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EP0912178A1 - Verfahren zur behandlung des bluthochdrucks - Google Patents

Verfahren zur behandlung des bluthochdrucks

Info

Publication number
EP0912178A1
EP0912178A1 EP97926817A EP97926817A EP0912178A1 EP 0912178 A1 EP0912178 A1 EP 0912178A1 EP 97926817 A EP97926817 A EP 97926817A EP 97926817 A EP97926817 A EP 97926817A EP 0912178 A1 EP0912178 A1 EP 0912178A1
Authority
EP
European Patent Office
Prior art keywords
indol
piperidin
compound
amino
tachykinin receptor
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Withdrawn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
EP97926817A
Other languages
English (en)
French (fr)
Other versions
EP0912178A4 (de
Inventor
Donald R. Gehlert
Mitchell I. Steinberg
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.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP0912178A1 publication Critical patent/EP0912178A1/de
Publication of EP0912178A4 publication Critical patent/EP0912178A4/de
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence.
  • Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's.
  • neurokinin A also known as substance K, neuromedin L, and neurokinin ⁇
  • neurokinin B also known as neuromedin K and neurokinin ⁇
  • Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
  • Substance P is believed inter aha to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis.
  • These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease.
  • Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.
  • Tachykinins play a major role in mediating the sensation and transmission of pain or nociception, especially migraine headaches. see, e.g.. S.L. Shepheard, et al.. British Journal of Pharmacology. 108: 11- 20 (1993); S.M. Moussaoui, et al.. European Journal of Pharmacology. 238:421-424 (1993); and W.S. Lee, et al.. British Journal of Pharmacology. 112:920-924 (1994).
  • tachykinin receptor antagonists In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions.
  • the earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.
  • Recent publications have described novel classes of non- peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists.
  • Patent Cooperation Treaty Patent Publication WO 96/11000 published April 18, 1996 and European Patent Publication EP 705,600, published April 10, 1996, describe a synergistic effect on the combination of a serotonin agonist and a tachykinin receptor antagonist in treating migraine.
  • United States Patent Application 08/387,056, filed February 10, 1995 describes a synergistic effect on the combination of a serotonin agonist and a tachykinin receptor antagonist in treating a variety of psychiatric disorders.
  • United States Patent Application 08/408,238, filed March 22, 1995 describes a synergistic effect on the combination of a serotonin agonist and a tachykinin receptor antagonist in treating a variety of types of pain and nociception.
  • Pulmonary hypertension represents a serious, life threatening spectrum of diseases of multiple etiology. These include congenital abnormalities of the lung, thorax and diaphragm, congenital or acquired valvular or myocardial disease, obstructive lung disease, and can be a complication of autoimmune diseases, vasculitis and collagen based diseases (Rubin, Chest. 104: 236, 1993). Patients with pulmonary hypertension frequently present with symptoms including dyspnea, fatigue, syncope, and chest pain, and have increased pulmonary artery pressure and demonstrate prominence of the main pulmonary artery, hilar vessel enlargement and decreased peripheral vessels on chest radiographs (Rich, Ann. Internal. Med.. 1Q7_: 216, 1987).
  • Vasodilators are effective in only a small subpopulation of patients with primary pulmonary hypertension and is complicated by systemic hypotensive responses. Prostacyclin infusion and high dose calcium channel blockers are also being used with limited efficacy.
  • Heart-lung and single lung transplantation have been used on patients which do not respond to vasodilator therapy, however, due to surgical morbidity and mortality, this approach is usually limited to those patients who continue to deteriorate despite aggressive therapy at centers experienced in management of this disease. Patients frequently die of right heart failure and those individuals which have signs of right heart failure have a mean survival of 6-12 months (Rubin, Drugs. 43: 37, 1992).
  • This invention provides methods of inhibiting pulmonary hypertensive disease in a mammal which comprise administering to a mammal in need thereof an effective amount of a compound having activity as a tachykinin receptor antagonist.
  • inhibitor includes its generally accepted meaning which includes prohibiting, preventing, restraining, and slowing, stopping or reversing progression, severity or a resultant symptom.
  • the present method includes both medical therapeutic and/or prophylactic administration, as appropriate.
  • Pulmonary hypertensive diseases include all conditions characterized by an increase in the blood pressure within the blood vessels supplying the lungs and can increase the complications associated with pulmonary embolism, heart failure, valvular disease, chronic lung diseases and autoimmunity.
  • the methods of the present invention employ various tachykinin receptors.
