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WO1998035677A1 - Composes d'antagonistes d'histamine non sedatifs, compositions et procedes d'utilisation de ces composes - Google Patents

Composes d'antagonistes d'histamine non sedatifs, compositions et procedes d'utilisation de ces composes Download PDF

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Publication number
WO1998035677A1
WO1998035677A1 PCT/US1998/002857 US9802857W WO9835677A1 WO 1998035677 A1 WO1998035677 A1 WO 1998035677A1 US 9802857 W US9802857 W US 9802857W WO 9835677 A1 WO9835677 A1 WO 9835677A1
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WO
WIPO (PCT)
Prior art keywords
compound
mammal
pharmaceutically acceptable
administering
antihistaminic
Prior art date
Application number
PCT/US1998/002857
Other languages
English (en)
Inventor
A. K. Gunnar Aberg
Ronald E. Weishaar
Philip M. Carabates
George E. Wright
Jan L. Chen
Original Assignee
Bridge Pharma, Inc.
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 Bridge Pharma, Inc. filed Critical Bridge Pharma, Inc.
Priority to AU61657/98A priority Critical patent/AU6165798A/en
Publication of WO1998035677A1 publication Critical patent/WO1998035677A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to non-sedating and non- cholinergic histamine (H I ) antagonist compounds, pharmaceutical compositions containing them and method of using said compounds and compositions for the prevention and treatment of allergic disorders including allergic rhinitis and cutaneous allergic reactions.
  • H I histamine
  • the present invention relates to certain substituted N-alkyl- , and N-hydroxyalkyl-heterocyclyl- piperidineamines having antihistaminic properties while avoiding, on administration to a mammal, adverse side effects such as drowsiness, sedation, dry mouth, blurry vision, tachycardia, and cardiac arrhythmias .
  • astemizole is a nonsedating antihistamine that is being sold worldwide. Astemizole has an unusually long biological half-life and additionally the drug may cause cardiac side effects, which limit its usefulness. Like loratadine . which is another non-sedating antihistamine, astemizole has anticholinergic side effects that may cause dry mouth, blurry vision etc.
  • L is H, CH 3 or CH 2 CH 2 OH; and R is H.
  • the publication teaches that these compounds have low oral activity.
  • L is H, C 1 6 -alkyloxycarbonyl or a phenylmethoxycarbonyl group; and R is a bivalent radical, 5-OH, 6-OH, or 5,6(OH) 2 . No biological effects are reported on compounds containing 5-OH, 6-OH, or 5,6(OH) 2 .
  • the present invention concerns compounds and compositions containing N-heterocyclyl-4-piperidinamines having a straight alkyl or a hydroxyalkyl moiety or a carboxymethoxyalkyl moiety or a carboxy- ethoxyalkyl or a carboxypropyloxyalkyl moiety at the L position and 5- OH, or 6-OH, or 5,6-(OH) 2 at the R position of the above-shown structure.
  • the compounds of the present invention are devoid of sedative side effects, which is believed to be due to an inability of the compounds to enter into the brain, and contrary to most other anti- histamines, the new compounds are characterized by unusually weak anticholinergic side effects.
  • the compounds of the present invention are orally well absorbed, have a shorter half-life than astemizole and do not have the cardiac side effects of astemizole.
  • L is selected from the group consisting of alkyl, hydroxyalkyl, chloroethyl, acetonitrile, alkylcarbonyl, carboxymethoxyalkyl, carboxyethoxyalkyl and carboxypropyloxyalkyl; and R is selected from the group consisting of H, 5-OH, 6-OH, 5,6(OH) 2 , 5-OCH 3 , 6-OCH 3 , 5,6-(OCH 3 ) 2 , 5-OC 2 H 5 , 6-OC 2 H 5 and 5,6-(OC 2 H 5 ) 2 ,
  • alkyl is preferably methyl, ethyl, propyl or butyl; wherein hydroxyalkyl is preferably hydroxyethyl, hydroxypropyl or hydroxybutyl ; wherein carboxymethoxyalkyl is preferably carboxymethoxymethyl, carboxymethoxyethyl, carboxymethoxypropyl.
  • carboxyethoxyalkyl is preferably carboxyethoxymethyl, carboxyethoxyethyl, carboxyethoxypropyl or carboxyethoxybutyl; wherein carboxypropyloxyalkyl is preferably carboxypropyloxymethyl, carboxypropyloxyethyl, carboxypropyloxypropyl or c ar boxy pro pyl ox y butyl .
  • the present invention provides compositions, containing a therapeutically active amount of at least one compound of this invention in pharmaceutically acceptable vehicles.
  • the present invention provides methods for the prevention of histamine-dependent disorders, such as allergic diseases, in a mammal predisposed to such diseases and the treatment of such diseases, by daily administering at least one antihistaminic compound of the invention, or a pharmaceutical composition containing at least one anti-histaminic compound of the invention to a mammal in need of such treatment.
  • Allergic diseases include, but are not limited to seasonal allergies, allergic rhinitis, cutaneous and ocular allergic reactions, asthma and the like.
