DE2642248A1 - 3-nitro-coumarin derivatives, processes for their preparation and pharmaceuticals containing these derivatives - Google Patents

Description

3-nitro-coumarin derivatives, processes for their preparation and pharmaceuticals containing these derivatives

claimed

Priority: 23 September 1975 - Great Britain - No. 39041/75

Sept. 23, 1975 - Great Britain - No. 39042/75

February 4, 1976 - Great Britain - No. 4321/76 Jun 12, 1976 - Great Britain - No. 24450/76

The invention relates to new 3-nitro-coumarin derivatives, processes for their preparation and containing these derivatives Drug.

It is known that certain types of cells are separated by antibody-antigenic agents activated and release substances that mediate an allergic reaction to a stimulus. It SRS-A, a slow-acting anaphylaxis substance, has been reported to from such cells, which by means of antibody

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Antigen preparations have been activated, a significant role plays in the development of allergic and asthmatic phenomena.

In U.S. Patent Application No. 461,267 there are certain nitro-coumarins have been proposed which have a valuable activity in that they cause the release of intermediate carriers therefrom Cells produced by means of the type of antibody-antigen preparations described above have been activated. It has now been found that J-nitro-coumarin derivatives of General formula I below have a valuable activity in mammals in that they reduce the effect of SRS-A and also against antibody-antigen release from SRS-A and other intermediate carriers of an allergic stimulus protection. These compounds are beneficial in the prevention and treatment of diseases or conditions such as bronchial asthma, Rhinitis, hay fever, allergic eczema and the like in which allergic subcarriers have such symptoms fight.

The present invention now relates to 3-nitro-coumarin derivatives of the general formula I.

(D

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In which R, and Rp are identical or different and denote hydrogen atoms or alkyl, alkenyl, alkynyl or alkoxy radicals having 1 to 6 carbon atoms or, when R 1 and R _{2 are} on adjacent carbon atoms, 1,4-buta-l , 3-dienylene group or an alkylene radical with j5 to 5 carbon atoms, A for a substituent of the general formula II

^R 3

X-Q

(II)

is in the 6- or 7-position of the Curnarin ring, in which X is an oxygen atom or the methylene group, Q is a straight-chain alkylene radical with 1 to 8 carbon atoms, with a different methylene group in the radical Q than the methylene group that is covalently bonded to the ether oxygen atom is, can be substituted by a hydroxyl group, and R ^, R ^ and R ₁ - are identical or different and are hydrogen or halogen atoms, the nitro, hydroxy, cyano, carboxyl, amino, phenyl, phenoxycarbdnyl or the benzyloxycarbonyl group or alkyl, alkenyl, alkynyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, mono- or dialkylamino, mono- or diacylamino or alkylphenyl radicals, where 2 of the radicals R, , E ₁ , or R ^ can also form an alkylene radical with 5 to 5 carbon atoms, including the 1,4-buta-1,3-dienylene group, and their pharmacologically acceptable salts.
The terms "3-nitro-coumarin ring" and

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264224ο

"Coumarin ring" means the group of the general formula ΪΙΙ

(IH)

the numbers referring to those of the nitrocoumarin derivatives mentioned above refer to specified positions.

3-nitro-coumarins of the general formula I can be used in a number of tautomeric forms exist:

Of course, the subject matter of the present invention also includes all tautomeric forms in the compounds according to the invention with a.

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When in the present invention from a "phenyl ring of the substituent A "is mentioned, reference is made to the phenyl ring of the general formula II with the radicals R ^, R ^ and R ^, where the positions corresponding to the numbers on the phenyl ring below of the substituent A are as follows:

X-Q

Examples of suitable lower alkyl radicals for the radicals R, to Rj- are the methyl, ethyl, n- and iso-propyl and the n-, iso- and tert-butyl group.

Examples of suitable lower alkenyl radicals for the radicals R, bis Rc are the 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 5-methyl-2- and -3-butenyl-, 1-, 2- , 3- and 4-methyl-2-, -3- and.-4-pentenyl-, 1- and 2-ethyl-2-propenyl- and the 1-, 2- and 5-ethyl-2- and -I-butenyl groups.