  • many different groups of non-peptidyl tachykinin receptor antagonists have been described.
  • the present invention is not limited to any one of the specific compound or class of compound.
  • the present invention encompasses any compound effective as a tachykinin receptor antagonist.
  • Patent Cooperation Treaty publication WO 94/01402 published January 20, 1994, describes a series of compounds best typified by the following compound.
  • A is a pharmaceutically acceptable anion
  • Patent Cooperation Treaty publication WO 94/07843 describes a series of cyclohexylamine derivatives typified by the following compound
  • Another group of compounds useful as tachykinin receptor antagonists is typified by the following compound.
  • a most preferred class of tachykinin receptor antagonists are those compounds of the following structure
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, methyl, methoxy, chloro, and trifluoromethyl, with the proviso that no more than one of R 1 and R 2 can be hydrogen;
  • R a , R b , and R c are independently selected from the group consisting of hydrogen and Ci- C 6 alkyl;
  • Chlorotrimethylsilane (70.0 ml, 0.527 mol) was added at a moderate rate to a stirred slurry of D-tryptophan (100.0 g, 0.490 mol) in anhydrous methylene chloride (800 ml) under a nitrogen atmosphere. This mixture was continuously stirred for 4.25 hours. Triethylamine (147.0 ml, 1.055 mol) was added, followed by the addition of a solution of triphenylmethyl chloride (147.0 g, 0.552 mol) in methylene chloride (400 ml) using an addition funnel. The mixture was stirred at room temperature, under a nitrogen atmosphere for at least 20 hours. The reaction was quenched by the addition of methanol (500 ml).
  • the solution was concentrated on a rotary evaporator to near dryness and the mixture was redissolved in methylene chloride and ethyl acetate. An aqueous work-up involving a 5% citric acid solution (2X) and brine (2X) was then performed. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness on a rotary evaporator. The sohd was dissolved in hot diethyl ether followed by the addition of hexanes to promote crystallization.
  • the mixture was allowed to warm to room temperature under a nitrogen atmosphere for at least 20 hours.
  • the mixture was concentrated on a rotary evaporator and then redissolved in methylene chloride and an aqueous work-up of 5% citric acid solution (2X), saturated sodium bicarbonate solution (2X), and brine (2X) was performed.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness on a rotary evaporator.
  • the desired product was then recrystallized from hot ethyl acetate to yield 215.8 g (0.381 mol, 95%) of analytically pure material.
  • Cyclohexylpiperazine (10.0 g, 0.059 mol) was added to ten volumes of methylene chloride at room temperature. To this mixture was added sodium hydroxide (36 ml of a 2N solution, 0.072 mol) and tetrabutylammonium bromide (1.3 g, 0.004 mol). After the addition of the sodium hydroxide and tetrabutylammonium bromide, methyl bromoacetate (7.0 ml, 0.073 mol) was added and the reaction mixture was stirred for four to six hours. The progress of the reaction was monitored by gas chromatography.
  • the organic fraction was separated and the aqueous phase was back-extracted with methylene chloride.
  • the organic phases were combined and washed twice with deionized water, once with saturated sodium bicarbonate solution, and then with brine.
  • the organic phase was dried over magnesium sulfate and the solvents were removed in vacuo to yield methyl 2-((4-cyclohexyl)piperazin-l-yl)acetate as a yeUowish oil.
  • the title compound was prepared by dissolving the methyl 2-((4-cyclohexyl)piperazin-l-yl)acetate as a yeUowish oil.
  • the title compound was prepared by dissolving the methyl 2-((4-cyclohexyl)piperazin-l-yl)acetate as a yeUowish oil.
  • the title compound was prepared by dissolving the methyl 2-((4-cyclohexyl)piperazin-l-yl)acetate as
  • the title compound was prepared by first cooling 2-((4- cyclohexyl)piperazin-l-yl)acetic acid potassium salt to a temperature between -8°C and - 15°C in 5 volumes of anhydrous methylene chloride. To this mixture was added isobutylchloroformate at a rate such that the temperature did not exceed -8°C. The resulting reaction mixture was stirred for about 1 hour, the temperature being maintained between -8°C and -15°C.
  • the reaction was quenched by the addition of 5 volumes of water.
  • the organic layer was washed once with a saturated sodium bicarbonate solution.
  • the organic phase was then dried over anhydrous potassium carbonate and filtered to remove the drying agent.
  • To the filtrate was then added 2 equivalents of concentrated hydrochloric acid, foUowed by 1 volume of isopropyl alcohol.
  • the methylene chloride was then exchanged with isopropyl alcohol under vacuum by distiUation.
  • the final volume of isopropyl alcohol was then concentrated to three volumes by vacuum.
  • the reaction mixture was cooled to 20°C to 25°C and the product was aUowed to crystallize for at least one hour.
  • the desired product was then recovered by filtration and washed with sufficient isopropyl alcohol to give a colorless filtrate.
  • the crystal cake was then dried under vacuum at 50°C. MS 560 (M+l + ).
