NO763233L - PROCEDURES FOR THE PREPARATION OF A NITROCUMARINE. - Google Patents

Description

The invention relates to methods of production

of new nitrocoumarin derivs.

It is known that some types of cells are activated by antibody/antigen combinations and release substances that mediate an allergic response. It has been reported that SRS-A

(the slow-reacting substance in anaphylaxis) which is released from such cells which have been activated by antibody/antigen combinations, plays a significant role in the development of allergic and asthmatic phenomena.

In the applicant's BRD-Off.skrift 2418344 it is revealed that certain nitrocoumarins have useful activity in that they inhibit the release of mediator substances from cells that are activated by the type of antibody/antigen combination described above.

Applicant has now discovered that nitrocoumarin derivatives of formula (I) below have useful activity in mammals in that they inhibit the action of SRS-A and additionally protect against the antibody/antigen release of SRS-A and other mediators of the allergic response. These compounds are therefore useful in the prophylaxis and treatment of diseases where allergic mediator substances regulate the symptoms, e.g. in bronchial asthma,

rhinitis, hay fever, allergic eczema, etc.

According to the invention there is provided a nitrocoumarin of formula (I): and the pharmaceutically acceptable salts thereof, where R^ and R 2 each represent hydrogen or lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl or R^ and R 2 < when they are on neighboring carbon atoms, together represent a 1,4-buta-1,3-dienylene group or an alkylene group containing 3-5 carbon atoms. A represents a substituent of formula (II):-

which occupies position 6 or position 7 of the nitrocoumarin nucleus, where X is oxygen or a methylene group, and Q represents a linear alkylene group containing 1-8 carbon atoms, being a methylene group within the group Q, which is not a methylene covalently bound to an ether -oxygen, optionally substituted with hydroxyl, and R3#R4and R5each represent hydrogen, halogen, nitro, hydroxy, cyano, carboxyl, amino, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkoxycarbonyl, lower acyl, lower acyloxy, mono- and di-lower alkylamino, mono- and di-lower acylamino, phenyl, lower alkylphenyl, phenoxycarbonyl, benzyloxycarbonyl, or any two of R^#

R4 „ or Rbc when sitting on neighboring carbon atoms, together represent an alkylene group containing 3-5 carbon atoms, or a 1,4-buta-1,3-dienylene group.

The terms lower alkyl, lower alkenyl and lower alkynyl, lower alkoxy and lower acyl mean in this description such groups which contain 1-6 carbon atoms inclusive.

The term nitrocoumarin nucleus shall here mean a group of formula (III):-

and the positions referred to by number in the nitrocoumarin are as indicated above. Nitrocoumarins of formula (I) can occur in a number of tautomeric forms: - and it should be understood that where reference is made in this description to these nitrocoumarins, tautomeric forms of these compounds are also meant to be included. When reference is made herein to the "phenyl ring of the substituent A", this means the phenyl ring shown in formula (II) bearing the substituents R 3 , R 1 and R 1 , and the positions referred to by number in the phenyl ring in substituent .A, is as indicated below:-

Examples of suitable lower alkyl substituents falling within the definitions for R 1 to R 8 are methyl, ethyl, n- and iso-propyl, n-, iso and t-butyl.

Examples of suitable lower alkenyl groups represented by R 1 to R 5 are 2-propenyl; 2- and 3-butenyl; 2-, 3- and 4-pentenyl; 2-, 3-, 4- and 5-hexenyl; 1- and 2-methyl-2-propenyl; 1-, 2- and 3-methyl-2- and 3-butenyl; 1-, 2-, 3- and 4-methyl-2-, 3- and 4-pentenyl; 1- and 2-ethyl-2-propenyl; 1-, 2- and 3-ethyl-2- and 3-butenyl.

Examples of suitable lower alkynyl groups represented by to R(. "are. 2-propynyl; 2- and 3-butynyl; 2-, 3-. and 4-pen£ynyl; 2-, 3-, 4- and 5-hexynyl 1-, and 2-methyl-2-propynyl;

1-, 2- and 3-methylS2- and 3-butynyl; 1-, 2-, 3- and 4-methyl-2-, 3- and 4-pentynyl; 1- and 2-ethyl-2-propynyl; 1-, 2- and 3-ethyl-2- and 3-butynyl.

Examples of suitable lower alkoxy substituents falling within the definitions for R 1 to R 1 . are methoxy, ethoxy, n- and iso-propoxy, n-, iso- and t-butoxy. Examples of suitable lower acyl groups included within this definition of R.j to are acetyl, propionyl, n- and iso-butyryl. Examples of lower acyloxy substituents included within this definition of R 1 to R 2 are methoxycarbonyl, ethoxycarbonyl, n- and iso-propoxycarbonyl, n- and iso-butoxycarbonyl. These previously mentioned examples of lower-alkyl and lower-acyl groups are also suitable as examples of the lower-alkyl and lower-acyl groups contained in mono- and di-lower-alkyl and lower-acylamino substituents included in the definition of R^ to R^. The suitable hal<p>gene atoms included within the definition of

R 8 to R 8 are fluorine, chlorine and bromine. The most suitable halogen is fluorine. It will be understood that if two or three of the above-mentioned substituents are all groups with complex stereochemistry, e.g. highly branched lower-alkyl or lower-alkoxy groups, etc., then these substituents will not occupy neighboring positions in either the coumarin core or the phenyl ring in substituent A, due to the difficulty of synthesizing such compounds. The alkyl, alkoxy, alkenyl, alkynyl, acyl, acyloxy and alkoxycarbonyl groups represented by R^ to R^ are preferably unbranched.

Examples of linear alkylene groups represented by Q

is methylene, ethylene, propylene, butylene, pentylene, hexylene or heptylene. The optional hydroxyl group may occupy any position on any such alkylene groups other than the methylene group attached to an ether oxygen. It will be understood in this respect that when the methylene within the group Q is substituted with hydroxyl, the thus substituted methylene is asymmetric. It must therefore be understood that when the compounds according to the invention are referred to here, mixtures of enantiomers as well as pure enantiomers are included.

Within the general framework of the compounds according to the invention, there are certain more suitable subgroups of compounds, depending on the nature of the substituents R 1 . to Rb_. Thus, a first, more suitable subgroup consists of the compounds of formula (I), where R^#R^ and R^ are as defined above, and R^ and Rn are hydrogen or lower alkyl. More suitable is only one of R 1 or R 2 hydrogen and the other a lower alkyl group which preferably occupies position 8.

