Claims
- 1. A compound of formula (1): ##STR24## or a pharmaceutically acceptable acid addition salt thereof in which R.sup.1 together with R.sup.3 forms a --CH.sub.2).sub.n -- group where n is 2, 3 or 4;
- R.sup.4 hydroxy or a phosphate group which is a group of the formula ##STR25## and q is 1 to 3; R.sup.5 is hydrogen, C.sub.1-4 alkyl, halogen, or amino;
- m is 2, 3 or 4; and
- R is a 2, 3, or 4-pyridyl or pyridyl N-oxide or N-C.sub.1 -C.sub.4 alkylpyridone group optionally substituted by one or two groups selected from C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy and hydroxymethyl.
- 2. A compound according to claim 1 in which R.sup.5 is hydrogen or halogen, n is 3, and m is 3.
- 3. A compound according to claim 1 in which R is 3-pyridyl, 6-methyl-3-pyridyl, 6-methyl-3-pyridyl N-oxide or 6-hydroxymethyl-3-pyridyl.
- 4. A compound according to claim 1 wherein R.sup.4 is hydroxy.
- 5. A compound according to claim 1 selected from the group consisting of
- 2-[3-(5,6,7,8-tetrahydroquinol-8-yl)propylamino]-3-hydroxy-5-(pyrid-3-ylmethyl)pyridine, and
- 2-[2-(5,6,7,8-tetrahydroquinol-8-yl)ethylamino]-3-hydroxy-5-(pyrid-3-ylmethyl)pyridine,
- or a pharmaceutically acceptable acid addition salt thereof.
- 6. A pharmaceutical composition having histamine H.sub.1 -antagonist activity which comprises, in an effective amount to produce said activity, a compound according to claim 1 and a pharmaceutically acceptable carrier.
- 7. A method of blocking histamine H.sub.1 -receptors which comprises administering to a subject an effective amount to block said receptors of a compound according to claim 1.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 8610867 |
May 1986 |
GBX |
|
Parent Case Info
This is a division of application Ser. No. 045,106 filed May 1, 1987 now U.S. pat. 4,764,519 issued Aug. 16, 1988.
This invention relates to certain pyridine derivatives, a process for their preparation, compositions containing them and their use as histamine H.sub.1 -antagonists.
Histamine, a physiologically active compound endogenous in mammals, exerts its action by interacting with certain sites called receptors. One type of receptor is known as a histamine H.sub.1 -receptor (Ash and Schild, Brit. J. Pharmac. 1966, 27, 427) and the actions of histamine at these receptors are inhibited by drugs commonly called "antihistamines" (histamine H.sub.1 -antagonists) a common example of which is mepyramine.
According to the present invention there are provided compounds of formula (1) : ##STR1## and pharmaceutically acceptable acid addition salts thereof in which R.sup.1 is hydrogen or can together with R.sup.3 form a --(CH.sub.2).sub.n - group where n is 2, 3 or 4;
Examples of alkyl groups for R.sup.3, R.sup.5 and the optional substituents in R are methyl, ethyl and n-propyl.
Examples of alkoxy groups for the optional substituents in R are methoxy, ethoxy and n-propoxy.
Examples of halogen atoms for R.sup.3 and R.sup.5 are fluorine, chlorine, bromine and iodine.
Examples of phosphate groups R.sup.4 are groups having the general formula: ##STR2## wherein q is 1 to 3. Preferably q is 1.
A first class of compounds of formula (1) in which R.sup.1 is hydrogen is illustrated by formula (2): ##STR3## in which R.sup.3, R.sup.4, R.sup.5, m and R are as defined for formula (1).
In this class of compound preferably the substituents have the following meanings : R.sup.3 is halogen, alkyl or amino, R.sup.5 is hydrogen, halogen or alkyl, and m is 3. Particularly R.sup.3 is alkyl (especially methyl) or amino and R.sup.5 is halogen (especially bromine) or alkyl (especially methyl). Particularly preferred meanings for combinations of R.sup.3 and R.sup.5 are R.sup.3 is methyl or amino and R.sup.5 is bromine.
