WO1998035677A1

WO1998035677A1 - Non-sedating histamine antagonist compounds, compositions and methods of use thereof

Info

Publication number: WO1998035677A1
Application number: PCT/US1998/002857
Authority: WO
Inventors: A. K. Gunnar Aberg; Ronald E. Weishaar; Philip M. Carabates; George E. Wright; Jan L. Chen
Original assignee: Bridge Pharma Inc
Current assignee: Bridge Pharma Inc
Priority date: 1997-02-18
Filing date: 1998-02-12
Publication date: 1998-08-20
Anticipated expiration: 1999-08-18
Also published as: AU6165798A

Abstract

Disclosed are a series of substituted heterocyclyl-piperidineamines, having useful antihistaminic properties, compositions and methods of use thereof.

Description

NON-SEDATING HISTAMINE ANTAGONIST COMPOUNDS, COMPOSITIONS AND METHODS OF USE THEREOF

BACKGROUND OF THE INVENTION

Field of the invention.

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.

More particularly, 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 .

Reported Development.

compounds are well-known in the prior art. Thus 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.

Compounds related i structure to those of the present invention are disclosed in U.S. Patent No. 4,219,559. The compounds disclosed in said patent are substituted and unsubstituted N-heterocyclyl-4- piperidine-amines. Other related disclosures include the following: J. Med. Chem. (1985) 28, 1934-1943 discloses the following compounds:

where

L is H, CH₃ or CH₂CH₂OH; and R is H. The publication teaches that these compounds have low oral activity.

U.S. Patent No. 4,835,161 discloses, inter alia, the compound:

where

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. Furthermore, 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. SUMMARY OF THE INVENTION

In accordance with the present invention, compounds having anti-histamine activity are provided comprising the formula

or pharmaceutically acceptable salts thereof, wherein:

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-OCH₃, 6-OCH₃, 5,6-(OCH₃)₂, 5-OC₂H₅, 6-OC₂H₅ and 5,6-(OC₂H₅)₂,

wherein alkyl is preferably methyl, ethyl, propyl or butyl; wherein hydroxyalkyl is preferably hydroxyethyl, hydroxypropyl or hydroxybutyl ; wherein carboxymethoxyalkyl is preferably carboxymethoxymethyl, carboxymethoxyethyl, carboxymethoxypropyl. or c arboxymethoxy butyl ; wherein carboxyethoxyalkyl is preferably carboxyethoxymethyl, carboxyethoxyethyl, carboxyethoxypropyl or carboxyethoxybutyl; wherein carboxypropyloxyalkyl is preferably carboxypropyloxymethyl, carboxypropyloxyethyl, carboxypropyloxypropyl or c ar boxy pro pyl ox y butyl .

In another aspect, the present invention provides compositions, containing a therapeutically active amount of at least one compound of this invention in pharmaceutically acceptable vehicles.

In still another aspect, 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.

In still another aspect, 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 .

The 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 .

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention can be prepared by the synthetic schemes shown hereunder. Scheme I - Synthesis of Example 4

trample ₄

Scheme I! - Synthesis of methoxylated intermediates

5-melhoxy intermediate 6-met oxy intermediate

Scheme HI - Synthesis of hydro xy analogs

5-hydroxy analogs L = Me, CH₂CH2θH

6- ydroxy analogs L = MΘ, CH₂CH₂OH

Scheme IV - Synthesis of Example 7

[E. Scheme I]

Example 7

Scheme V - Synthesis of 5,6-dihydroxy analogs

^K.C03

Example 1.

Utilizing appropriate starting materials, the compound having the formula,

commonly known as NORASTEMIZOLE, was prepared according to methods known in the prior art (J. Med. Chem. 1985, 28: 1934-1943).

Example 2.

Utilizing appropriate starting materials, the compound having the formula,

was prepared according to methods known in the prior art (J. Med. Chem. 1985, 28: 1934-1943).

Example 3.

Utilizing appropriate starting materials, the compound having the formula,

was prepared according to methods known in the prior art (J. Med. Chem. 1985, 28: 1934-1943). Example 4.

Utilizing appropriate starting materials, the compound having the formula,

was prepared according to Scheme I and as described hereinunder:

Preparation of A.

