may contain an additional heteroatom selected from O and NR 6 ;
  • R 5 is alkyl of 1-6 carbon atoms
  • R 6 is selected from hydrogen and alkyl of 1-3 carbon atoms
  • R 1 and R 2 are selected from hydrogen and alkyl of 1-3 carbon atoms
  • Growth hormone secretagogues of formula I that are useful in methods of the invention include, but are not limited to, the following:
  • Growth hormone secretagogues of formula IN that are useful in methods of the invention include, but are not limited to, the following:
  • cardiovascular disease including congestive heart failure (See, Nass, et al, Growth Hormone Secretago ues 263 (1999), Berti, etal, Growth Hormone Secretagogues 301 (1 99), and Rosen, supra);
  • growth retardation See, Strobl, supra, which may result from any number of causes, including renal failure or renal insufficiency, chronic illness, obesity, Prader- illi syndrome, Turner's syndrome, Down's syndrome, or Noonan's syndrome;
  • hyperinsulinemia See Saenger, Horm. Res. 53 (Suppl. l):60-69 (2000), Nam, Strobl and Rosen, supra).
  • Compounds of formula I, II, III and IN are preferably used in the treatment or prevention of osteopenia and osteoporosis, and in the promotion of bone growth and bone fracture healing.
  • the present invention also includes use of pharmaceutically acceptable salts of the compounds of formula I, II, III and IN.
  • Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, sulphonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid.
  • basic salts of inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, sulphonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,
  • pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li + ⁇ a + or K + ), alkaline earth cations (e.g., Mg +2 , Ca +2 or Ba +2 ), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, NN-diethylamine, NN-dicyclohexylamine, pyridine, NN- dimethylaminopyridine (DMAP), l,4-diazabicyclo[2.2.2]octane (DABCO), 1,5- diazabicyclo[4.3.0]non-5-ene (DB ⁇ ) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • a number of the compounds of formula I, II, III and IN possess asymmetric carbons and can therefore exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to those skilled in the art.
  • the present invention encompasses the use of any racemic or optically active forms of the compounds described in formula I, II, III and IN for the treatment or prevention of diseases or conditions resulting from deficiencies in growth hormone.
  • the therapeutic agents of the invention may be employed alone or concurrently with other therapies.
  • a growth hormone secretagogue of formula I, II, III or IN may be administered in combination, either concurrently or sequentially, with other known growth hormone secretagogues, anabolic agents or bone antiresorptive agents.
  • the compounds may be administered in dose ranges from one one-hundredth to one times the dose levels winch are effective when these compounds are used alone.
  • growth hormone secretagogues include, but are not limited to, the growth hormone releasing peptides (GHRP-1, GHRP-2, and GHRP-6), growth hormone releasing factor (growth hormone releasing hormone) and its analogs, B-HT920, hexarelin, somatomedins (IGF-1 and IGF-2), ⁇ -adrenergic agonists (clonidine), serotonin 5HTlDa agonists (sumitriptan), and agents that inhibit somatostatin or its release (physostigmine and pyridostigmine). Additionally, growth hormone secretagogues disclosed, for example, in U.S. Pat. Nos.
  • Anabolic agents that may be useful in combination with compounds of formula I, II, III or IN include, but are not limited to, bone morphogenic proteins or active fragments thereof, thyrotropin releasing hormone or an active fragment thereof, diethylstilbeserol, estrogens, ⁇ -agonists, parathyroid hormone or an active fragment thereof, theophylline, anabolic steroids, enkephalins, prostaglandins and their agonists/antagonists, and sodium fluoride. Additionally, anabolic agents disclosed, for example, in U.S. Pat. ⁇ os.
  • the compounds of formula I, II, III and IN may be used in combination with a calcium source, vitamin D or analogues of vitamin D, and/or bone antiresorptive therapies, such as estrogen replacement therapy, treatment with a fluoride source, or treatment with calcitonin or a calcitonin analogue.
  • bone antiresorptive therapies such as estrogen replacement therapy, treatment with a fluoride source, or treatment with calcitonin or a calcitonin analogue.
  • combined therapy to inhibit bone resorption, prevent osteoporosis and/or osteopenia, reduce skeletal fracture, enhance bone fracture healing, stimulate bone fonnation and increase bone mineral density can be effectuated by combinations of a compound of formula I, II, III or IN and a bisphosphonate. See, e.g.,
  • Bone antiresorptive agents that may also be used in combination with a growth hormone secretagogue of formula I, II, III or IN include estrogen agonist/antagonist.
  • estrogen agonist/antagonist refers to compounds that bind the estrogen receptor, inhibit bone turnover and prevent bone loss.