A second class of compounds of formula (1) in which R.sup.1 and R.sup.3 together form a --(CH.sub.2).sub.n -- group is illustrated by formula (3): ##STR4## in which R.sup.4, R.sup.5, n, m and R are as defined for formula (1). For this class of compound preferably R.sup.5 is hydrogen or halogen (particularly bromine), particularly preferably hydrogen, and n is 3, and m is 3.
For both the compounds of formula (2) and formula (3) preferably R is 3- or 4-pyridyl or pyridyl-N-oxide optionally substituted by methyl, hydroxymethyl or methoxy.
Particularly preferably R is 3-pyridyl, 6-methyl-3-pyridyl, 6-methyl-3-pyridyl N-oxide or 6-hydroxymethyl-3-pyridyl.
Examples of preferred compounds of formula (1) are:
The compounds of formula (1) where R.sup.4 is hydroxy can exist in the zwitterionic forms, particularly when in aqueous solution. ##STR5## The compounds of formula (1) in which R is pyridyl substituted by hydroxy can also exist in tautomeric dihydropyridone forms. All such tautomers and zwitterionic forms are included within the scope of this invention.
The compounds of formula (3) exhibit optical isomerism and the present invention covers both optical isomers of these compounds in racemic and resolved states.
Solvates of compounds of the formula (1) and their salts, for example hydrates and alcoholates, are also within the scope of the present invention.
The compounds of formula (1) can be prepared from a 3-aminopyridyl derivative of formula (4): ##STR6## in which R.sup.6 and R.sup.7 have the same meanings as R.sup.3 and R.sup.5 in formula (1) except that any amino group present must be protected with an amino-protecting group which is stable under mild acidic conditions, and R.sup.1, m and R are as defined for formula (1). Examples of amino-protecting groups which are stable under mild acidic conditions are well known to the art, see for example "Protective Groups in Organic Synthesis", T. W. Greene, 1981 (Wiley), and acetyl and benzoyl are specific examples.
Suitably the compounds of formula (4) are diazotised to give a triazolopyridine of formula (5): ##STR7## in which R, R.sup.1, R.sup.6, R.sup.7 and m are as defined for formula (4). Suitably this diazotisation is carried out under acidic conditions. Suitably the diazotisation is carried out using sodium nitrite in aqueous acid, e.g. dilute sulphuric acid.
The triazolopyridine of formula (5) can be hydrolytically decomposed to give the compound of formula (1) wherein R.sup.4 is hydroxy with deprotection of any aminoprotecting groups present. Suitably this reaction is carried out in polyphosphoric acid. Suitably the reaction is carried out at a temperature of 150.degree. to 250.degree. C., preferably 190.degree. to 210.degree. C.
The amines of formula (4) can be prepared by reducing a nitro compound of formula (6): ##STR8## in which R, R.sup.1 and m are as defined for formula (1) and R.sup.6 and R.sup.7 are as defined for formula (4). When R.sup.6 or R.sup.7 are halogen a selective reducing agent will be necessary, for example hydrazine and Raney nickel, or stannous chloride.
The nitro compounds of formula (6) can be prepared by reacting an amine of formula (7): ##STR9## in which R.sup.1, R.sup.3, R.sup.5 and m are as defined for formula (1), except that when R.sup.3 and/or R.sup.5 are amino groups, these are optionally protected; with a compound of formula (8): ##STR10## in which R is as defined for formula (1) and Q is a leaving group displaceable with an amine; and thereafter, when R.sup.3 and/or R.sup.5 are unprotected amino, reacting these with a reagent suitable for introducing an amino protecting group. Examples of leaving groups displaceable with an amine are halogen, C.sub.1-4 alkylthio, and C.sub.1-4 alkoxy. Preferably Q is chlorine. Preferably the reaction is carried out in the absence of a solvent or in dipolar protic or dipolar aprotic solvent at an elevated temperature. Examples of protic solvents are C.sub.1-4 alkanols and examples of dipolar aprotic solvents are dimethylformamide, dimethylsulphoxide, pyridine, picolines and anisole. Preferably the reaction is carried out in ethanol at the reflux temperature of the reaction mixture. Preferably when Q is halogen an excess of a non-nucleophilic base is added. Examples of non-nucleophilic bases are pyridine and triethylamine.