Examples of suitable lower alkynyl radicals for the radicals R ₁ to Rp. Are 2-propynyl, 2- and 3-butynyl, 2-, 3- and 4-pentynyl, 2-, 3-1-4 and 5-hexynyl -, 1- and 2-methyl-2-propynyl-, 1-, 2- and 3-methyl-2- and -3-butynyl-, 1-, 2-, 3- and 4-methyl-2-, - 3- and 4-pentynyl, 1- and 2-ethyl-2-propynyl and the 1-, 2- and 3-ethyl-2- and -3-butynyl groups.

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Examples of suitable lower alkoxy radicals for the radicals PL bis Rp. Are the methoxy, ethoxy, n- and iso-propoxy and the η, iso- and tert-butoxy group. Examples of suitable lower acyl radicals for the radicals R-, to R, - are the acetyl, propionyl and the n- and iso-butyryl group. Examples of lower acyloxy radicals for the radicals R ^ to Rp- are the methoxycarbonyl, ethoxycarbonyl, n- and iso-propoxycarbonyl and the n- and iso-butoxycar-

bonyl group. The hydrocarbon radicals listed above in the radicals R, to Rp- are preferably straight-chain.

These above-mentioned examples of lower alkyl and lower acyl radicals also apply as examples of the lower ones Alkyl and lower acyl radicals in the mono- and dialkylamino or mono- and diacylamino radicals in the definition of the radicals R ^ to Rp- are included. Suitable halogen atoms in the residues R ^ to Rp- are fluorine, chlorine and bromine atoms. The most functional Halogen atom is fluorine. It goes without saying that where two or three of the aforementioned substituents are all groups of complex stereochemistry are, for example, heavily branched lower alkyl or lower alkoxy radicals, these substituents then do not occupy any adjacent positions either in the coumarin ring or in the phenyl ring of the substituent A, since the synthesis such connections is difficult. Examples of straight chain Alkylene radicals in the radical Q are the methylene, ethylene, propylene, Butylene, pentylene, hexylene or heptylene groups. An optional hydroxyl group can be on any With the exception of the methylene groups bonded to the ether oxygen atoms, there are methylene groups of the radical Q. When a methylene group is substituted with a hydroxyl group within the radical Q, then the so substituted methylene group

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asymmetrical. When it comes to such compounds at the present Invention, mixtures of enantiomers and also the pure enantiomers are then included.

Within the general scope of compounds of the present invention there are certain subsets of more suitable compounds, which depend on the nature of the. Radicals R to R ₁ - depend. Thus, a first subgroup of more suitable compounds of the general formula I consists in that the radicals R ^, Rh and Rj- have the meanings given above and R ₁ and Rp stand for hydrogen atoms or lower alkyl radicals. Preferably R 1 is a hydrogen atom and Rp is an alkyl radical in the 8-position.

A second subgroup of more suitable compounds are those in which the phenyl ring of the substituent A bears no more than two polar groups. In this class of compounds of the general formula I, R 1 and R p are hydrogen atoms or lower alkyl or alkenyl radicals, R is a hydrogen or halogen atom, a lower alkyl, lower alkoxy, lower acyl, lower acyloxy, lower Alkoxycarbonyl, lower mono- or dialkylamino or lower mono- or diacylamino radical or the phenyl, cyano, carboxy, nitro, hydroxy or amino group, Eu stands for a lower alkyl, lower alkoxy, lower acyl, lower acyloxy or lower alkoxycarbonyl radical, and represents Rj- a V / water atom or a lower alkyl radical, with 2 of the radicals R ^, R ^ or R ^, if they are on adjacent carbon atoms, alkylene radicals with 3 to 5 Carbon atoms, including the 1,4-buta-l, ^ - dienylene group.