Another, more suitable group of compounds falling within the general scope of this invention are those where the phenyl ring in the substituent A does not carry more than two polar groups. This class of compound is of formula (I), and R 1 and R 2 are hydrogen, lower alkyl, lower alkenyl; R^ is hydrogen, lower alkyl, lower alkoxy, lower acyl, lower acyloxy, lower alkoxycarbonyl, phenyl, cyano, carboxy, halogen, nitro, hydroxy, amino, mono- and di-lower alkylamino, mono- and di-lower- acylamino, R^ is lower alkyl, lower alkoxy, lower acyl or lower acyloxy or lower alkoxycarbonyl, and R^ is hydrogen or a lower alkyl group, or any two of R^, R^ and R^, when they are on neighboring carbon atoms, represents an alkylene group containing 3-5 carbon atoms, or a 1,4-but-1,3-dienylene group.

A third suitable group of compounds that fall within the scope of the invention are those where the phenyl ring in substituent A carries a single lower alkyl substituent, i.e. that R^ and R^ are hydrogen and R^ is lower alkyl. Particularly suitable as lower alkyl groups are methyl, ethyl and n-propyl. Most advantageously, this lower alkyl group occupies position 2' in the phenyl ring.

A fourth suitable group of compounds that fall within the scope of the invention are those where the phenyl ring in substituent A carries a single fluorine atom, i.e. that R3 is fluorine and R4 and R(. are both hydrogen. Most suitable, the fluorine substituent occupies position 4' in the phenyl ring"

A fifth group of compounds that fall within the scope of the invention are those where R^ is a fluorine atom in position 4' of the phenyl ring in substituent A, R^- is a lower alkyl group, preferably propyl, at position 2', and R^ is a hydrogen atom .

A particularly well-suited combination of groups for incorporation into the phenyl ring in substituent A and which results in a favorable level of activity for the nitrocoumarin, consists of one polar group, e.g. lower acyl, one hydrophilic group, e.g. hydroxyl, and one hydrophobic group, e.g. lower alkyl. It is particularly suitable in such a combination that the lower acyl group R4 occupies position 4', the lower alkyl group Rg occupies position 2' and the hydroxyl group R^ occupies position 3' in the phenyl ring. In this combination, R4 is preferably acetyl and R^ is preferably n-propyl. In the compounds according to the invention, R₁ and R₂, R₂, R₂ and R₂ need not be other than hydrogen. This means that neither the phenyl ring in substituent A nor the coumarin core is necessarily substituted.

A group of compounds of this type that fall within the scope of the invention bear only substituents in the coumarin nucleus and have the general formula (I), where R.sup.1 and R.sup.2 are as previously defined with respect to formula (I), and R.sup.4, R.sup.4 and R.sup.5 are all hydrogen.

A further group of compounds of this type only bear substituents within the phenyl ring in substituent A and are of formula (I) where R 1 and R 2 are both hydrogen and R 3 , R 4 and R 1 are as previously defined.

Yet another group of compounds falling within the scope of the invention bear substituents neither in the coumarin nucleus nor in the phenyl ring in substituent A. These compounds are of the general formula (I) where<R>1<#>R2, R3, R4 and Rg all represent hydrogen. Compounds of this type bearing few substituents are preferred because of ease of synthesis.

The substituent AO occupies either position 6 or position 7 in the coumarin core, but preferably this substituent occupies position 7. The substituents R^^ and R2 can occupy any of the remaining positions within the core, but preferably occupies position 8.

Within the general framework of the compounds according to the invention, X represents oxygen or a methylene group. Among the compounds of formula (I) where X is a methylene group, have. those compounds where Q is also methylene, useful oral absorption properties.

Examples of compounds of formula (I) where X is a methylene group and in particular R^ R2, R3»R4 and R5 are all hydrogen are:- 4-hydroxy-3-nitro-6-(2-phenylethoxy)coumarin, 4- hydroxy-3r-nitro-7-(2-phenylethoxy)coumarin, 4-hydroxy-3-nitro-7-(3-phenylpropoxy)coumarin, and 4-hydroxy-3-nitro-7-(4-phenylbutoxy)coumarin .

Examples of compounds of formula (I) where X is a methylene group and R 1 and R 2 are hydrogen are: -7-(2-[4-fluorophenyl]ethoxy)-4-hydroxy-3-nitrocoumarin, 7- (3-[ 4^-acetylphenyl]propoxy)-4-hydroxy-3-nitrocoumarin, . 7-(4-[4-chlorophenyl]butoxy)-4-hydroxy-3-nitrocoumarin,

4-hydroxy-7-(4-[4-methylphenyljbutoxy)-3-nitrocoumarin,

7-(2-[2-n-propyl-4-fluorophenyl]-ethoxy)-4-hydroxy-3-nitrocoumarin.

Of these compounds, particular preference is given to: 4-hydroxy-3-nitro-7-(2-phenylethoxy)coumarin,

7-(2-14-rfluorophenyl]ethoxy)-4-hydroxy-3-nitrocoumarin, and 7-(2-[2-n-propyl-4-fluorophenyl]ethoxy)-4-hydroxy-3-nitrocoumarin.

Where X is an oxygen atom, Q is preferably methylene, but rather ethylene, propylene, butylene, pentylene or hexylene, optionally substituted with hydroxyl, a particularly suitable group being 2-hydroxypropylene.

Examples of compounds of formula (I) where X is oxygen and R 1 , R 2 , R 3 , R 4 and R 1 , all hydrogen, are: -4-hydroxy-3-nitro-6-(3-phenoxypropoxy)coumarin, 4- hydroxy-3-nitro-6-(2-phenoxyethoxy)coumarin, 4-hydroxy-3-nitro-6-(6-phenoxyhexoxy)coumarin,

4-hydroxy-3-nitro-7-(3-phenoxypropoxy)coumarin, 4-hydroxy-3-nitro-7-(5-phenoxypentoxy)coumarin, 4-hydroxy-3-nitro-7-(4-phenoxybutoxy) coumarin, 4-hydroxy-3-nitro^7-(2-hydroxy-3-phenoxypropoxy)coumarin, 4-hydroxy-3-nitro-7-(6-phenoxyhexoxy)coumarin, and 4-hydroxy-3-nitro-7 -(2-f enoxyethoxy)chiimarin.