The compounds of formula (8) in which Q is chlorine can be prepared by reacting a compound of formula (9): ##STR11## PG,9 in which R is as defined for formula (1), with a chlorinating agent. Preferably the chlorinating agent is phosphoryl chloride. The compounds of formula (8) in which Q is other than chlorine can be prepared from the compounds of formula (8) in which Q is chlorine or in the case of Q being alkylthio by reacting a compound of formula (9) with a thionating reagent such as phosphorus pentasulphide and alkylating the product.
The intermediates of formula (9) can be made by processes described in the Examples and processes analogous thereto.
The amines of formula (7) in which R.sup.3 and R.sup.1 together form a --(CH.sub.2).sub.n -- group and in which R.sup.5 is other than halogen can be prepared by reacting a compound of formula (10): ##STR12## where R.sup.8 is hydrogen, C.sub.1-4 alkyl, nitro or protected amino, and n is 2, 3 or 4, with a compound of formula (11):
Examples of strong bases are alkali metal hydrides, particularly sodium hydride. The reaction is carried out in the presence of a polar solvent for example dimethylsulphoxide. Preferably R.sup.9 is amino and the reaction is carried out using sodamide in liquid ammonia.
In formula (11) X can be chlorine, bromine, or iodine. Preferably X is chlorine when sodamide is the base.
The protected amino group can be converted into amino by standard methods, for example when it is phthalimido by reaction with concentrated hydrochloric acid or hydrazine.
Alternatively, the compounds of formula (10) can be reacted with an organolithium compound (e.g. phenyl-lithium or butyllithium) and subsequently reacted with a compound of formula (11). (See for example Aldrichimica Acta II, 15, (1978)).
The amines of formula (7) in which R.sup.3 and R.sup.1 together form a --(CH.sub.2).sub.n -- group and in which R.sup.5 is halogen can be prepared by carrying out a Sandmeyer reaction on a 3-amino compound of formula (12): ##STR13## (in which m and n are as defined for formula (1)) that is by diazotisation of the aromatic amino group under strongly acidic conditions and displacing the resulting diazo group with halogen.
The amines of formula (7) in which R.sup.5 is bromine can also be prepared by the direct bromination of the amines of formula (7) in which R.sup.5 is hydrogen. Preferably the bromination is carried out with electrophilic bromine, for example using bromine in sulphuric acid.
The amines of formula (7) in which R.sup.1 is hydrogen can be prepared by known methods, e.g. as described in EP No. 0068833.
Compounds of the formula (1) wherein R.sup.4 is a phosphate group can be prepared, for example, by reaction of triazolopyridines of the formula (5) with polyphosphoric acid under conditions designed to minimise hydrolysis of the phosphate to the corresponding free hydroxy compound.
Phosphates can also be prepared from the corresponding 3-hydroxypyridine of the formula (1) wherein R.sup.4 is hydroxy by methods known per se or analogous thereto, for example by reaction of the said 3-hydroxypyridine with the appropriate phosphorylhalide.
The histamine H.sub.1 -antagonist activity of the compounds of formula (1) can be demonstrated in vitro in the guinea pig ileum test. In this test an isolated portion of the guinea pig ileum is secured under tension (500 mg) between an anchorage and a transducer in a 10 ml tissue bath and immersed in magnesium free Tyrode solution with constant aeration at a temperature of 30.degree. C. The output from the transducer is amplified. The amplified output is in turn fed to a flat bed recorder. Measured amounts of histamine are added to the tissue bath so that the histamine concentration increases step-wise until the force of the contraction reaches a maximum. The tissue bath is washed out and filled with fresh magnesium free Tyrode solution containing compound under test. The solution is left in contact with the tissue for 8 min. and measured amounts of histamine are added again until a maximum contraction is recorded. The assay is repeated with increasing concentrations of test compound and the dose of histamine giving 50% of maximum contraction is noted. A dose ratio (DR) was calculated by comparing the concentrations of histamine required to produce 50% maximum response in the absence and in the presence of the antagonist. A plot of Log DR-1 against Log D (the concentration of compound under test) is made and the point of intersection with the Log (DR-1) ordinate is taken as the measure of the activity (pA.sub.2 value).