  • examples of estrogen agonist/antagonist include, but are not limited to, droloxifene, raloxifene, tamoxifen, 4-hydroxy tamoxifen, toremifene, clometherone, delmadinone, centchroman, levormeloxifene, nafoxidine, nitromifene, ormeloxifene, trioxifene, and idoxifene.
  • Estrogen agonist/antagoinst are disclosed, for example, in U.S. Pat. ⁇ os. 3,274,213; 4,133,814; 4,230,862; 4,323,707; 4,380,635; 4,400,543; 4,418,068; 4,536,516; 5,254,594, the disclosures of which are hereby incorporated by reference.
  • Other estrogen agonist/antagonist are disclosed in, for example, EP 0 062 503, EP 0 054 168, EP 0260 066, EP 0 470 310, EP 0 651 998, and EP 0 652 005.
  • Any estrogen receptor agonist or antagonist may be useful in combination with a growth hormone secretagogue of formula I, II, III or IN in methods of the invention.
  • the methods of the invention are intended to be employed for treatment of diseases or conditions resulting from deficiencies in growth hormone in both humans and other mammals.
  • the compounds of formula I, II, III and IV may also be useful in stimulating the immune system in companion animals, treating disorders of aging in companion animals, promoting growth in livestock, or stimulating wool growth in sheep.
  • the growth hormone secretagogues of formula I, II, III, and TV and/or any co-administered compounds may be administered orally, dermally, parenterally, by injection, by inhalation or spray, or sublingually, rectally or vaginally in dosage unit formulations.
  • administered by injection includes intravenous, intraarticular, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques.
  • Dermal administration may include topical application or transdermal admimstration.
  • One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and, if desired, other active ingredients.
  • compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions.
  • Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations.
  • Tablets contain the growth hormone secretagogue of formula I, II, III or IV in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients maybe, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions containing a growth hormone secretagogue of formula I, II, III or IV in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a nat ⁇ ally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or «-propyl, j9-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or «-propyl, j9-hydroxybenzoate
  • coloring agents for example ethyl, or «-propyl, j9-hydroxybenzoate
  • coloring agents for example ethyl, or «-propyl, j9-hydroxybenzoate
  • flavoring agents for example ethyl, or «-propyl, j9-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • the growth hormone secretagogue of formula I, II, III or IV may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which maybe formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Methods of the invention may also include administration of pharmaceutical compositions containing a growth hormone secretagogue of formula I, II, III or IN in the form of oil-in- water emulsions.
  • the oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • a growth hormone secretagogue of formula I, II, III or IV may also be administered in the form of suppositories for rectal or vaginal admimstration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug.
  • suitable non-irritating excipient include cocoa butter and polyethylene glycols.
  • Methods of the invention may also include transdermal administration of a growth hormone secretagogue of formula I, II, III or IV using methods known to those skilled in the art (see, e.g., Chien; "Transdermal Controlled Systemic Medications”; Marcel Dekker, Inc.; 1987. Lipp et al. WO 94/04157 3Mar94).
  • a solution or suspension of a compound of formula I, II, III or IN in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms.
  • a solution or suspension of a compound of formula I, II, III or IN may be fonnulated into a lotion or salve.
  • Suitable solvents for processing transdermal delivery systems include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane.
  • lower alcohols such as ethanol or isopropyl alcohol
  • lower ketones such as acetone
  • lower carboxylic acid esters such as ethyl acetate
  • polar ethers such as tetrahydrofuran
  • lower hydrocarbons such as hexane, cyclohexane or benzene
  • halogenated hydrocarbons such as dichloromethane, chloroform, trichlor
  • Suitable solvents may also include mixtures of one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.
  • Suitable penetration enhancing materials for transdermal delivery systems are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated C 8 - C 18 fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C 8 -C 18 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-bvtyl, ee-butyl isobutyl tert-butyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palm
  • Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether.
  • Suitable penetration enhancing formulations may also include mixtures one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C 8 -C 18 fatty alcohols, saturated or unsaturated C 8 -C 18 fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.
  • Suitable binding materials for transdermal delivery systems include polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene coploymers, and natural and synthetic rubbers.
  • Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.
  • the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
  • the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight.
  • the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
  • the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg.
  • the daily inhalation dosage regimen will preferably be from 0.01 to 10 mg/Kg of total body weight.
  • the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.