Examples of compounds of formula (I) where R^^ and R 2 are hydrogen are: -7-(4-chlorophenoxymethoxy)-4-hydroxy-3-nitrocoumarin,

7-(2-[4-acetyl-3-hydroxy-2-hydroxy-2-n-propylphenoxy]-ethoxy)-4-hydroxy-3-nitrocoumarin,

4-hydroxy-3-nitro-7-(3-phenoxypropoxy)-8-n-propylcoumarin, 7-(3-[4-chlorophenoxy]propoxy)-4-hydroxy-3-nitrocoumarin, 7-(3-[4 -carboxyphenoxy]propoxy)-4-hydroxy-3-nitrocoumarin, 7-(3-[4-carbomethoxyphenoxy]propoxy)-4-hydroxy-3-nitrocoumarin,

7-(3-[4-acetylphenoxy]propoxy)-4-hydroxy-3-nitrocoumarin, 4-hydroxy-7-(3-[4-methyl-2-nitrophenoxy]propoxy)-3-nitrocoumarin,

7-(3-[4-acetyl-3-hydroxyphenoxy]propoxy)-4-hydroxy-3-nitrocoumarin,

4-hydroxy-7-(3-[2-methylphenoxypropoxy)-3-nitrocoumarin, 1-(3-[4-acetyl-3-hydroxy-2-n-propylphenoxy]propoxy)-4-hydroxy-3-nitrocoumarin,

7-(3-[4-carboxyphenoxy]-2-hydroxy-propoxy)-4-hydroxy-3-nitrocoumarin,

4-hydroxy-7-(2-hydroxy-3-phenoxypropoxy)-3-nitrocoumarin, 7-(3-[4-acetyl-2-n-propylphenoxy]-2-hydroxypropoxy)-4-hydroxy-3-nitrocoumarin,

7-(3-[4-acetyl-3-hydroxyphenoxy]2-hydroxypropoxy)-4-hydroxy-3-nitrocoumarin,

7-(3-[4-acetyl-3-hydroxy-2-methyl-phenoxy]-2-hydroxypropoxy)-4-hydroxy-3-nitrocoumarin, 7-(3-[4-acetyl-2-ethyl-5- hydroxyphenoxy]-2-hydroxypropoxy)-4-hydroxy-3-nitrocoumarin,

6-(3-t 4-acetyl-3-hydroxy-2-n-propyl-phenoxy]-2-hydroxypropoxy)-4-hydroxy-3-nitrocoumarin, 4-hydroxy-7-(2-hydroxy-3-[ 3-hydroxy-4-propionyl-2-n-propyl-phenoxy]propoxy)-3-nitrocoumarin,

4-hydroxy-7-(3-[3-methylphenoxy]propoxy)-3-nitrocoumarin, 4-hydroxy-7-(3-[4-methylphenoxy]propoxy)-3-nitrocoumarin, 4-hydroxy-7-(3 -[4-methoxyphenoxy]propoxy)-3-nitrocoumarin, 7-(3-[4-fluorophenoxy]propoxy)-4-hydroxy-3-nitrocoumarin, 7-(3-[4-cyanophenoxy]propoxy)-4-hydroxy -3-nitrocoumarin, 4-hydroxy-7-(3-[4-phenylphenoxy]propoxy)-3-nitrocoumarin, 4-hydroxy-3-nitro-7-(3-[5,6,7,8-tetrahydro- 2-naphthyloxy]

propoxy)coumarin

4-hydroxy-7-(2-hydroxy-3-t 2-n-propyl-phenoxy]propoxy)-3-riitrocoumarin,

and

7-(3-[4-acetyl-3-hydroxy-2-n-propyl£enoxy]-2-hydroxypropoxy)-4-hydroxy-3-nitrocoumarin.

Examples of compounds of formula (I) where one of and R2 is something other than hydrogen are: -4-hydroxy-5-methyl-3-nitro-7-(3-phenoxypropoxy)coumarin, 6-ethyl-4-hydroxy- 3-nitro-7-(3-phenoxy-propoxy)coumarin, 7-(3-[ 4-acetyl-3-hydroxy-2-n^-propylphenoxy]-2-hydroxypropoxy)-4-hydroxy-8-methyl -3-nitrocoumarin, ,

7-(3-[4-acetyl-3-hydroxy-2-n-propylphenoxy]-2-hydroxypropoxy)-4-hydroxy-3-nitro-8-n-propylcoumarin,

Particularly preferred compounds are: -7-(3-[4-acetyl-3-hydroxy-2-n-propylphenoxy]-propoxy)-4-hydroxy-3-nitrocoumarin,

7-(3-[4-acetyl-3-hydroxy-2-n-propylphenoxy]-2-hydroxypropoxy)-4-hydroxy-3-nitrocoumarin, 7-(3-[4-acetyl-3-hydroxy-2- n-propylphenoxy]-2-hydroxypropoxy)-4-hydroxy-8-methyl-3-nitrocoumarin, 7-(3-[4-acetyl-3-hydroxy-2-n-propylphenoxy]-2-hydroxypropoxy)-4- hydroxy-8-n-propyl-3-nitrocoumarin,

7-(3-12-n-propylphenoxy]-2-hydroxypropoxy)-4-hydroxy-3-nitrocoumarin, 7-(3-[2-methylphenoxy]-propoxy)-4-hydroxy-3-nitrocoumarin, 7-( 3-[4-fluorophenoxy]-propoxy)-4-hydroxy-3-nitrocoumarin, 7-(3-[2-n-propyl-4-fluorophenoxy]-2-hydroxypropoxy)-4-hydroxy-3-nitrocoumarin, and

4-hydroxy-3-nitro-6-phenoxyhexoxycoumarin.

Examples of suitable salts of the compounds of formula (I) are alkali metal salts, especially of sodium and potassium; alkaline earth metal salts, e.g. of calcium and magnesium; the aluminum salt and the salts with organic bases such as amines or amino compounds, e.g. N-methyl-D-glucamine.

For administration purposes, preparations according to the invention can be presented in several dosage forms.

According to the invention, there is also provided a pharmaceutical preparation having SRS-A inhibitory activity, comprising a compound of formula (I) as defined above, together with a pharmaceutically acceptable carrier.

Examples and preferred values of R^, R^ and A and Q, R^# and R^i A are as previously discussed.

The preparations according to the invention can be presented as a microfine powder for snorting (in such a case the particles of active compound often have diameters of less than 50 microns, preferably less than 10 microns) or in the form of an aerosol or a solution for a fog generator. The preparations can also be presented together with a sterile liquid carrier for injection, or in an ointment, cream, lotion or a solution for topical application, or as suppositories.

Compounds of formula (I) which are active when given orally can be put together in the form of syrups, tablets, capsules, pills and the like. The preparations are preferably in unit dose form or in one form which enables the patient to administer a single dose to himself, e.g. when the preparation is in the form of a tablet, pill, lozenge, powder, or a form of pastille.

Any suitable pharmaceutical carrier can be used for the composition of solid preparations, e.g. magnesium stearate, starch, lactose, glucose, sucrose, rice flour, talc and lime. The preparation can also be in the form of an indigestible capsule (e.g. of gelatin) containing the compound, or in the form of a syrup, a liquid solution or a suspension. Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerol, saline and water together with aroma-trapping coloring agents for forming syrups. A suitable unit dose may contain from 0.1 to 500 mg of active ingredient.