  • Deionized water (1.2 L) was then added to the mixture and the layers separated. The aqueous layer was back-extracted with methylene chloride (2.4 L). The organic fractions were combined and washed with deionized water (3 x 1.2 L), a saturated sodium bicarbonate solution (1.1 L) and a saturated sodium chloride solution (1.1 L). The organic fraction was then dried over anhydrous magnesium sulfate and concentrated to an oil on a rotary evaporator to yield 1.613 kg (93.5%) of methyl 2-(4-(piperidin-l-yl)piperidin-l-yl)acetate.
  • the title compound was prepared by first admixing (R)-2- a ⁇ mno-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]propane dihydrochlori.de (50.0 g, 0.118 mol) with 100 ml of methylene chloride under a nitrogen atmosphere.
  • reaction mixture was removed from the ice bath and aUowed to warm to 15-20°C and the reaction was quenched by the addition of 200 ml of water.
  • the pH of the solution was adjusted to 2.3- 2.7 by the additon of IN sulfuric acid.
  • the layers were separated and the aqueous layer was washed with 100 ml of methylene chloride.
  • reaction mixture was then cooled to -35°C and sohd (R)- 2-amino-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)amino]propane dihydrochloride (0.60 kg, 1.14 mol) was added at such a rate that the reaction temperature was maintained at less than -20°C. After the addition, the reaction mixture was stirred for about one hour with the temperature being maintained between -37°C and -20°C. The reaction was quenched by the addition of deionized water (7.5 L). The reaction mixture was basified to pH 12.8-13.2 by the addition of 5 N sodium hydroxide. The aqueous fraction was removed and retained.
  • the organic fraction was dried over anhydrous magnesium sulfate, filtered, and solvent exchanged from methylene chloride to acetone (3.75 L) on a rotary evaporator.
  • An aqueous solution of hydrochloric acid (0.48 L of 6 N solution, 2.88 mol) and seed crystals (2 g) were added and mixture was stirred for 30-90 minutes.
  • Acetone (13.2 L) was then added and the slurry stirred for one hour.
  • a compound believed to be effective as a tachykinin receptor antagonist may be confirmed by employing an initial screening assay which rapidly and accurately measured the binding of the tested compound to known NK-1 and NK-2 receptor sites.
  • Assays useful for evaluating tachykinin receptor antagonists are weU known in the art. See, e.g.. J. Jukic, et al.. Life Sciences. 49: 1463-1469 (1991); N. Kucharczyk, et al.. Journal of Medicinal Chemistry. 36:1654-1661 (1993); N. Rouissi, et al.. Biochemical and Bionhvsical Research Communications. 176:894-901 (1991).
  • Radioreceptor binding assays were performed using a derivative of a previously published protocol. D.G. Payan, et al.. Journal of Immunology. 133:3260-3265 (1984). In this assay an ahquot of IM9 ceUs (1 x 10 6 ceUs/tube in RPMI 1604 medium supplemented with 10% fetal calf serum) was incubated with 20 pM 125 I -labeled substance P in the presence of increasing competitor concentrations for 45 minutes at 4°C.
  • the IM9 ceU fine is a weU-characterized ceU fine which is readfly available to the pubhc. See, e.g.. Annals of the New York Academy of Science. 190: 221-234 (1972); Nature (London).
  • ceUs were routinely cultured in RPMI 1640 supplemented with 50 ⁇ g/ml gentamicin sulfate and 10% fetal calf serum.
  • reaction was terminated by filtration through a glass fiber filter harvesting system using filters previously soaked for 20 minutes in 0.1% polyethylenimine. Specific binding of labeled substance P was determined in the presence of 20 nM unlabeled hgand.
  • the CHO-hNK-2R ceUs a CHO-derived ceU line transformed with the human NK-2 receptor, expressing about 400,000 such receptors per ceU, were grown in 75 cm 2 flasks or roUer bottles in minimal essential medium (alpha modification) with 10% fetal bovine serum.
  • minimal essential medium alpha modification
  • the gene sequence of the human NK-2 receptor is given in N.P. Gerard, et al.. Journal of Biological Chemistry. 265:20455-20462 (1990).
  • Membranes were prepared by homogenization of the ceU peUets in 300 ml 50 mM Tris buffer, pH 7.4 with a Tekmar® homogenizer for 10-15 seconds, foUowed by centrifugation at 12,000 RPM (20,000 x g) for 30 minutes using a Beckman JA-14® rotor. The peUets were washed once using the above procedure, and the final peUets were resuspended in 100-120 ml 50 mM Tris buffer, pH 7.4, and 4 ml aliquots stored frozen at -70°C. The protein concentration of this preparation was 2 mg/ml.
  • AU samples and standards were added to the incubation in 10 ⁇ l dimethylsulfoxide (DMSO) for screening (single dose) or in 5 ⁇ l
  • DMSO dimethylsulfoxide
  • assays may be used to demonstrate the ability of such a compound to control or treat hypertension. Typical such assays are described below.
  • the increase in perfusion pressure (vasoconstriction) induced by thromboxane mimetics in the presence of estradiol is determined and the ability to block the thromboxane effects with a trst compound or the estradiol potentiation of the thromboxane effects will be determined.
  • Activity of compounds having activity as tachykinin receptor antagonists is iUustrated by a reduction in pulmonary perfusion pressure increase foUowing thromboxane mimetic stimulation.
  • P23ID pressure transducer (Rein del et al.. Tox and Applid. Pharm. 106: 179-200 (1990), incorporated herein by reference. A test compound is administered and the effect on the rats are evaluated.