A solution of 4-methoxy-2-nitroaniline ( 106 grams) and 4- dimethylaminopyridine (6 grams) in 600 ml of pyridine was stirred and treated with 4-fluorobenzoyl chloride (100 grams) during 5 minutes. After 60 minutes stirring, the solution was poured into 2 L of water, and the yellow solid was collected by filtration. The chloroform layer was concentrated and the solid filtered and dried at 60 °C in a vacuum oven, yielding 168.4 grams of A (92%), m.p. 137-138 °C.

Preparation of B.

Compound A (29 grams) was added to a suspension of palladium on carbon ( 1.5 grams, 10%) in 500 ml of 95% ethanol. The mixture was heated to reflux with stirring, and ammonium formate (20 grams) was added in portions during 5 minutes causing an exothermic reaction. After an additional 45 minutes reflux the precipitate was collected by filtration, washed several times with acetone, and the acetone washings were evaporated to give a white solid. After washing with water and drying at 60 °C in vacuo, 25.4 grams (98%) of B was obtained, m.p. 177- 178 °C.

Preparation of C.

Compound B (25 grams) was added in portions to a solution of lithium aluminum hydride (8 grams) in 950 ml tetrahydrofuran. The suspension was stirred at reflux for 6 hours, and allowed to stand overnight. The mixture was filtered through Celite, and the Celite was washed several times with dichloromethane. After evaporation of solvents a red oil was obtained that crystallized on standing giving 23 grams of C. Preparation of D.

Compound C (23 grams) and N-ethoxycarbonyl 4-thiocyanatopiperidine (2.3 grams) [prepared according to J. Med. Chem. 28, 1985: 1925-1933] were added to 250 ml of methanol, and the solution was refluxed for 1 hour. The solution was concentrated in vacuo yielding compound D as a foam which was not purified.

Preparation of E.

S solution of crude D in 500 ml of absolute ethanol was treated with yellow mercuric oxide (38.2 grams) and sulfur (0.6 grams). After reflux for 3 hours the black solution was filtered, and the filtrate was concentrated to a foam. The foam was dissolved in 130 ml of 1- chlorobutane and diluted into 425 ml of diisopropyl ether. After stirring for several hours the tan solid which was formed was filtered and crystallized several times from toluene (using activa-ted charcoal), to yield 14.6 grams (40%) of compound E, m.p. 151-154 °C.

Example 4.

A solution of compound E ( 1.94 grams) in 30 ml of 48% hydrobromic acid was refluxed for 3 hours. The solution was evaporated leaving a gum, which was suspended in 20 ml of water and concentrated to a solid. After treatment with ethanol and evaporation, the solid was crystallized from 2-propanol and dried at 60 °C in vacuo, yielding 2.1 grams (89%) of the hydrobromide salt of Example 4, m.p. 320-322 °C. The hydrochloride was obtained by making a solution of the hydrobromide alkaline with concentrated ammonium hydroxide, evaporation to leave a gum, and dissolving the gum in tetrahydrofuran. Concentrated hydrochloric acid was added, and the solution was concentrated to give a tan solid, which was crystallized twice from ethanol to give the hydrochloride, m.p. 275-280 °C.

Example 5,

Utilizing appropriate starting materials, the compound having the formula

was prepared according to Scheme III, utilizing the 5-methoxy intermediate prepared according to Scheme II.

Example 6 ,

Utilizing appropriate starting materials, the compound having the formula

was prepared according to Scheme III, utilizing the 6-methoxy intermediate prepared according to Scheme II.

Example 7

Utilizing appropriate starting materials, the compound having the formula

was prepared according to Scheme IN as described hereinunder. Preparation of A.

A solution of compound E of Scheme I (5.3 grams) in 70 ml of methanol was treated with 15.7 grams of 85% potassium hydroxide. After reflux for 23 hours the solution was acidified with acetic acid, concentrated to dryness in vacuo, and the residue made alkaline with concentrated ammonium hydroxide. The solution was extracted three times with chloroform, and the extracts evaporated to give a white foam. After evaporation with dichloromethane the white solid was collected by filtration and dried at 60 °C in vacuo, giving 4 grams (89%) of compound A, m.p. 159- 160 °C.

Preparation of B.