  • the present invention provides methods for increasing the sensitivity of a tumor to an antineoplastic agent when the tumor is resistant to the antineoplastic agent by administering to the subject harboring the resistant tumor a potentiating agent of the present invention concurrently with an antineoplastic agent.
  • Resistance to the antineoplastic agent may be an intrinsic property of the tumor or develop in response to prior treatment with the same antineoplastic agent or to another antineoplastic agent.
  • An additional aspect of this invention is a method of selectively inhibiting the growth of tumor cells in a subject in need of such treatment by concurrently administering to the subject an antineoplastic agent and a potentiating agent.
  • the potentiating agent is administered in an amount effective to reduce the amount of the antineoplastic agent required to achieve the same growth inhibiting effect on the tumor cells by the antineoplastic agent achieved without the concurrent administration of the potentiating agent; or inhibit the development of multiple drug resistance in the tumor cells after treatment with the antineoplastic agent over time.
  • Another aspect of the present invention is a method of inhibiting multiple drug resistance in a subject in need of such treatment by administering the subject a potentiating agent in an amount effective to combat multiple drug resistance .
  • compositions of compounds of the present invention in combination with anti-inflammatory or analgesic agents are useful for the treatment of cough, cold, cold- and/or flu-like symptoms and the headache, pain, fever and general malaise associated therewith.
  • the aforementioned combinations may optionally include one or more active components from the class consisting of decongestants, cough suppresants/antitussives, and expectorants .
  • NORASTEMIZOLE commonly known as NORASTEMIZOLE
  • Example 2 was prepared from N-hydroxyethyl-norastemizole (Example 2) by reaction with bromoacetic acid and potassium carbonate in refluxing dimethyl formamide .
  • the antihistaminic activity of the compounds is determined in ligand binding assays. Published and well established methods are used (Chang, et al. J. Neurochemistry 1979, 32: 1653- 1663).
  • membranes rich in HI receptors are obtained from bovine cerebellum tissues and incubated with [ H]mepyramine, that binds to the Hl- receptors with high affinity.
  • the radioactive mepyramine is displaced by a test compound that is allowed to compete for the same HI binding sites.
  • the reaction is terminated by rapid vacuum filtration onto glass fiber filters.
  • the radioactivity that is trapped onto the filters is determined by liquid scintillography and IC 50 values are determined, demonstrating the relative affinities of the test compounds for the histamine HI receptors and compared to control values.
  • the anticholinergic activity of the . compounds is determined in ligand binding assays. Published and well established methods are used (Watson, M. et al., Life Sciences, 1983, 32: 3001-3011 ; Luthin, G.R. and Wolfe, B.B., Molec. Pharmac. 1984, 26: 164-169).
  • membranes rich in M l receptors are obtained from bovine striatal membranes and incubated with [ 3 H]pirenzepine, that binds to the M l -receptors with high affinity.
  • the radioactive pirenzepine is displaced by a test compound that is allowed to compete for the same M l binding sites.
  • the reaction is terminated by rapid vacuum filtration onto glass fiber filters.
  • the radioactivity that is trapped onto the filters is determined and IC50 values are determined, demonstrating the relative affinities of the test compounds for the muscarinic Ml receptors and compared to control values.
  • IC50 values are determined, demonstrating the relative affinities of the test compounds for the muscarinic Ml receptors and compared to control values.
  • the physostigmine-induced lethality test is a modification of the sedation test technique reported by COLLIER et al., Br. J. Pharmac, 1968, 32: 295-310.
  • physostigmine (1.9 mg/kg s.c.) produces 100% lethality when given to grouped mice with 10 animals in each plastic cage (approx. 1 1x26x13 cm).
  • Mice administered a sedating antihistamine prior to physostigmine are protected by the sedative effects of the drug and survive. Animals given a non-sedating test compound will not be protected and will therefore not survive.
  • test agents were administered orally dose of 0.25 Mmol/kg body weight, 60 minutes prior to physostigmine. The number of survivors are counted 20 minutes after physostigmine administration.
  • Chrysalis USA, Olyphant, PA, USA. Test results Sedative side effects.
  • Conc lusions Asicmi/.olc - although marketed as a non-sedating antihistamine caused sedation in the dose tested. Examples 2. 3, 4, and 7 did not cause sedation.
  • .Male Hartley guinea pigs weighing roughly 350-450 g, are used for this study The guinea pigs are acclimatized under a 12-hr light- dark cycle for a one-week period prior to the tests. On the day of the studs , the guinea pigs are injected with sodium hepa ⁇ n ( 1000 U kg, IP). Fifteen min. later they are anesthetized with CO, after which the heart are rapidly excised and placed in a beaker of ice-cold saline until contraction ceases (usually within 30 sec).