The effective dose of compound (I) depends on the particular compound used, but is generally in the range from 0.01 mg/kg/day to 100 mg/kg of body weight per day. day.

Where appropriate, small amounts of anti-asthmatics and bronchodilators may be included, e.g. sympathomimetic amines, e.g. isoprenaline, isoetarine, salbutamol, phenylephrine and ephedrine; xanthine derivatives, e.g. theophylline and amino-. phyllin; and corticosteroids, e.g. prednisolone and adrenal stimulants, e.g. ACTH. As usual in practice, the preparations will usually be accompanied by written or printed instructions for use in the medical treatment in question, in this case as an anti-allergenic agent for the treatment of e.g. asthma, hay fever or rhinitis.

Compounds of formula (I) can be prepared by nitration of the corresponding coumarin derivatives.

Accordingly, the invention also provides a method for producing compounds of formula (I), and this method comprises reacting a compound of formula (IV) or a salt thereof

where A', and R 2 are as defined above with respect to formula (I), with a nitrating agent. The nitration can be carried out with any conventional nitrating agent, e.g.:-

(i) acetic acid and concentrated nitric acid, or

(ii) fuming nitric acid in chloroform. The temperature at which the reaction is carried out depends on the nitrating agent used. To avoid nitration. of the phenyl ring in the substituent A in formula. (II):-

it is most preferable to use a temperature of less than 10°C and a reaction time of up to 90 minutes.

The nitrating agent is preferably fuming nitric acid in chloroform, and the reaction is preferably carried out at a temperature in the range from -5°C to +5°C, most preferably at 0°C, between 15 and 90 minutes.\

Alternatively, the compounds according to the invention, excluding compounds bearing an amino group or substituted amino group, can be prepared by nitrosation of the intermediate products of formula (IV) and subsequent oxidation of the resulting nitroso compound.

Accordingly, the invention also provides one method for the preparation of a compound of formula (I), by which a compound of formula (IV) is nitrosated where R 1 , R 2 , R 3 , R 4 , 9 R 5 are as formula (I) provided that none of to R,, represents amino or a substituted amino group, with an alkali metal nitrite in the presence of a lower alkanoic acid and then oxidizing the nitroso compound.

The nitrosation reaction is carried out in a polar solvent at a temperature between room temperature and 60°. The alkali metal nitrite is usually sodium or potassium nitrite. The lower alkanoic acid is usually acetic acid. The oxidation step can preferably be carried out in situ by rapid stirring or rapid passage of air through the redox product.

Also included within the scope of the invention are the intermediate products of formula (IV).

where R 1 , R 2 and A are as defined above with respect to formula (I).

A suitable method for preparing the intermediates (IV) is the condensation of a suitably substituted o-hydroxyacetophenone (V) with diethyl carbonate in the presence of sodium hydride.

The desired substituent A is introduced into a suitable dihydroxyacetophenone (VI) by coupling with a halide, e.g. a chloride or bromide, of the general formula AY in the presence of potassium carbonate in acetone as shown in Scheme 1. In Scheme 1, R^,

R 2 and A as defined with respect to formula (I), and Y represents chlorine or bromine.

Ski erna 1

Another suitable method for the preparation of intermediates of formula (IV) is, as shown in scheme 2 above, for the coupling of halide AY with a hydroxy-4-iminocoumarin (VII) using sodium hydride in dimethylformamide (DMF). The resulting 4-iminocoumarin ((VIII) is then hydrolysed to the corresponding 4-hydroxycoumarin (IV) with strong acid. The hydroxy-4-iminocoumarins (VII) are made by standard methods. For example, 7-hydroxy-4-iminocoumarin is made from ethyl cyanoacetate and resorcinol. This process is particularly useful for the preparation of 7-aryloxyalkylenoxycoumarins of the general formula (IX):-

where Q, R 2 , R 2 , R 2 , and R 2 are as defined for formula (I) above, especially when Q is substituted with hydroxyl.

A further method for the preparation of intermediates of formula (IV) is shown in scheme 3 below.

A halide AY, e.g. a chloride, is coupled with a hydroxy-4-benzyloxycoumarin (x) using sodium hydride in dimethylformamide (DMF). Alternatively, if Y is bromine, the reaction can be carried out using potassium carbonate in acetone or butanone. The resulting 4-hydroxycoumarin is obtained after removal of the benzyl group by hydrogenation with hydrogen and palladium. In the scheme, R 1 , R 2 and A are as defined for formula (I), Y is a halogen atom, and Bz means benzyl.

Alternatively, the intermediate (IV) can be made by coupling an epoxide of formula (XII) with either a 4-iminocoumarin of formula (VII) or 4-benzyloxycoumarin of formula (X). These two ways are illustrated in form 4 below. The 4-hydroxycoumarin of formula (XIII) is released either by hydrolysis of the iminocoumarin (XIV) or hydrogenolysis of the benzyloxycoumarin (XII). This 4-hydroxycoumarin falls within the definition of formula (IV). In scheme 4, the symbols are as defined above, and n is an integer from 1 to 4.

EXAMPLES

Example 1

2- Hydroxv-4-(3- Phenoxvpropoxy) acetophenone

A mixture of l-bromo-3-phenoxypropane (21.5 g; 6.1 mol), 2,4-dihydroxyacetophenone (15.2 g; 0.1 mol) and anhydrous potassium carbonate (20.8 g; 0.15 mol) in 300 mL of dry acetone was stirred at reflux for 24 h when TLC analysis indicated complete reaction. After cooling, the potassium salts were removed by filtration and the filtrate evaporated to a pink solid. Recrystallization from ethanol in the presence of charcoal gave 21.94 g (77%) of a white solid with TLC purity, m.p. 82-82.5°;\>max. (mull) 1618, 1600, 1595 cm"<1>; t(CDC13); 7.73 (2H, quintet, J 6.3Hz); 7.48(3H,s); 5.85(2H, t, J 6.3Hz); 5.79(3H, t, J 6.3Hz); 3.54(2H, m); 3.22-2.38(5H, complex m); 2.37(1H, d , J 9.5Hz); 1 low-field exchangeable proton. (Found: C, 71.28; H, 6.58; C17H18°4 required C'71'31?H'6»34%)«

In a similar manner, the examples in Table (I) were carried out.