  • Activity of compounds having activity as tachykinin receptor antagonists is iUustrated by a reduction in uptake of fluorescein conjugated dextran from bronchial alveolar lavage fluids of animals treated with a compound of formula 1, indicating a reduction in pulmonary edema.
  • Rat lungs will also be removed from thorax, perfused with modified Karnovskys fixitive and processed for histopathology.
  • a reduction in thickening of the arterial walls in treated rats is evidence for the protective role of compounds of formula 1 as is a decrease in pulmonary artery pressure.
  • compositions comprising a pharmaceuticaUy acceptable excipient and at least one active ingredient.
  • These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions.
  • Such compositions are prepared in a manner weU known in the pharmaceutical art and comprise at least one active compound. See, e.g.. REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
  • the active ingredient is usuaUy mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or hquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, piUs, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a sohd or in a hquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to miU the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantiaUy insoluble, it ordinarily is miUed to a particle size of less than 200 mesh. If the active compound is substantiaUy water soluble, the particle size is normaUy adjusted by milling to provide a substantiaUy uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium sihcate, microcrystalline ceUulose, polyvinylpyrrohdone, ceUulose, water, syrup, and methyl ceUulose.
  • the formulations can additionaUy include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usuaUy about 1.0 to about 30 mg, of the active ingredient.
  • unit dosage form refers to physicaUy discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compounds are generaUy effective over a wide dosage range. For examples, dosages per day normaUy faU within the range of about 0.01 to about 30 mg/kg of body weight.
  • the range of about 0.1 to about 15 mg/kg/day, in single or divided dose is especiaUy preferred.
  • the amount of the compound actuaUy administered wiU be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases stiU larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaUer doses for administration throughout the day.
  • Hard gelatin capsules containing the foUowing ingredients are prepared:
  • Quantity Ingredient (mg/cansule ⁇
  • the above ingredients are mixed and fiUed into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • a dry powder inhaler formulation is prepared containing the foUowing components:
  • the active ingredient, starch and ceUulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • ceUulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and fiUed into hard gelatin capsules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient are made as foUows:
  • the medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline ceUulose and sodium carboxymethyl ceUulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • Capsules each containing 15 mg of medicament, are made as foUows:
  • Quantity Ingredient (mg/capsule)
  • the active ingredient(s), ceUulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
  • An intravenous formulation may be prepared as foUows:
  • a topical formulation may be prepared as foUows:
  • the white soft paraffin is heated until molten.
  • the hquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixture is then cooled until sohd.
  • Subhngual or buccal tablets each containing 10 mg of active ingredient, may be prepared as foUows:
  • the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90°C.
  • the solution is cooled to about 50-55°C and the medicament is slowly admixed.
  • the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
  • trans dermal dehvery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controUed amounts.
  • the construction and use of transdermal patches for the dehvery of pharmaceutical agents is weU known in the art. See, e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand dehvery of pharmaceutical agents.
  • indirect techniques which are generaUy preferred, usuaUy involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
  • Latentiation is generaUy achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more hpid soluble and amenable to transportation across the blood-brain barrier.
  • the dehvery of hydrophilic drugs may be enhanced by intr a- arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • the type of formulation employed for the administration of the compounds employed in the methods of the present invention may be dictated by the particular compounds employed, the type of pharmacokinetic profile desired from the route of administration and the compound(s), and the state of the patient.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP97926817A 1996-05-24 1997-05-23 Verfahren zur behandlung des bluthochdrucks Withdrawn EP0912178A4 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US1826696P 1996-05-24 1996-05-24
US18266P 1996-05-24
PCT/US1997/009225 WO1997044035A1 (en) 1996-05-24 1997-05-23 Methods of treating hypertension