  • the optimal course of treatment i.e., the mode of treatment and the daily number of doses of a compound of formula I, II, III or IN, or a pharmaceutically acceptable salt thereof, given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
  • the growth hormone secretagogues of formula I, II, III and IN may be prepared by use of known chemical reactions and procedures, from known compounds (or from starting materials which, in turn, are producible from known compounds) through the preparative methods described below, as well as by other reactions and procedures known to those skilled in the art.
  • Such reactions and procedures include, but are not limited to, esterification, hydrolysis, alkylation, acylation neutralization, coupling, oxidation, reduction, condensation, elimination and substitution reactions.
  • the following general preparative methods are presented to aid practitioners in synthesizing the compounds of the invention, with more detailed particular examples being presented in the experimental section. The examples are for illustrative purposes only and are not intended, nor should they be construed, to limit the invention in any way.
  • substituents may appear on reagents or intermediates which may act as protecting groups or other non-participating groups. Utilizing methods well known to those skilled in the art, such groups are introduced and/or removed during the course of the synthetic schemes to provide the compounds of the present invention. All variable groups not defined below are as described hereinabove.
  • the compounds of formula I, II, III and IN may be prepared by the use of known chemical reactions and procedures, some from starting materials that are commercially available. Some of the compounds of formula I, II, III and IN are known in the art and methods of preparing them have been described. (See, Holmann, DE 1,938,583 and DE 1,938,584.) Nevertheless, general preparative methods are provided below to aid one skilled in the art in synthesizing these compounds.
  • Aromatic synthesis and functional group interconversions may be accomplished using standard methods (March, Advanced Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985); Larock, Comprehensive Organic Transformations; NCH Publishers: New York (1989)).
  • 5H-Dibenzo[a,d]cyclohepten-5-one and substituted 5H- dibenzo[a,d]cyclo-hepten-5-ones (ketone 1, Scheme 1) may be prepared using known methods (Cope, J. Am. Chem. Soc. 1951, 73, 1673; Klinkhammer, Chem. Ber. 1951, 84, 671; Campbell, Helv. Chim. Acta 1953, 36, 1489).
  • Treatment of ketone 1 with bromine affords dibromoketone 2.
  • Subsequent dehydrobromination using a base, such as KOH delivers the vinyl bromide 3 (Tochtermann, Justus Liebigs Ann. Chem. 1967, 705, 169).
  • oxime 6 Reaction of ketone 5 with H 2 NOH'HCl in the presence of a base, such as pyridine will deliver oxime 6 (Scheme 2).
  • a base such as pyridine
  • oxime 6 Reaction of ketone 5 with H 2 NOH'HCl in the presence of a base, such as pyridine will deliver oxime 6 (Scheme 2).
  • oxime 6 for example using NaOEt, followed by alkylation with electrophile 7, in which L stands for a leaving group, such as a halogen (Cl, Br or I) or a sulfonate ester, gives amine 8.
  • ketone 12 Reaction of ketone 12 with H 2 NOHHCl in the presence of a base, such as pyridine will deliver oxime 13 (Scheme 4; Whitmann DE 1,938,584 (1971)).
  • a base such as pyridine
  • ketone 5 with nucleophile 15, in which M stands for counterions, such as Li + or XMg + (i.e., organolithium or Grignard reagents) leads to amino alcohol 16.
  • M stands for counterions, such as Li + or XMg + (i.e., organolithium or Grignard reagents)
  • olefin 18 Dehydration of amino alcohol 17 to afford olefin 18 may be induced using one of a variety of standard methods (March, Advanced Organic Chemistry, 3 rd Ed.; John
  • Reduction of alcohol 16 may also be accomplished using triethylsilane/BF3'Et 2 O (Scheme 7).
  • ketone 5 may be reduced to alcohol 21 with NaBH 4 (Scheme 8). Treatment with anhydrous HCl will then generate chloride 22. Reaction of chloride 22 with nucleophile 15, in which M stands for counterions, such as Li + or XMg (i.e., organolithium or Grignard reagents) leads to amino alcohol 20.
  • M stands for counterions, such as Li + or XMg (i.e., organolithium or Grignard reagents) leads to amino alcohol 20.
  • olefin 25 Dehydration of amino alcohol 24 to afford olefin 25 may be induced using one of a variety of standard methods (March, Advanced Organic Chemistry. 3 rd Ed.; John Wiley: New York (1985); Larock, Comprehensive Organic Transformations: NCH Publishers: New York (1989)).
  • acid-catalyzed elimination of the alcohol moiety will afford olefin 25 (Scheme 10).
  • conversion of the alcohol into a leaving group for example formation of the chloride using SOCl 2 , followed by or with concommittant base- mediated elimination, for example using pyridine, will generate olefin 25.