Example 28

l- chloro- 3- phenoxy- 2- propanol

A mixture of phenol (94 gj 1.0 mol) and epichlorohydrin (138.8 g; 1.5 mol) was stirred vigorously at 100°C in the presence of 2.0 g piperidine hydrochloride for 6 hours, cooled, and the excess of epichlorohydrin removed at 100° in vacuo. The residue was cooled, dissolved in equal parts chloroform and stirred vigorously with an excess of concentrated hydrochloric acid for 1/2 hour. After separation of the phases, the organic layer was washed with water, dried and evaporated to a colorless oil. Distillation gave 116.4 g (62.5%) of 1-chloro-3-phenoxy-2-propanol, bp ^ 112° as a GLC pure material, Vmax (film) 3310, 1603, 1590,'1495, 1245 cnf<1>} T (CDC13); 7.40 (wide interchangeable s) in 6.25 (2H, d, J 3.5Hz); 5.90 (2H, s); 5.90 (1H, m); 3.21-2.56 (5H, m).

Likewise, the compounds listed in Table II were prepared.

Example 38

3, 4- dihydro- 7-( 2- hydroxy- 3- phenoxypropoxy)- 4- iminocoumarin

To a warm, stirred suspension of 3,4-dihydro-7-hydroxy-4-iminocoumarin (17.7 g; 0.1 mol) in 75 mL of dry DMF was added sodium hydride (2.4 ; 0.1 mol) portionwise, and the mixture was refluxed for 1.5 hours until complete formation of the sodium salt. A solution of 1-chloro-3-phenoxy-2-propanol (18*7 g; 0.1 mol) in 10 mL of dry DMF was added dropwise at reflux, and the mixture was stirred at reflux for a further 4 h. The solvent was removed in vacuo and 200 ml of water added to the residue. The yellow solid was filtered off, washed well with water and dried in vacuo over P2°5 to give 30.0 g (92%) of crude product which was suitable for most purposes. Recrystallization from ethyl acetate gave material with m.p. 213-214°} Vmax. (mull) 3320, 3200, complex carbonyl region 1690-1590 cm"<1>, T(DMSO); 5.82(5H, m); 5.35(2H, broad, exchangeable s); 4*85( 1H, s) ; 3.20-2.52(8H, m with 1 proton removed

after D20 yield); 2.02(1H, d,)(Found: C, 64.52; H, 15.26;

N, 3.78; C18H17N050.5H20 requires: C, 64.28; H, 5.39; N, 4.16%).

By the same procedure, the compounds in Table III were prepared*

Example 44

4- benzyloxy- 7- hydroxycoumarin

A solution of 4,7-dihydroxycoumarin {(1.78 g, 0.01 mol) in 7.<5>ml DMF was stirred while adding 100% sodium hydride (0.24 g, 0.01 mol) and the mixture stirred in 1 hour at 100°. A solution of benzyl chloride (1.27 g, 0.01 mol) in 1 mL of dry DMF was added dropwise and stirring continued at 100 µL for an additional 4 h. After removal of the solvent in vacuo, water was added and the oily solid that precipitated was separated. Recrystallization from ethanol gave 0.623 g (23%) of the desired compound with m.p. 234° -Omax. (in null) 3150, 3050, 1710, 1630 cm"1, x(DMSO) 4.67(2H, s); 4.19 (1H, s) ; 3.28

(1H near s); 3.20(1H, d.d., J 2.0Hz* 5.0Hz) 2.66-2.26 (6H, m) , 1 broad, exchangeable, low-field proton- (Found: C, 71.51; H, 4 .70;

C16<H>12°4revers C'71'64».H'4.51%).

Example 45

4- benzyloxy- 7-( 2-[ 4- fluorophenyl] ethoxy) coumarin

A mixture of 4-benzyloxy-7-hydroxycoumarin (5.36 0.02 mol), 4.0 g of anhydrous potassium carbonate and 4.06 g of 1-bromo-2-(4-fluorophenyl)ethane in 100 ml of acetone was stirred at refluxed for 20 hours, and the inorganic material was filtered off. Evaporation of the filtrate in vacuo gave an oil which quickly solidified to a solid on scraping. 200 ml of chloroform was added and the mixture was filtered to remove unchanged 4-benzyloxy-7-hydroxycoumarin. Re-evaporation of the filtrate gave a white solid, 3.34 g (43%) m.p. 120°,\)max. (mull) 1715, 1675, 1620 cm<-1>; (CDCl-j); 6.93(2H, t, J 6.7Hz); 5.80(2H, t, J 6.7Hz);

4.87(2H,S); 4.38(1H, ); 3.29-2.49 (6H, m) 2.32 (1H, d, J 10Hz);

(Found: G, 73.75; H, 5.14; C24H19F04 required: C, 73.84; H, 4.91%).

Example 46

7-(3-[4-acetylphenyl]propoxy)-4-benzyloxycoumarin

Alkylation of 4-benzyloxy-7-hydroxycoumarin (2.68 0.01 mol)- with 1-(4-acetylphenyl)-3-bromopropane (2.4l g; 0.01 mol) as described in Example 45 gave 3, 28 g (77%) of the desired compound with m.p. (EtOH) 117°; V max. (mulle) 1725, 1682,

1620 cm"<1>;T(DMSO); 7.92(2H, m); 7.48(3H, s); 7.18(2H, m); 5.94 (2H, t, J 6, 4Hz); 6.69(2H, s); 6.16(1H, s); 3.17-2.00(12H, m). Found: C, 75.14; H, 5.52; C2] <H>2<4>05 requires: C, 75.68; H, 5.65%.

Example 47

2- hydroxy- 3- n- propyl- 4-( tetrahydropyran- 3- yloxy) acetophenone

Three drops of concentrated hydrochloric acid were added to a mixture of 10 g of 2,4-dihydroxy-3-n-propylacetophenone and 25 ml of dihydropyran. The mixture was warmed and a solution formed. After standing at ambient temperature overnight, ether was added and then 2.5n...sodium hydroxide solution. The phases were separated and the aqueous phase extracted with ether. The combined organic phases were washed with water, dried (MgSO 4 ) and evaporated to an oil which was distilled to give 12.05 g (77%) ether boiling at 152-172° at 0.4 mm x/max . (film) 2680 (wide) 1725, 1630, 1590, 1494 cm""<1>.

Example 48

4- hydroxy- 8- n- propyl- 7-( tetrahydropyran- 3- yloxy) coumarin

A solution of 2-hydroxy-3-propyl-4-(tetrahydropyran-3-yloxy)acetophenone (12.05 g; 0.043 mol) in 100 mL of dry benzene was added to a stirred suspension of sodium hydride (2.40 g; 0.043 mol).