  • the isolated hearts are then mounted via the aortic root to cannulas and perfused retrogradely at a pressure of 88 mmHg with a physiological salt solution (PSS).
  • PSS physiological salt solution
  • the PSS is maintained at 37° C and contains: 1 1 8 mM NaCl, 4.7 mM KCI. 2.25 mM CaCL. 1 . 18 M KH PO,. 1. 17 mM MgS0 , 25 mM NaHCO,, and 11 mM dextrose.
  • the PSS is aerated with a mixture of 95% O, and 5% C0 2 at pl l 7.4.
  • the hearts are paced at a rate of 225 bpm within a waterjacketed organ bath which is maintained at 37°C. Each heart is allowed to stabil ize for 1 0- 1 5 min.. during which time a Millar pressure transducer is placed in the lumen of the left ventricle via a small incision in the left atrium. The Millar pressure transducer is used to measure left ventricular pressure. The following measurements are made prior to and following treatment with each concentration of test compound or reference agent: : - +dP/dt m. left ventricular end-diastolic pressures
  • a decreased dP/dt m ⁇ in the lollowmg lablc indicates a decreased rate of pressure development in the lclt ventricle and is an indicator of a cardiodepresMve cllcel ol the test compound.
  • Example 1 100 82 76 - 66
  • Example 1 1 00 1 50 1 70 - - 2 1 0
  • An additional aspect of this invention is a method of selectively inhibiting the growth of tumor cells in a subject in need of such treatment by concurrently administering to the subject an antineoplastic agent and a potentiating agent.
  • the potentiating agent is administered in an amount effective to reduce the amount of the antineoplastic agent required to achieve the same growth inhibiting effect on the tumor cells by the antineoplastic agent achieved without the concurrent administration of the potentiating agent; or inhibit the development of multiple drug resistance in the tumor cells after treatment with the antineoplastic agent over time.
  • Another aspect of the present invention is a method of inhibiting multiple drug resistance in a subject in need of such treatment by administering the subject a potentiating agent in an amount effective to combat multiple drug resistance.
  • a preferred category of multiple drug resistant tumor cells to be treated by a method of the present invention are multiple drug resistant cells characterized by the multidrug transporter, mediating continuous pumping of antineoplastic agents out of the tumor cells.
  • the multidrug transporter protein is described in M. Gottesman and I. Pastan, J. Biol. Chem. 1988, 263 , 12163 and in A. Fojo et al. Cancer Res. 1985, 45, 3002.
  • tumor cells treated by the present invention are preferably those characterized by the expression of the multidrug transporter protein at high levels, or the ability to express the multidrug transporter protein upon stimulation by an antineoplastic agent.
  • tumor cells which express the multidrug transporter at high levels are adenocarcinoma cells, pancreatic tumor cells, carcinoid tumor cells, chronic myelogenous leukemia cells in blast crisis, and non-small cell lung carcinoma cells.
  • a preferred group of tumor cells for treatment in the present invention are the adenocarcinomas, including adenocarcinomas of adrenal, kidney, liver, small intestine and colon tissue, with kidney adenocarcinoma cells particularly preferred.
  • Preferred antineoplastic agents for use in the present invention are those to which tumor cells develop resistance.
  • exemplary of such antineoplastic agents are vinca alkaloids, epipodophyllotoxins, anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, taxol, colchicine, cytochalasin B, emetine, maytansine, and amsacrine ("mAMSA").
  • mAMSA vinca alkaloids, epipodophyllotoxins. anthracycline antibiotics, actinomycin D and plicamycin.
  • the potentiating agents of the present invention are administered in an amount effective to enhance the efficacy of the antineoplastic agent.
  • the potentiating agent is preferably administered in a total amount per day of not more than about 50 mg/kg body weight, more preferably not more than 25 mg/kg, and most preferably not more than about 5 mg/kg.
  • the potentiating agent is preferably administered in a total amount per day of at least 0.01 mg/kg, more preferably at least about 0.1 mg kg, and most preferably at least about 1 mg/kg.
  • the potentiating agent may be administered once or several times a day .
  • a prophylactic or therapeutic dose of the compounds of this invention in the acute or chronic management of disease will vary with the severity and nature of the condition to be treated and the route of administration.
  • the dose and the frequency of the dosing will also vary according to the age, body weight and response of the individual patient.