The activity of compounds of formula (1) as histamine H.sub.1 -antagonists can be demonstrated in vivo by the inhibition of histamine induced bronchoconstriction. Guinea pigs of either sex are anaesthetised by intraperitoneal injection of sodium pentobarbitone, 90 mg/kg. The trachea is cannulated. The animal is respired artificially with a fixed volume of air just adequate to inflate the lungs. The pressure needed to inflate the lungs is monitored from the respiratory system using a pressure transducer. Intravenous injection of histamine causes dose-dependent increases in the pressure to inflate the lungs reflecting the bronchoconstrictor action of histamine. Responses to histamine can be antagonised using histamine H.sub.1 -receptor antagonists.
Dose-response curves to histamine are established at 20, 40, 80, 160 and 320 nmols/kg. Antagonists are then administered by intravenous injection and 5 minutes later a new histamine dose-response curve is established increasing the doses of histamine as necessary. The effect of the antagonist can be quantified by the displacement, to the right, of the histamine dose-response curve, expressed as a dose-ratio. A series of doses of antagonists may be given to each animal allowing calculation of dose-ratios for each dose of antagonist.
The biological activities of the compounds of the Examples are described in Table 1 below.
In order to use the compounds of the invention as histamine H.sub.1 -antagonists, they can be formulated as pharmaceutical compositions in accordance with standard pharmaceutical procedure.
The invention also includes pharmaceutical compositions comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
Compounds of formula (1) and their pharmaceutically acceptable salts can be administered topically or systemically.
Topical formulations for administration to the skin include lotions and creams. Topical formulations for administration to the respiratory tract include solutions for application via a nebulizer or as an aerosol, or a microfine insufflatable powder. The active ingredient in an insufflatable powder has a small particle size i.e. less than 50 microns and preferably less than 10 microns. The active material is co-presented with a solid carrier for example lactose which has a particle size of less than 50 microns.
Systemic administration can be achieved by rectal, oral or parenteral administration. A typical suppository formulation comprises the active compound with a binding agent and/or lubricating agent for example gelatine or cocoa butter or other low melting vegetable waxes or fats. Typical parenteral compositions consist of a solution or suspension of the active material in a sterile aqueous carrier or parenterally acceptable oil.
Compounds of formula (1) which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation generally consists of a suspension or solution of the compound in a liquid carrier for example ethanol, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a capsule, the solid in granular form optionally with a binding agent is encased in a gelatin shell. Where the composition is in the form of a tablet, any suitable pharmaceutical carrier routinely used for preparing solid formulations can be used. Examples of such carriers include magnesium stearate, starch, lactose, glucose, sucrose, and cellulose. Preferably the composition is in unit dose form for example a tablet, capsule or metered aerosol so that the patient may administer to himself a single dose.
Where appropriate, small amounts of bronchodilators and anti-asthmatics for example sympathomimetic amines particularly isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives particularly theophylline and aminophylline; and corticosteroids particularly prednisolone and adrenal stimulants particularly ACTH can be included. As in common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned, in this case as a histamine H.sub.1 -antagonist for treatment of, for example, asthma, hayfever, rhinitis or allergic eczema.
Each dosage unit for oral administration contains preferably from 5 to 200 mg of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free base.
The pharmaceutical compositions of the invention will normally be administered to a man for the treatment of rhinitis, hayfever, bronchial asthma or allergic eczema. An adult patient will receive an oral dose of between 15 mg and 400 mg and preferably between 15 mg and 200 mg or an intravenous, subcutaneous or intramuscular dose of between 1 mg and 50 mg, and preferably between 1 mg and 10 mg of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day.
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
|
4532252 |
Sach |
Jul 1985 |
|
Divisions (1)
|
Number |
Date |
Country |
| Parent |
45106 |
May 1987 |
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Patent Grant
4863933