0.1 mol) in 100 ml of dry benzene during 30 minutes under reflux. After a further 10 minutes, a solution of diethyl carbonate (10.7 g; 0.087 mol) in 100 ml benzene was added over 1 hour and the mixture stirred at reflux overnight. Water was added to the cooled solution and the brown aqueous phase was washed with ether, cooled to below 5°C and gently acidified. A pale yellow solid separated out and this was filtered off and washed well with water. Recrystallization gave 6.986 g (53%) of a product with m.p. 163-165°, V max.

(mull) 2710, 2600, 1660, 1630, 1600 cm"<1>T (DMSOj)., 9.08 (3H, t,

J 7.0Hz); 8.34 (8H, m); 7.25 (2H, m); 6.36 (2H, broad); 4.50 (1H, sharp, replaceable s); 4.33 (1H, wide s) 2.62 (2H, AB quartet, J 9.0Hz; £v35Hz). 1 wide, replaceable low-field proton.

Found: C, 67.49; H, 6.89; C17H20<0>5 requires: C, 67.09; H, 6.62%).

Example 49

4- benzyloxy- 7- hydroxy- 8- n- propylcoumarin

Sodium hydride (0.528; 10% excess) was added to a solution of 4-hydroxy-8-n-propyl-7-(tetrahydropyran-3-yloxy)-coumarin (6.08 g; 0.002 mol) in 10 mL of dry DMF, and the stirred mixture was heated to 100°. A solution of benzyl chloride

(2.76 g; 2.5 mL; 10% excess) in 2 mL dry DMF was added over 30 min and the mixture held at 100-110° for 6 h. After cooling, the solvent was removed in vacuo, and water was added. The precipitated sticky solid was taken up in chloroform, washed with dilute sodium hydroxide solution and then water, and dried. Evaporation gave a pink solid which, after recrystallization from ethanol, gave white crystals in an amount of 1.533 g (19.5%) of the tetrahydropyranyl ether of the desired compound, m.p. 146-147° \)max. (mullein) 1735, 1625, 1615 cm"<*1>;

T(DMSO) 9.11. (3H, t, J 7.5Hz); 8.36 (8H, m); .7.28 (2H, t, J 7.5Hz) 6.44 (2H, in); 4.70 (2H, S); 4.40 (1H, S); 4.18 (1H, S); 2.94

(1H, d, J 9Hz); 2.58 (5H, m); 2.40 (1H, d, J 9Hz).

(Found: C, 73.14; H, 6.78; C24H26°5 requires: C'73*08?H, 6.64%).

The alkaline washes gave, on acidification, a brown tar which, on dissolution in ethanol, deposited the desired compound, 0.905 g, (15%) on standing. The product had m.p. 213-214°, Vmax. (mull) 3050 (broad); 1675, 1605, 1570 cm"<1>; t(DMSO) 9.09

(3H, t, J 7.5Hz); 8.46 (2H, p, J 7.4Hz); 7.31 (2H, t, J 7.5Hz);

4.70 (2H, s); 4.22 (1H,S); 3.15 (1H, d, J 9Hz); 2.56 (6H, m) 1 exchangeable low-field proton. (Found: C, 73.54; H, 6.07;

<C>1<gH>1804 requires: C, 73.53; H, 5.85%).

Cleavage of the tetrahydropyranyl ether isolated from the ether phase with methanolic acid gave the desired compound in 71% yield, and with m.p. 212°, after recrystallization.

Example 50

7-(3-[ 4- acetyl- 3- hydroxy- 2- n- propylphenoxy]- 2- hydroxypropoxy)-4- benzyloxycoumarin

A solution of 4-benzyloxy-7-hydroxycoumarin (5.36 g;

6.02 mol) in 30 ml of dry DMF was treated with 100% sodium hydride

(0.48 g; 0.02 mol) and stirred at 100° for approx. 1 hour. To this was added a solution of 7 g of 1-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-3-chloro-2-propanol in 2 ml of DMF, and the mixture was stirred at 100° for a further 4 hours. After removal of the solvent in vacuo, water was added and the product extracted

chloroform. Chromatography of the extract on 300 g of silica gel

and elution with chloroform gave the desired compound as a white crystalline solid with Rf-0.38, m.p. (EtOH) 172-173°. Yield 4.38 g (42%). V max. (mullein) 1715, 1630, 1620 cm"<1>.

T(DMSO) 9.19 (3H, t, J 7.0Hz); 8.58 (2H, sextuplet, J. 7.0Hz); 7.48 (3H, S + 2H m); 6.71 (1H sharp, replaceable); 5.80 (5H, S); 4.68 (2H, S); 4.50 (1H, wide, replaceable); 4.13 (1H, S); 3.32 (1H, d, J 9Hz); 3.12 - 2.15 (12H, m); 1 sharp, replaceable low-field .

(Found C, 69.30; H, 5.80; C30H30<0g>required: C, 69.49; H, 5.83%).

By an analogous procedure, although chromatography was not always necessary, the compounds listed in Table IV were prepared.

Example 65

4- hydroxy- 7-( 3- phenoxypropoxy) coumarin

A solution of 2-hydroxy-4-(3-phenoxypropoxy)acetophenone (14.55 g; .0.0509 mol) in 100 mL of dry benzene was added to

a stirred, refluxing suspension of 60% sodium hydride in mineral oil (4.60 g; 0.115 mol) in 100 mL of dry benzene for 30 minutes. After a further 10 minutes, a solution of diethyl carbonate (12.02 g; 0.102 mol) in 100 ml of dry benzene was added over a<y>1 hour at reflux and the solution was kept at reflux for a further 19 hours. After cooling, the mixture was poured onto ice-cooled 2N hydrochloric acid (550 ml) and the precipitated solid was filtered off and washed well with water. Recrystallization from ethanol in the presence of charcoal gave 10.35 g (65%) of the desired compound as a white solid, m.p. 190-192° (dec); V max. (mull) 3270, 2600 (br), 1715, 1650, 1610 cm"1; T(DMSO), 7.74 (2H, quintet, J 6.5Hz); 5.80 (2H, t, J 5.5Hz ); 5.68 (2H, t, J 7.0Hz); 4.38 (1H, s); 3.17-2.48 (7H, m);

2.20 (1H, d, J 9jOHz); 1 exchangeable low-field proton.

Found: C, 69.22; H, 5.21; C18H16<0>5 requires: C, 69.22; H, 5.16%).

The compounds listed in Table V were prepared in an analogous manner.