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. 26A2248

A third subgroup of suitable compounds within the scope of the present invention includes those compounds in which the phenyl ring of the substituent A bears a single lower alkyl radical, ie that R ₁ and R 1 are hydrogen atoms and R 1 - is a lower alkyl radical. Particularly suitable lower alkyl radicals are the methyl, ethyl and n-propyl groups. Most advantageously, the lower alkyl radical is in the 2'-position of the phenyl ring.

A fourth subgroup of suitable compounds within the scope of the present invention includes those compounds in which the phenyl ring of the substituent A bears a single fluorine atom, that is to say that R ^ is a fluorine atom and R ^ and R ^ are hydrogen atoms. Most appropriately, the fluorine atom is in the 4 ¹ -position of the phenyl ring.

A fifth subgroup of suitable compounds includes those in which R-, a fluorine atom in the 4 ^! -Position of the phenyl ring of the substituent A, Rp- is a lower alkyl radical, most advantageously the propyl group in which 2'-StClIuHg is and Rh is a hydrogen atom.

A particularly useful combination of groups or radicals on the phenyl ring of the substituent A, which has a favorable level of Effectiveness exerted on the 3-nitro-coumarin derivatives consists in a polar group, such as a lower acyl radical, a hydrophilic one Group such as hydroxyl group and a hydrophobic group such as lower alkyl. With a particularly suitable one Combination is the lower acyl radical R ^ in the 4'-place

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ment, the lower alkyl radical R ^ in the 2'-position and the hydroxyl group R-, in the j5 'position of the phenyl ring. In this combination, it is most advantageous if R ^ the acetyl group and R ₁ . is the n-propyl group.

In the compounds of the present invention, the radicals R _{1 , R 2} , R ^, Rn and R 1 - need not have any other meaning than hydrogen atoms. Thus, neither the phenyl ring of the substituent A nor the coumarin ring need necessarily be substituted.

A group of compounds of this type, which falls within the scope of the present invention, bears only substituents on the coumarin ring of the general formula I, where R ₁ and Rp have the meanings given above, and R ^, R ^

and Rr- are all hydrogen atoms. 5

Another group of compounds of this type has only substituents on the phenyl ring of the substituent A of the general formula I, where R ₁ and Rg are hydrogen atoms, and R 1, Rn and Rc- have the meanings given above.

Another group of compounds which is included in the present invention bears no substituents either on the phenyl ring of the substituent A or on the coumarin ring. In these compounds of general formula I, all of the radicals R ₁ , R ₂ , R- *, R ^ and R _{1 are} hydrogen atoms. Compounds of this type with few substituents are preferred for reasons of their ease of preparation.

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The AO- substituent is either in the 6-position or, preferably in 7 position. The radicals R ^ and Rp can do the rest Take positions on the coumarin ring, but they are preferably and most appropriately in the 8-position.

Within the general scope of the compounds of the present invention, the radical X represents an oxygen atom or the methylene group. Among the compounds of general formula I in which X is the methylene group are those compounds in which Q also represents the methylene group, with such compounds have valuable oral absorption properties.

Examples of compounds of the general formula I in which X is the methylene group, and in particular R ₁ , R _p , R ^, R ₁ , and R _{K represent} hydrogen atoms, are:

4-hydroxy-5-nitro-6- (2-phenylethoxy) -coumarin, 4-Hydroxy-j5-nitro-7 ~ (2-phenylethoxy) -coumarin, 4-Hydroxy-j5-nitro-7- (> -phenylpropoxy) -coumarin and 4-Hydroxy-3-nitrO-7- (4-phenylbutoxy) coumarin.

Examples of compounds of the general formula I in which X is the methylene group and Rp and R are hydrogen atoms, are:

7- (2-Zi-fluorophenyl7-ethoxy) -4-hydroxy -> - nitro-coumarin, 7- (3- / 5-acetylphenyl7-propoxy) -4-hydroxy-; 5-nitr o-coumarin, 7- (4- / 4-chlorophenyl7-butoxy) ^ - hydroxy-J-nitro-coumarin, 4-hydroxy-7- (4- / 5-methylphenyl7-butoxy) -3-nitro-coumarin and

7- (2- / 2-n-propyl-4-fluorophenyl-7-ethoxy) -4-hydroxy-3-nitro-coumarin.