  • the total daily dose range for the compounds of this invention for the conditions described herein is from about 1 mg to about 100 mg in single or divided doses, preferably in divided doses.
  • the therapy can be initiated at a lower dose, and may be increased up to about 100 mg depending on the patient's global response.
  • Any suitable route of administration may be employed for providing the patient with an effective dosage of the compounds of this invention.
  • oral, sublingual, rectal, parental (subcutaneous, intramuscular, intravenous), ocular, dermal, transdermal, aerosol and like forms of administration may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, micro- encapsulated systems, sprays, eye drops, dry powders, transdermal delivery systems, and the like.
  • the compound astemizole has the drawback of being very slowly metabolized in the body, causing the drug to have a pharmacokinetic half-life (T 1/2B) up to 19 days.
  • T 1/2B pharmacokinetic half-life
  • Hismanal® drug astemizole
  • the compounds of the present invention are hydroxylated, making the molecules predisposed to glucuronidation, and therefore of significantly shorter duration than astemizole.
  • the pharmacokinetic half-lives (T1/2B) of the compounds of the present inventions have been estimated at not more than 20 hours.
  • pharmaceutically acceptable salts or “a pharmaceutically acceptable salt thereof” refer to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids or bases or organic acids or bases.
  • suitable pharmaceutically acceptable acid addition salts for the compound of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pathothenic, phosphoric, p-toluenesulfonic, succinic, sulfuric, tartaric, and the like.
  • bases include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc
  • appropriate organic bases may be selected, for example, from N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine.
  • compositions of the present invention comprise at least one compound of the present invention as an active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
  • the compositions of the present invention include suspensions, solutions and elixirs; aerosols; or solid dosage forms. Carriers such as starches, sugars, and microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like are suitable in the case of oral solid preparations (such as powders, capsules, and tablets), and oral solid preparations may be preferred over the oral liquid preparations for administration to adults, while oral liquid preparations may be preferred for administration to children.
  • compositions of the present invention suitable for oral administration may be presented as discrete unit dosage forms such as capsules, cachets, or tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • tablets and capsules represent one of the more advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed.
  • a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersing agent.
  • Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • tablets may be coated by standard aqueous or nonaqueous techniques. All of the foregoing techniques are well know to persons of skill in the pharmaceutical art.
  • Each tablet may contain from about 0.5 mg to about 25 mg of the active ingredient. The following examples demonstrate how tablets and capsules may be formul ated .
  • the active ingredient is sieved through a suitable sieve and blended with the lactose until a uniform blend is formed. Suitable volumes of water are added and the powders are granulated. After drying, the granules are then screened and blended with the magnesium stearate. The resulting granules are then compressed into tablets of desired shape. Tablets of other strengths may be prepared by altering the ratio of active ingredient to the excipient(s) or the compression weight.
  • the active ingredient is sieved and blended with the excipients.
  • the mixture is filled into suitably sized two-piece hard gelatin capsules using suitable machinery.
  • Other doses may be prepared by altering the fill weight and if necessary, changing the capsule size to suit.
  • the compounds of the present invention may also be administered by controlled release means and delivery devices such as those described in U.S. Patent Nos.: 2.538, 127; 3 ,536,809; 3 ,598, 123 ; 3,845,770; 3,916,899; 4,008,719; 4,698,359; 5 ,250,287 ; 5 ,464,387; 5 ,693,608 and PCT application WO92/20377, the disclosures of which are hereby incorporated by reference.
  • compounds of the present invention may inhibit the cellular release of histamine and inflammatory mediators, which will add to the therapeutic usefulness of compositions containing these compounds.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une série d'hétérocyclyl-pipéridineamines substitués, dotés de propriétés antihistaminiques utiles, ainsi que des compositions et procédés d'utilisation de ces composés.
PCT/US1998/002857 1997-02-18 1998-02-12 Composes d'antagonistes d'histamine non sedatifs, compositions et procedes d'utilisation de ces composes WO1998035677A1 (fr)