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EP0912178A1 true EP0912178A1 (de) 1999-05-06
EP0912178A4 EP0912178A4 (de) 2000-08-16

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JP (1) JP2000511193A (de)
AU (1) AU3149297A (de)
CA (1) CA2255910A1 (de)
WO (1) WO1997044035A1 (de)

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GB9927125D0 (en) * 1999-11-16 2000-01-12 Univ Reading The Placental human neurokinin B precursor
JP2010516731A (ja) 2007-01-24 2010-05-20 グラクソ グループ リミテッド ２−メトキシ−５−（５−トリフルオロメチル−テトラゾール−１−イル）−ベンジル］−（２ｓ−フェニル−ピペリジン−３ｓ−イル）−アミンを含む医薬組成物

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994001402A1 (en) * 1992-07-13 1994-01-20 Merck Sharp & Dohme Limited Heterocyclic amide derivatives as tachykinin derivatives
EP0591040A1 (de) * 1992-09-30 1994-04-06 Sanofi Quarternäre basische Amide als Tackykinine Antagoniste
WO1994007843A1 (en) * 1992-09-25 1994-04-14 Merck Sharp & Dohme Limited Cyclohexyl amine derivatives and their use as tachykinin antagonists
EP0699665A1 (de) * 1994-06-10 1996-03-06 Eli Lilly And Company Imidazolin-Derivate, deren Herstellung und deren Verwendung als Tachykinin-Rezeptor Antagonisten
WO1996026183A1 (en) * 1995-02-22 1996-08-29 Novartis Ag 1-aryl-2-acylamino-ethane compounds and their use as neurokinin especially neurokinin 1 antagonists
EP0739892A2 (de) * 1995-04-24 1996-10-30 Ciba-Geigy Ag Chromon-Derivate

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5344830A (en) * 1992-12-10 1994-09-06 Merck & Co., Inc. N,N-diacylpiperazine tachykinin antagonists

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994001402A1 (en) * 1992-07-13 1994-01-20 Merck Sharp & Dohme Limited Heterocyclic amide derivatives as tachykinin derivatives
WO1994007843A1 (en) * 1992-09-25 1994-04-14 Merck Sharp & Dohme Limited Cyclohexyl amine derivatives and their use as tachykinin antagonists
EP0591040A1 (de) * 1992-09-30 1994-04-06 Sanofi Quarternäre basische Amide als Tackykinine Antagoniste
EP0699665A1 (de) * 1994-06-10 1996-03-06 Eli Lilly And Company Imidazolin-Derivate, deren Herstellung und deren Verwendung als Tachykinin-Rezeptor Antagonisten
WO1996026183A1 (en) * 1995-02-22 1996-08-29 Novartis Ag 1-aryl-2-acylamino-ethane compounds and their use as neurokinin especially neurokinin 1 antagonists
EP0739892A2 (de) * 1995-04-24 1996-10-30 Ciba-Geigy Ag Chromon-Derivate

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US AN: 122:262621, XP002140086 *
See also references of WO9744035A1 *

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WO1997044035A1 (en) 1997-11-27
EP0912178A4 (de) 2000-08-16
AU3149297A (en) 1997-12-09
CA2255910A1 (en) 1997-11-27

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