Example 92

4- hydroxy- 7-( 2- hydroxy- 3- phenoxypropoxy) coumarin

A solution of 3,4-dihydro-7-(2-hydroxy-3-phenoxypropoxy)-4-iminocoumarin (6.5 g; 0.02 mol) in 80 g of 50% w/v% sulfuric acid was stirred at 100° for 3-6 hours. The initially pale red solution precipitated a yellow solid which, after cooling and dilution with water, was separated by decantation. After several decantations with water, the oily solid was taken up in hot ethanol, treated with charcoal, filtered and the filtrate gradually diluted with water. The precipitated oily solid crystallized overnight to give 2.934 g of a leather-colored solid, m.p. 145-175°. Recrystallization from aqueous methanol gave 2.275 g (34%) of a material with m.p. 181-183°, vmax (mol) 3250, 3060, 1705, 1610 cm"<1>; x(DMSO); 5.85 (5H, m);

4.75 (1H wide, replaceable); 4.50 (1H, sharp, replaceable singlet);

3.19-2.50 (7H, complex m); 2.22 (1H, d, J 9.10Hz); 1 replaceable low field singlet. Found: C, 65.48; H, 5.19$. C18H16°6 letters: C, 65.85; H, 4.91%).

The compounds in Table VI were prepared in a similar manner.

Example 98

7-( 3-[ 4- acetyl- 3- hydroxy- 2- n- propylphenoxy]- 2- hydroxypropoxy)-4- hydroxycoumarin

Hydrogenation of 7-(3-[4-acetyl-3-hydroxy-2-n-propyl-phenoxy]-2-hydroxypropoxy)-4-benzyloxycoumarin (3.42 g; 0.0066 mol) in 60 mL DMF at atmospheric pressure using 10% palladinized charcoal gave the desired compound; 2.86 g as a TLC pure foam. r(DMSO); 9.13 (3H, t, J 6.7Hz); 8.59 (2H, m) 7.4C (3H, s); 7.40 (2H, m); 6.30 (1H, wide, replaceable); 5.75 (5H, s); 4.75 (1H, wide, replaceable); 4.50 (1H, replaceable) 3.30 (1H, d,

J 9.3Hz); 3.01 (2H, m); 2.23 (1H, d, J 9.6Hz); 2.15 (1H, d,

J 9.3Hz); 1 sharp, replaceable low-field. Molecular ion at

m/e 428.

By a similar procedure, the compounds i

table VII produced.

Example 114 7-(3-[4-Acetyl-3-hydroxy-2-n-propylphenoxy]-2-hydroxypropoxy)-4-hydroxy-3-nitrocoumarin 9 ml fuming nitric acid was added to a stirred suspension of 2.8 g of 7-(3-[4-acetyl-3-hydroxy-2-n-propyl-phenoxy]-2-hydroxypropoxy)-4-hydroxycoumarin in 300 ml of chloroform during 1 hour at 0°, and the dark mixture was stirred for an additional 1/2 hour at this temperature. 150 ml of dilute hydrochloric acid was added and the chloroform was removed in vacuo at 0°. The solid which separated out was removed by filtration and recrystallized from ethanol to give 2.42 g, (78%) of a yellow solid with m.p. 201-203° (cleaves).\)max. (mull<1>)) 3350 (br), 1770, 1620, 1610, 1540 cm"<1>; r(DMSO); 9.17 (3H, t,

J 6.9Hz); 8.55 (2H, m, J about 7Hz); 7.43 (3H, S + 2H, m); 5.78 (5H, S); 3.20 (3H,m); 2.16 ;(2H, exchangeable S) ; 2.16 (2H, near doublet); 1 wide, replaceable low-field). Found: C, 58.49;

H, 5.07; N, 3.04; C23<H>23NO1O requires: C'58'35; H'4.90;

N, 2.96%).

The sodium salt, prepared in the usual way, had m.p. 262°

(split); max. (mull) 1720, 1620, 1605 cm"1; Found:

C, 56.01; H, 4.77; N, 2.80; Na, 4.73; C 23 H 22 NNap 10 requires: C, 55.76; H, 4.48; N, 2.83; Well, 4.64%).

By a similar procedure, the examples indicated in Table VIII were prepared.

Example 155

4- hydroxy- 7-( 3-[ 2- methylphenoxy] propoxy)- 3- nitrocoumarin

Sodium nitrite (0.24 g; 0.003 mol) was added in one portion to a vigorously stirred suspension of 1 g of 4-hydroxy-7-(3-[2-methylphenoxy]propoxy)coumarin in 30 mL of glacial acetic acid. After 2 hours at ambient temperature, the reddish solution was poured into 150 ml. water and the precipitated yellow solid filtered off. Recrystallization from aqueous ethanol gave 0.815 g (70%) of a yellow 3-nitro derivative with m.p. 146°; V max. (mull) 1750, 1615, 1600, 1525 cm"1; T(DMSO); 7.85 (3H, S) ; 7.82 (2H, quintet); 5.88 (2H, t, J 7.2Hz) ; 5.72 (2H, t, J 7.2Hz); 3.23-2.73 (6H, m); 2.13 (1H, d, J 9.3Hz); 1 sharp, exchangeable low-field proton. Found : C, 61.25; H, 4.56; N, 3.58; C19H17NO?required: C, 61.45; H, 4.61; N, 3.77%).

The sodium salt had m.p. 225°. (Found: C, 57.80;

H, 4.38; N., 3.38; Na, 5.96; C19H16NNaO7 requires: C, 58.02;

H, 4.10; N, 3.56; Well, 5.86%).

By a similar procedure, the compounds listed in Table IX can be prepared.

moxoqisKe gara

SRS-A antagonist activity

The compounds have been assessed as direct antagonists of slow-reacting substance in anaphylaxis (SRS-A) in research where isolated guinea pig ileum was used.

SRS-A rat was obtained from the peritoneal cavity of the rat after passive peritoneal anaphylaxis by a method as directed by R.P. Orange, D.J. Stechschulte and K.F. Austen, J. Immunology, 105 1087 (1970) as described by B.A. Spicer, J.W. Ross and H. Smith, Clin.exp. Immunol. 1975, 21, 419. The sensitizing serum containing reagin antibody was produced in rats as described by B.A. Spicer et al. ibid. 2 ml of a 1:5 dilution of the sensitizing serum was injected peritoneally into recipient rats, and after 2 hours 5 ml of Tyrode's solution containing 0.4 mg/ml ovalbumin (Sigma Grade III) and 50 µg/ml heparin injected by the same route.

Five minutes after the injection, the rats were rendered unconscious, and a blood sample was taken from them, and the peritoneal fluids were collected in

polycarbonate tubes in ice. After centrifugation at 150 G for 5 min. the supernatants were combined, heated in a boiling water bath for 5 minutes, cooled and stored at -20°C. The combined peritoneal fluids contained SRS-A and were used in the antagonism studies.