Ethylene carbonate ( 1 gram) and potassium carbonate (0.3 gram) were added to a solution of compound A (3.2 grams) in 15 ml dimethylformamide. After 3 hours at reflux, the cooled solution was diluted to 200 ml with water and extracted three times with dichloromethane. After washing with water the extracts were evaporated leaving a brown oil. Treatment with ethereal hydrogen chloride gave a gum, which was stirred with a 9: 1 mixture of ethyl acetate:butanone. The resulting solid was crystallized from absolute ethanol, yielding 0.5 gram ( 12%) of compound B as the hydrochloride, m.p. 260-263 °C.

Example 7.

Compound B was converted to the free base. A solution of the free base (540 mg) in 50 ml of 1 ,2-dichloroethane was treated with a solution of boron tribromide:dimethyl sulfide complex ( 1.27 grams) in 10 ml of the same solvent. After reflux for 1 .5 hours the mixture containing a white precipitate was cooled, and 10 ml of methanol were added dropwise. After reflux for an additional 1 hour the solution was concentrated to a gum. The product was purified by preparative thin layer chromatography ( 1 mm silica gel, 88: 12 chloroform:2% isopropylamine in methanol). The product was treated with ethereal hydrogen chloride, and the solid was filtered and dried at 60 °C in vacuo, yielding 613 mg (90%) of Example 7 as the hydrochloride, M.P. 125- 130 °C.

[An alternate method of preparing Example 7 employs the sequence of Scheme III, utilizing the 5-methoxy intermediate of Scheme II.] E ample 8 ,

Utilizing appropriate starting materials, the compound having the

formula

was prepared according to Scheme III.

Example 9.

Utilizing appropriate starting materials, the compound having the formula

was prepared from N-hydroxyethyl-norastemizole (Example 2) by reaction with bromoacetic acid and potassium carbonate in refluxing dimethyl formamide .

Example 10.

Utilizing appropriate starting materials, the compound having the formula

was prepared by reaction of Exemple 8 with bromoacetic acid and potassium carbonate in refluxinf dimethylformamide, followed by demethylation according to Scheme III. Example 1 1.

Utilizing appropriate starting materials, the compound having the formula

was prepared by reaction of the 6-methoxy isomer [corresponding to Example 8] with bromoacetic acid and potassium carbonate in refluxing dimethylformamide, followed by demethylation according to Scheme III .

Example 12.

Utilizing appropriate starting materials, the compound having the formula

was prepared by reaction of the methylenedioxy intermediate of

Scheme V, where L = CH₂CH₂OH, with bromoacetic acid and potassium carbonate in refluxing dimethylformamide, followed by demethylation according to Scheme V. Example 13.

Utilizing appropriate starting materials, the compound having the formula

was prepared according to Scheme V.

Example 14.

Utilizing appropriate starting materials, the compound having the formula

was prepared according to Scheme V.

Compounds of the present invention were tested for the following effects utilizing art accepted methods referred hereunder:

A. Biological effects: H., receptor affinity.

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). In short, 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 IC₅₀ values are determined, demonstrating the relative affinities of the test compounds for the histamine HI receptors and compared to control values.

Test results: H, receptor affinity :

Test Compound IC50 (M)

Astemizole 1.76 x 10-8

Example 1 2.21 x 10-9 ( norastemizole)

Example 2 1.18 x 10-8

Example 3 3.04 x 10-9

Example 4 3.75 x 10-9

Example 7 2.32 x 10-8

Example 8 > 1.0 x 10-7

Conclusions: All compounds with the exemption of Example 8 were potently binding to histamine- 1 receptors (antihistamines).

B. Biological effects : Anticholinergic side effects.

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). In short, membranes rich in M l receptors are obtained from bovine striatal membranes and incubated with [³H]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. Experiments performed by NOVASCREEN, Baltimore, MD, USA.

Test results: M, receptor affinity:

Test Compound IC50 (M)

Astemizole 1.12 x 10-6

Example 1 2.27 x 10-7

(norastemizole)

Example 2 8.27 x 10-7

Example 3 2.61 x 10-7

Example 4 1.06 x 10-6

Example 7 »10-5

Example 8 »10-5

Conclusions: The ratios between histaminic and cholinergic receptor affinities were approximately 100 for the reference compounds and more than 1000 (too low activity to be measured) for the compound of Examples 7 and 8.