  • Reduction of the olefin for example using catalytic hydrogenation or by reaction with diimide, will then generate amine 26.
  • Reduction of alcohol 23 may also be accomplished using triethylsilane/BF 3 "Et 2 O (Scheme 11).
  • ketone 12 may be reduced to alcohol 28 with NaBH 4 (Scheme 12). Treatment with anhydrous HCl will then generate chloride 29. Reaction of chloride 29 with nucleophile 15, in which M stands for counterions, such as Li + or XMg (i.e., organolithium or Grignard reagents) leads to amino alcohol 27.
  • M stands for counterions, such as Li + or XMg (i.e., organolithium or Grignard reagents) leads to amino alcohol 27.
  • Compounds of formula I, II, III and IN stimulate the release of growth hormone in a mammal and promote the formation of bone in a mammal.
  • Dawley male rats (Harlan Sprague Dawley, Inc., Indianapolis, IN) at ages of 50-55 days were used in this experiment.
  • the rats were sacrificed using CO .
  • the rats were dipped in a 70% aqueous ethanol solution, and the pituitary was removed using instruments that were pre-sterilized in a 70% aqueous ethanol solution.
  • Three sets of instruments were used - one to peel the skin, cut the head off, and break the bone between eyes; a second to cut the head bone layer and take the brain tissue away; and a third to remove the pituitary gland.
  • the pituitary glands were placed in Hanks' balanced salt solution modified to include a Penicillin Streptomycin solution (HBSS+P/S; 1% Penicillin Streptomycin solution (Gibco 15140-122) in HBSS (Gibco 14025-092)) in a 50 mL conical tube cooled to 0 °C over an ice bath.
  • the glands were taken to a class II cell culture hood in which all subsequent operations were performed.
  • the pituitary glands were washed three times with HBSS + P/S (ten-fold volume, 30 mL) and transferred to a petri dish.
  • the glands were minced with sterile disposable scalpels #21 into fine pieces.
  • the minced tissue was then transferred to a 50 mL disposable tube by suspending the tissue fragments in three successive 10 mL aliquots of digestion mixture (0.2% Collagenase Type I (Gibco 1700-017) and 0.2% hyaluronidase (Sigma H3506) in HBSS).
  • the two cell suspensions were then combined and centrifuged again at 800 x g for 10 min.
  • the cell pellet was resuspended in 50 mL of culture media and strained through a cell strainer with 100 ⁇ M.
  • the cells were seeded at lxl 0 5 cells/ 1 mL/well in 24- well poly(lysine) coated plates.
  • the cells were placed in a humidified incubator at 37 °C in a culture medium under a 5% CO 2 atmosphere for 3 days.
  • the culture medium consisted of (1) DMEM (Gibco 11995-065); (2) 10% heat inactivated horse serum (Gibco 26050-070); (3) 2.5% heat inactivated Fetal Bovine Serum (FBS) (Gibco 10082-139); (4) 1% nonessential amino acids (Gibco 11140-050 lot 1025957); (5) 1% MEM Amino Acids (Gibco 11130- 051); (6) 1% L-Glutamine (Gibco 25030-081, 200mM stock); (7) 1% Nystatin (Gibco
  • the cell media was replaced with 1 mL fresh culture medium plus 20 nM somatostatin.
  • the cells were then incubated at 37 °C overnight.
  • the cells are washed twice with challenge medium (culture medium with 25 mM HEPES, pH 7.4), then the cells were challenged with a compound of formula I or
  • GHRP-6 for 15 min. The supernatant was removed, spun down and frozen in aliquots until analyzed. The media was analyzed using a BIOTRAK Rat Growth Hormone Elisa kit (Amersham RPN2561).
  • Figure 1 shows the amount of released growth hormone (GH) from the rat pituitary cells by a compound of formula I compared to the amount of released growth hormone from rat pituitary cells by GHRP-6.
  • OVX rat model is a small animal model for estrogen deficient bone loss in humans (postmenopausal osteoporosis) (Wronski, et al, 1985, Calcif Tissue hit 37, 324-
  • Fifty female Sprague-Dawley rats (Harlan Sprague Dawley, Inc., Indianapolis, IN) are obtained at 90 days of age. Thirty rats are ovariectomized and twenty are sham operated at Harlan Sprague Dawley using a dorsal approach. Rats are allowed to acclimate in-house for 10 weeks. At week ten, rats are divided into groups based on body weight with OVX rats in three groups often and Sham rats in two groups of seven and one group of six. Fourteen previously Sham-operated rats (two groups of seven) are ovariectomized using a dorsal approach (Waynforth HB, 1987, Academic Press, London).