The SRS-A studies were performed on isolated strips of _7 guinea pig ileum in Tyrode's solution containing atropine 5 x 10 m qg mepyramine 10 - 6 m as described by W.E. Brocklehurst,

J. Physiology, 151, 416 (1960).

The activity of the antagonists was determined by their ability to reduce submaximal responses induced by *SRS-A. The antagonists were added to the 4 ml bath in 0.1 ml volume portions in aqueous solution half a minute before the addition of SRS-A and were present during induced contraction. Two or three concentrations of antagonist were used and percent inhibition of SRS-A response was plotted against bath concentration of antagonist. The line of best fit was drawn and the concentration causing 50% inhibition, IC5Q was read graphically.

Passive cutaneous anaphylaxis

Serum containing heat-labile homocytotropic antibody was cultured in rats to crystallized ovalbumin XOA by the method of Mota (l. Mota, Immunology, 7,681 (1964) with Bordettela pertussis vaccine as adjuvant.

Passive cutaneous anaphylaxis (PCA) was performed by a method which was, as indicated by Ovary and Bier (A. Ovary and P.G. Bier, Proe. Soc. Exp. Biol. Med. 81, 584, (1952), modified by Goose and Blair .

Male Wistar rats weighing 250-300 g were given 0.1 ml of each of six two-fold serial dilutions of pooled antiserum in 0.9% saline, injected intradermally at separate sites on their shaved backs. 72 hours later, the animals were injected intravenously with 0.3 ml of a 1% solution of ovalbumin in an isotonic solution of saline buffered with 0.5 M Sørensen buffer pH 7.2 (PBS), mixed with 0.2 ml of a 5% solution of Pontamine Sky Blue (6BX CI. 24410, Raymond A. Lamb, London) in isotonic saline. The rats were killed after 20 minutes, and the diameter of the blue, swollen areas where the antibody had been injected was measured on the

outer surface of the skin. The starting solution of the serum was adjusted so that there was no response, after the injection, at the injection site with the highest dilution and a maximum response

at the lowest dilutions. Typically, six-fold serial dilutions of the serum from 1/4 to 1/128 were used.

The compounds were tested for their ability to reduce the diameter of the raised sites at the intradermal sites which in the control animals produced a less than maximal response.

Each dose of the compound was administered intravenously to six rats in isotonic saline, adjusted to pH 7 with sodium bicarbonate if necessary (2 ml/kg body weight) just before intravenous injection of ovalbumin. Control groups consisting of six animals were given the same volume of vehicle fluid at the same time.

The results were calculated as follows: % inhibition of PCA=100 (1 - a/b) where a=sum of the diameters of the swollen sites produced in the experimental animal at the sites of antibody dilutions used in control groups, and b=mean sum of the diameters of the raised.sites produced in the control group of animals at the antibody sites where at least five out of six of the animals go less than maximal response. A typical variation in the control group of animals was SEM+6%. The dose of compound required to inhibit the PCA response by 50% was

Toxicity;

None of the compounds described in the examples showed any toxic effect during the biological assessment.

Acute toxicity;

The following compounds: -4-hydroxy-3-nitro-7-(2-phenylethoxy)coumarin

7-(3-[2-n-propylphenoxy]-2-hydroxypropoxy)-4-hydroxy-3-nitrocoumarin

7-(3-[4-Acethylphenyl]propoxy)-4-hydroxy-3-nitrocoumar in 7-(3-[4-Acetyl-3-hydroxy-2-methylphenoxy]-2-hydroxypropoxy)-4-hydroxy -3-nitrocoumarin, and

7-(3-[4-acetyl-3-hydroxy-2-n-propylphenoxy]-2-hydroxypropoxy)-8-n-propyl-3-nitrocoumar in

was given 100 mg/kg intravenously to mice. No one died within 5 days.

Claims (6)

1. Process for the preparation of a nitrocoumarin of formula (i):- and the pharmaceutically acceptable salts thereof, wherein and R 2 each represent hydrogen or lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, or R 1 and R 2 , when on adjacent carbon atoms, together represent a 1,4-buta-l ,3-dienylene group or an alkylene group containing 3-5 carbon atoms; A represents a substituent of formula (II):- which occupies position 6 or position 7 in the nitrocoumarin nucleus, where X is oxygen or a methylene group, and Q represents a linear alkylene group containing 1-8 carbon atoms, with one methylene group within the group Q that is not methylene covalently bound to an ether oxygen, optionally substituted with hydroxyl, and R^ , R^ and R^, each represent hydrogen, halogen, nitro, hydroxy, cyano, carboxyl, amino, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkoxycarbonyl, lower acyl, lower acyloxy, mono- and di-lower alkylamino, mono- and di-lower acylamino, phenyl, lower alkylphenyl, phenoxycarbonyl, benzyloxycarbonyl, or any two of R^, R^, or Rg, when on adjacent carbon atoms, together represent an alkylene group containing 3-5 carbon atoms, or a 1,4-buta-1,3-dienylene group, characterized by nitration of a compound of formula (IV) with a nitrating agent and then, if desired, salt formation of the compound of formula (I). 2. Method as stated in claim 1, characterized in that acetic acid and concentrated nitric acid are used as nitrating agents. 3.Procedure as specified in claim 2, characterized in that the nitrating agent used is fuming<*> nitric acid in chloroform. 4. Process for the preparation of a nitrocoumarin of formula (I) :- and the pharmaceutically acceptable salts thereof, wherein and R^ each represent hydrogen or lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, or R^ and R^, when on adjacent carbon atoms, together represent a 1,4-buta-l ,3-dienylene group or an alkylene group containing 3-5 carbon atoms; A represents a substituent of formula (II):- which occupies position 6 or position 7 of the nitrocoumarin nucleus, where X is oxygen or a methylene group, and Q represents a linear alkylene group containing 1-8 carbon atoms, one methylene group within the group Q that is not methylene being covalently bonded to an ether oxygen , optionally substituted with hydroxyl, and R^, R^, and R^ each represent hydrogen, halogen, nitro, hydroxy, cyano, carboxyl, lower alkyl, lower alkenyl, lower alkynyl, phenyl, lower-alkylphenyl, phenoxycarbonyl, benzyloxycarbonyl, or any two of R^, R^ or R^, when on adjacent carbon atoms, together represent an alkylene group containing 3-5 carbon atoms, or a 1,4-buta-1,3-dienylene group, characterized by addition of a compound of formula (IV) with an alkali metal nitrite in the presence of a lower alkanoic acid, and then oxidizing the resulting nitroso compound to form a compound of formula (I) and, if desired, salting the compound of formula (I). 5. Method as stated in claim 4, characterized in that sodium nitrite is used as alkali metal nitrite. 6. Method as stated in claims 5 and 6, characterized in that acetic acid is used as lower alkanoic acid. '