C. Biological effects: Sedative side effects.

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. In short, 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. In the present study, 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. Experiments performed by Chrysalis USA, Olyphant, PA, USA. Test results : Sedative side effects.

Percentage of

Test Compound A nimals Sedated

Vehicle (0.257r mcthvl cellulose) 0

Astemizole 9 0

Example 1 ( norastemizole) 1 0

Example 2 0

Example 3 0

Example 4 0

Example 7 0

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.

D. B iological effects : Cardiac side effects.

.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 hepaπn ( 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). 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% C0₂ 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

Two to three measurements are made during the stabilization period. Once the cardiodynamic parameters have stabilized, a procedure similar to that previously described by Haleen et al. (1) is used to assess the direct effects of each test compound, on the isolated guinea pig heart. Increasing concentrations of the test compound are added to the perfusate at 10-15 min. intervals (depending on the time required to obtain a stable response). Measurements are repeated during the last one to two min. of the perfusion period for each concentration of the test compound. Each treatment group contains three hearts and the results are expressed in percent of the average basal (pie-drug) value.

Rclcicncc Haleen Si Stcltcn R. Sircar 1. Ma|or T. Taylor MD. Pugsley TA,

Weishaar RU J Pharm Ther. 198^L>; 250: 22.

Experiments pcπormed

MED Inc . Troy, NY, USA

Test results: Cardiac side effects.

Left λcturicular contractility (dP/dt_{m Λ x})__

A decreased dP/dt_{m λ} 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.

Vehicle h s i value 1375 ± lfW mmHg/scc. All values expressed as percent of group basal values

dP/dt_max in percent of basal (predrug) values Compound Basal O.lμM l.OμM 3.0μM lO.OμM

Astemizole 100 100 74 48 *)

Example 1 100 82 76 - 66

(Nori'ste i/ole >

Example 2 100 116 104 - 64

Example 3 100 79 66 - 47

*) Two .'l three hearts could not be paced at this concentration because of cardio- depres^ani ..emit) ot the lesl compound. Left ventricular end-diastolic pressure (LVEDP)

An significantly increased LVEDP by a drug indicates a disability of the cardiac muscle to empty the heart and is a strong indicator of cardiodepressive activity. Vehicle basal value 9 + 2 mmHg. All values expressed as % of group basal values.

LNEDP in percent of basal (predrug) values Compound Basal O.lμM l.OμM 3.0μM lO.OμM

Astemizole 1 00 1 63 23 8 350 *)

Example 1 1 00 1 50 1 70 - - 2 1 0

(Norastemizole)

Example 2 1 00 88 1 00 - - 1 3 8

Example 3 1 00 1 1 4 1 29 - - 1 3 9

*) Two of three hearts could not be paced at this concentration because of cardio- depressant activity of the test compound.

Conclusions: Drug-induced impairment of cardiac contractility was characterized by decreased maximal contractile force development of the left ventricle (dP/dt_max) and increased left ventricular end-diastolic pressure (LVEDP). Astemizole significantly affected both parameters, norastemizole significantly increased LVEDP, while the compounds of Examples 2 and 3 were less cardiodepressant.

Multiple drug resistance.

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. Thus, 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.

Exemples of tumor cells which express the multidrug transporter at high levels (intrinsically resistant cells) 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"). Preferred are vinca alkaloids, epipodophyllotoxins. anthracycline antibiotics, actinomycin D and plicamycin. These antineoplastic agents are described in detail in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 1225 - 1287 (9th ed. 1995).

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 .

Clinical doses of compounds of the present invention.

The magnitude of 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. In general, 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. In managing the patient, 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. It is further recommended that patients over 65 years and those with impaired renal or hepatic function initially receive low doses and that they be titrated based on individual response(s) and plasma drug level(s). It may be necessary to use dosages outside these ranges, as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response. The terms "a therapeutically effective amount" and "an amount sufficient to treat an allergic reaction " are encompassed by the above-described dosage amounts and dose frequency schedule.

Routes of administration of the present invention.

Any suitable route of administration may be employed for providing the patient with an effective dosage of the compounds of this invention. For example, 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.

Pharmacokinetic considerations.