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Of these compounds, the following are particularly preferred:

4-Hydroxy-j5-nitro-7- (2-phenylethoxy) -coumarin, 7- (2- / i-pluophenyl7-ethoxy) -4-hydroxy-3-nitro-coumarin and 7- (2- / 2-U-ErOPyI-4-fluoropheny l7-ethoxy) -4-hydroxy-5-nitrocoumarin.

When X represents an oxygen atom, Q is expediently the methylene group, but more suitably the ethylene, propylene, butylene, pentylene or hexylene group, which optionally can be substituted by a hydroxyl group, a particularly suitable group being the 2-hydroxypropylene group is.

Examples of compounds of the general formula I in which X is an oxygen atom and R ,, R ₂ * R- ,, R ₁ , and Rj- all mean hydrogen atoms are:

4-Hydroxy-j5-nitro-6- (3-phenoxypropoxy) - coumarin, 4-hydroxy-3-nitro-6- (2-phenoxyethoxy) -coumarin, 4-hydroxy-3-nitro-6- (6-phenoxyhexoxy) -coumarin, 4-Hydroxy-j5-'nitro-7- (3-phenoxypropoxy) -coumarin, 4-hydroxy-3-nitro-7- (5-phenoxypentoxy) -coumarin, 4-hydroxy-3-nitro-7- (4-phenoxybutoxy) -coumarin, 4-Hydroxy-j5-nitro-7- (2-hydroxy-3-phenoxypropoxy) - coumarin, 4-Hydroxy-j5-nitro-7- (6-phenoxy hexoxy) -coumarin and 4-Hydroxy-3-nitro-7- (2-phenoxyethoxy) coumarin.

Examples of compounds of the general formula I in which R, ■ and Rp mean hydrogen atoms are:

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7_ (4-chlorophenoxymethoxy) -4-hydroxy-3-nitro-coumarin, ^ ^ ^ö

7- (2- / 5-acetyl-3-hydroxy-2-hydroxy-2-n-propylphenoxy_7-ethoxy) -

^ l-hydroxy - ^ - nitro-coumarin,

4-Hydroxy-3-nitro-7- (3-phenoxypropoxy) -8-n-propyl-coumarin, 7- (5- / i-chlorophenoxy_7-propoxy) - ^ - hydroxy - ^ - nitro-coumarin, 7- ( 3-Z? ~ Carboxyphenoxy7-propoxy) - ^ - hydroxy - ^ - nitro-coumarin, 7- (J - ^ - carbomethoxyphenoxyy-propoxy) - ^ hydroxy - ^ - nitro-coumarin, 7 - (^ - / i-acetylphenoxyy -propoxy) -4-hydroxy - ^ - nitro-cumacin, 4-hydroxy-7- (3- / ⁱ T-methyl-2-nitrophenoxy_7-propoxy) -3-nitro-

coumarin,

coumarin,

4-Hydroxy-7- (3 - ^ - methylphenoxy_7-propoxy) -3-nitro-coumarin, 7- (3- ₍ A-acetyl-3-hydroxy-2-n-propylphenoxyy-propoxy) -4-hydroxy

3-nitro-curaarin,

7 ~ (3- _< / ^ - carboxyphenoxy7 ⁷ -2-hydroxy-propoxy) -4-hydroxy-3-nitro--

coumarin,

4-Hydroxy-7- (2-hydroxy-3-phenoxypropoxy) -3-nitro-curaarin, 7- (3- ₍ A-acetyl ~ 2-n-propylphenoxyy-2-hydroxypropoxy) -4-hydr oxy-

3-nitro-coumarin,

7- (3 - ^ / acetyl-3-hydroxyphenoxy_7-2-hydroxypropoxy) -4-hydroxy-3-

nitro-coumariti, 7- (3- _J A-acetyl-3-hydroxy-2-methyl-phenoxy ^{; r} -2-hydroxypropoxy) -4-hydroxy-3-nitro-coumarin,