  • the left femurs are cut into halves. Following fixation with NBF for 48 hours, the distal halves are dehydrated with a series of graded ethanol and embedded in poly(methyl methacrylate). Sections are cut with a Jung Polycut E microtome (Reinchart Jung, Germany) into longitudinal sections 4 ⁇ m thick. Those sections are used unstained for dynamic histomorphometric analyses of the cancellous bone.
  • Right femurs are fixed in NBF for 48 hours and dehydrated through a graded ethanol series, undecalcified femurs are cut in halves. Proximal halves are used for cortical bone measurements at the mid-diaphyses.

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Abstract

L'invention concerne des procédés relatifs au traitement ou à la prévention d'affections ou de maladies liées aux carences en hormone de croissance, consistant à administrer des 8-(aminoalcoxyimino)-8H-dibenzo[a,e]triazolo[4,5-c]cycloheptènes. Parmi les maladies ou affections visées, on peut citer les cas suivants: ostéoporose, ostéopénie et obésité. L'invention concerne également des procédés relatifs à la stimulation de la sécrétion de l'hormone de croissance chez un mammifère, par administration de 8-(aminoalcoxyimino)-8H-dibenzo[a,e]triazolo[4,5-c]cycloheptènes. Enfin, l'invention concerne la stimulation de la croissance osseuse chez un mammifère, en particulier la croissance osseuse du type endocortical, périostique ou spongieux, par administration de 8-(aminoalkoxyimino)-8H-dibenzo[a,e]triazolo[4,5-c]cycloheptènes.
PCT/US2001/048259 2000-12-22 2001-12-14 8-(aminoalcoxymino)-8h-dibenzo[a,e]triazolo[4,5-c]cycloheptenes en tant que secretagogues de l'hormone de croissance WO2002057241A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002056873A2 (fr) * 2000-12-22 2002-07-25 Bayer Pharmaceuticals Corporation Dibenzo[a,e]1,2,3-triazolo[4,5-c][7]annulene-8-ones a substitution en 2, comme secretagogues de l'hormone de corsante
JP2010529020A (ja) * 2007-05-31 2010-08-26 塩野義製薬株式会社 オキシイミノ化合物およびその使用
US7994127B2 (en) 2007-06-08 2011-08-09 Massachusetts Institute Of Technology Treatment of rett syndrome

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1938584A1 (de) * 1969-07-30 1971-02-11 Bayer Ag Basisch substituierte Oximaether des 8H-Dibenzo-[a,e]-triazolo-[4,5-c]-cyclohepten-8-ons
WO1999065917A1 (fr) * 1998-06-15 1999-12-23 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Utilisation de diazepines pour la preparation de medicaments destines a traiter les etats pathologiques ou les maladies dans lesquels un des recepteurs de la somatostatine est implique
WO2000054729A2 (fr) * 1999-03-12 2000-09-21 Bristol-Myers Squibb Company Composes heterocycliques aromatiques utilises comme secretagogues d'hormones de croissance

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1938584A1 (de) * 1969-07-30 1971-02-11 Bayer Ag Basisch substituierte Oximaether des 8H-Dibenzo-[a,e]-triazolo-[4,5-c]-cyclohepten-8-ons
WO1999065917A1 (fr) * 1998-06-15 1999-12-23 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Utilisation de diazepines pour la preparation de medicaments destines a traiter les etats pathologiques ou les maladies dans lesquels un des recepteurs de la somatostatine est implique
WO2000054729A2 (fr) * 1999-03-12 2000-09-21 Bristol-Myers Squibb Company Composes heterocycliques aromatiques utilises comme secretagogues d'hormones de croissance

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002056873A2 (fr) * 2000-12-22 2002-07-25 Bayer Pharmaceuticals Corporation Dibenzo[a,e]1,2,3-triazolo[4,5-c][7]annulene-8-ones a substitution en 2, comme secretagogues de l'hormone de corsante
WO2002056873A3 (fr) * 2000-12-22 2003-08-07 Bayer Pharmaceuticals Corp Dibenzo[a,e]1,2,3-triazolo[4,5-c][7]annulene-8-ones a substitution en 2, comme secretagogues de l'hormone de corsante
JP2010529020A (ja) * 2007-05-31 2010-08-26 塩野義製薬株式会社 オキシイミノ化合物およびその使用
US8563732B2 (en) 2007-05-31 2013-10-22 Shionogi & Co., Ltd. Oxyimino compounds and the use thereof
US7994127B2 (en) 2007-06-08 2011-08-09 Massachusetts Institute Of Technology Treatment of rett syndrome

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