The compound astemizole, the chemical structure of which is previously shown, 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. Thus, there is a high risk for drug accumulation in the patient and the drug astemizole (Hismanal®) carries a serious warning to patients not to administer more than 10 mg of the drug on a daily basis. 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.

Pharmaceutical acceptable salts and pharmaceutical compositions of the present invention.

The terms "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. Examples of 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. Examples of such bases include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, while appropriate organic bases may be selected, for example, from N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine.

The pharmaceutical 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. Pharmaceutical 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. In general, 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.

Because of their ease of administration, tablets and capsules represent one of the more advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed. For example, 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. If desired, 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 .

Oral Formulation - Tablets.

Formula Quantity per Tablet in mg.

Tablet Tablet Tablet A B C

Active ingredient according to Example 7 5.0 10.0 20.0

Lactose BP 148.5 143.5 133.5

Starch BP 30.0 30.0 30.0

Pregelatinized Maize 15.0 15.0 15.0 Starch BP

Magnesium Stearate 1.5 1.5 1.5

Compression Weight 200.0 200.0 200.0

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.

Oral Formulation - Capsules

Formula Quantity per Capsule in mg.

Capsule Capsule Capsule A B C

Active ingredient according to Example 4 5 .0 1 0 .0 20 .0

Starch 1500 94 .0 8 9 .0 7 9 .0

Magnesium Stearate BP 1 .0 1 .0 1 .0

Compression Weight 1 00 .0 1 00 .0 1 00 .0

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.

In addition to the common dosage forms set out above, 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.

EQUIVALENTS

Those skilled in the art realize that 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.

Claims

WHAT IS CLAIMED IS:

1 . A compound of the formula

or a pharmaceutically acceptable salt thereof,

wherein L is selected from the group consisting of alkyl, hydroxyalkyl, chloroethyl, acetonitrile, alkylcarbonyl, carboxymethoxyalkyl, carboxyethoxyalkyl, and carboxypropyloxyalkyl; and wherein R is selected from the group consisting of 5-OH, 6-OH, 5,6- 6-OCH₃, 5,6-(OCH₃)₂, 5-OC,H₅, 6-OC,H₅, and

2. A compound of Claim 1 , wherein alkyl is methyl, ethyl, propyl or butyl; wherein hydroxyalkyl is hydroxyethyl, hydroxypropyl or hydroxybutyl ; wherein carboxymethoxyalkyl is carboxymethoxymethyl, carboxymethoxyethyl, carboxymethoxypropyl or carboxy- methoxybutyl ; wherein carboxyethoxyalkyl is carboxyethoxymethyl, carboxyethoxy- ethyl , carboxyethoxypropyl or carboxyethoxybutyl; wherein carboxypropyloxyalkyl is carboxypropyloxymethyl, carboxypropyloxyethyl , carboxypropyloxypropyl or c ar bo xy propyl ox y butyl .

A compound of Claim 1 , where L consists of hydroxyethyl and R consists of 5-OH, or a pharmaceutically acceptable salt thereof.

4. A compound of Claim 1 , where L consists of carboxymethoxyethyl and R consists of 5-OH or a pharmaceutically acceptable salt thereof.

5. A solid, semi-solid, liquid, suspension, aerosol or transdermal pharmaceutical composition, comprising an antihistaminic effective amount of a compound of the formula of Claim 1 , or a pharmaceutically acceptable salt thereof, in combination with pharmaceutically acceptable carrier or carrier system.

6. A composition as defined in Claim 5 in unit dosage form.

7. A method for preventing or treating allergic disorders in a mammal comprising: administering a therapeutically effective amount of a compound of the formula of Claim 1 to the mammal in need of such prevention or treatment, while avoiding the concomitant liability of adverse side-effects selected from the group consisting of sedation, memory impairment, cardiodepression, arrhythmogenicity, dry mouth, blurry vision, tachycardia, drug accumulation due to pharmacokinetic half-life of more than 48 hours.

8. The method of administering by parenteral, transdermal, ocular, nasal, sublingual, oral or by rectal administration an antihistaminic pharmaceutical composition, comprising an inert carrier material and as an active ingredient an effective antihistaminic amount of a chemical compound of Claim 1.