Priority Applications (1)

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AU61657/98A AU6165798A (en) 1997-02-18 1998-02-12 Non-sedating histamine antagonist compounds, compositions and methods of use thereof

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US3883597P 1997-02-18 1997-02-18
US60/038,835 1997-02-18

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WO1998035677A1 true WO1998035677A1 (fr) 1998-08-20

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10160796B2 (en) 2016-09-08 2018-12-25 Emergo Therapeutics, Inc. Mast cell stabilizers for treatment of hypercytokinemia and viral infection
CN114702390A (zh) * 2022-03-08 2022-07-05 常州佳德医药科技有限公司 一种4-氯-3-硝基苯甲醚的制备方法
US11478463B2 (en) 2016-10-18 2022-10-25 Emergo Therapeutics, Inc. Mast cell stabilizers for treatment of chronic inflammatory conditions

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US5340565A (en) * 1987-08-25 1994-08-23 Oxi-Gene, Inc. Tumor or cancer cell killing therapy and agents useful therefor

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US5340565A (en) * 1987-08-25 1994-08-23 Oxi-Gene, Inc. Tumor or cancer cell killing therapy and agents useful therefor

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10160796B2 (en) 2016-09-08 2018-12-25 Emergo Therapeutics, Inc. Mast cell stabilizers for treatment of hypercytokinemia and viral infection
US10494420B2 (en) 2016-09-08 2019-12-03 Emergo Therapeutics, Inc. Mast cell stabilizers for treatment of hypercytokinemia and viral infection
US10501527B2 (en) 2016-09-08 2019-12-10 Emergo Therapeutics, Inc. Mast cell stabilizers for treatment of hypercytokinemia and viral infection
US10787502B2 (en) 2016-09-08 2020-09-29 Emergo Therpeutics, Inc. Mast cell stabilizers for treatment of hypercytokinemia and viral infection
US11072648B2 (en) 2016-09-08 2021-07-27 Emergo Therapeutics, Inc. Mast cell stabilizers for treatment of fever
US11478463B2 (en) 2016-10-18 2022-10-25 Emergo Therapeutics, Inc. Mast cell stabilizers for treatment of chronic inflammatory conditions
CN114702390A (zh) * 2022-03-08 2022-07-05 常州佳德医药科技有限公司 一种4-氯-3-硝基苯甲醚的制备方法
CN114702390B (zh) * 2022-03-08 2024-07-30 常州佳德医药科技有限公司 一种4-氯-3-硝基苯甲醚的制备方法

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