9. The method of administering a pharmaceutical composition comprising an antihistaminic compound of Claim 1 to a mammal suffering from an allergic disorder, said allergic disorder being selected from a group consisting of allergic rhinitis, atopic dermatitis, urticaria, retinopathy, pulmonary allergic disorders, asthma, bronchitis, cough or drug-induced airway hyperreactivity.

10. The method of Claim 9, wherein said antihistaminic compound is administered to said mammal in an amount of from about 0.5 mg to about 40 mg, once or more times per day.

1 1 . A method for preventing or treating allergic disorders in a mammal comprising: administering an effective amount of a compound having the structural formula

where n = 1 or 2 and the OH- groups are positioned as 5-OH, or 6-OH or

5 ,6-(OH)₂, or a pharmaceutically acceptable salt thereof, to a mammal in need of such prevention or treatment, while avoiding the concomitant liability of adverse side-effects selected from the group consisting of sedation, memory impairment, cardiodepression, arrhythmogenicity, dry mouth, blurry vision, tachycardia, drug accumulation due to pharmacokinetic half-life of more than 48 hours.

12. A method for preventing or treating allergic disorders in a mammal comprising: administering a pharmaceutically acceptable composition containing an effective antihistaminic amount of a compound of the formula of Claim 11 , or a pharmaceutically acceptable salt thereof, and a solid, a semi-solid, a liquid, a suspension, an aerosol or a transdermal carrier or carrier system.

13. A composition as defined in Claim 12 in unit dosage form.

14. The methods of administering by parenteral, transdermal, ocular, nasal, sublingual, oral or by rectal administration an antihistaminic pharmaceutical composition, comprising an inert carrier material and as an active ingredient an effective antihistaminic amount of a compound of the formula of Claim 11.

15. The method of administering a pharmaceutical composition comprising an antihistaminic compound of the formula of Claim 11 to a mammal suffering from an allergic disorder, said allergic disorder being selected from a group consisting of allergic rhinitis, atopic dermatitis, urticaria, retinopathy, pulmonary allergic disorders, asthma, bronchitis, cough or drug-induced airway hyperreactivity.

16. The method of Claim 15, wherein said antihistaminic compound is administered to said mammal in an amount of from about 0.5 mg to 40 mg, once or more times per day.

17. The method of increasing the sensitivity of a tumor to an antineoplastic agent, which tumor is harbored in a subject and which tumor is resistant or partly resistant to said antineoplastic agent, comprising concurrently administering to said subject said antineoplastic agent and a potentiating agent, said potentiating agent selected from the class consisting of a compound of the formulas of Claim 1, or a pharmaceutically acceptable salt thereof.

1 8. The method of increasing the sensitivity of a tumor to an antineoplastic agent, which tumor is harbored in a subject and which tumor is resistant or partly resistant to said antineoplastic agent, comprising concurrently administering to said subject said antineoplastic agent and a potentiating agent, said potentiating agent selected from the class consisting of a compound of the formulas of Claim 11 , or a pharmaceutically acceptable salt thereof.

1 9. The method of treating cough, cold, cold-like or flu symptoms and the discomfort, headache, pain, fever and general malaise associated therewith, in a mammal, while avoiding the concomitant liability of adverse side-effects selected from the group consisting of sedation, memory impairment, cardiodepression, arrhythmogenicity, dry mouth, blurry vision, tachycardia, drug accumulation due to pharmacokinetic half-life of more than 48 hours, comprising administering to said mammal a composition, said composition comprising (i) a therapeutically active amount of a compound of the formulas of Claim 1 , or a pharmaceutically acceptable salt thereof, together with one or more drugs of the class consisting on non-steroidal antiinflammatory agents, non-narcotic analgesics, decongestants, cough suppressants and expectorants .

20. The method of treating cough, cold, cold-like or flu symptoms and the discomfort, headache, pain, fever and general malaise associated therewith, in a mammal, while avoiding the concomitant liability of adverse side-effects associated with the administration of non-sedating antihistamines, cardiodepressive antihistamines, arrhythmogenic antihistamines or anticholinergic antihistamines, comprising administering to said mammal a composition, said composition comprising (i) a therapeutically active amount of a compound of the formulas of Claim 11 , or a pharmaceutically acceptable salt thereof, together with one or more drugs of the class consisting on non-steroidal antiinflammatory agents, non-narcotic analgesics, decongestants, cough suppressants and expectorants.