7- (3- / i-acetyl-6-ethyl-3-hydroxyphenoxy_7-2-hydroxypropoxy) -4-

hydroxy-3-nitro-coumarin,

6- (3- / 4-acetyl-3-hydroxy ~ 2-n-propyl-phenoxy-2-hydroxypropoxy)

4-hydroxy-3-nitro-coumarin,

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4-Hydroxy-7- (2-hydroxy-j5 - </ ^ - hydroxy-4-propionyl-2-n-propylphenoxy / -propoxy) -3-nitro-coumarin,

4-Hydroxy-7- (^ - ^ - methylphenoxyJZ-propoxy) - ^ - nitro-coumarin, 4-hydroxy-7- (3-Z -? ^Me thylphenoxyy-propoxy) -3-nitro-4-hydroxy-coumarin _J 7- (3- / im ^e thoxyphenoxyJ7-propoxy) -3-ni tr o-coumarin,

7- (5- / i-Pluorphenoxy_7-propoxy) -ty-hydroxy-jj-nitro-coumarin, 7- (^ - / ^ - Cyanophenox ^ Z-propoxy) - ■ 'f-hydroxy - ^ - nitro-coumarinj

4-Hydroxy-7- (3-Z ^ -Phenylphenoxy_7-propoxy) - ^ - nitro-coumarin, 4-hydroxy-3-nitro-7- (5- / 5,6,7,8-tetrahydro-2-naphthyloxy_7-

propoxy) coumarin,

4-Hydroxy-7- (2-hydroxy-3-Z? -N-propyl-phenoxy_7-propoxy) -3-nitro-coumarin,

4-hydroxy-3-nitro-coumarin.

Examples of compounds of the general formula I in which R, and Rp have other meanings than hydrogen atoms are:

4-Hydroxy-5-methyl-3-nitro-7-C3-phenoxypropoxy) coumarin, 6-ethyl-4-hydroxy-3-nitro-7- (3-phenoxy-propoxy) -coumarin,

4-hydroxy-8-methyl - ^ - nitro-coumarin,

7- (5- / 5-acetyl-3-hydroxy-2-n-propylphenoxy _ / - 2-hydroxypropoxy) -

4-hydroxy - ^ - nitro-8-n-propyl-coumarin.

Particularly preferred compounds are:

7- (3 - ^ - acetyl-3-hydroxy-2-n-propylphenoxy / 7-propoxy) -4-hydroxy 3-nitro-coumarin,

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7- (^ - ^ - acetyl - ^ - hydroxy ^ -n-propylphenoxyy ^ -hydroxypropoxy) -

^ -hydroxy-5-nitro-coumarin,

7- (3-Z ^ ~ ^Acet yl ~ 3-hydroxy-2-n-propylphenox27-2-hydroxypropoxy) -

4-hydroxy-8-methyl-j5-nitro-coumarin,

7- (3- / i ~ acetyl-3-hydroxy-2-n-propylphenoxy / -2-hydroxypropoxy) -

4 ~ hydroxy-8-n-propyl-3-nitro-coumarin,

7- (3-Z2-n-propylphenoxyJ7-2-hydroxy-propoxy) -4-hydroxy-5-nitro-

coumarin,

7- (3- / 2-Methylpherioxy_7-propoxy) -4-hydroxy - ^ - nitro-coumarin, 7 - (^ - Zi-Pluorphenoxy ^ -propoxy) - ^ - hydroxy - ^ - nitrο-coumarin,

2-hydroxy 7- (3- / 2-n-propyl-4-fluorophenoxy_ / 7 ^) ropoxy) -4-hydroxy-3-nitrocoumarin and
4-Hydroxy-5-nitro-6-phenoxyhexoxy-coumarin ...

Examples of suitable salts of the compounds in general Formula I are the alkali metal salts, in particular the sodium and potassium salts, furthermore alkaline earth metal salts, such as the calcium and magnesium salts, then aluminum salts and salts with organic bases such as amines or amino compounds, for example N-methyl-D-glucamine.

The new 3-nitro-coumarin derivatives are valuable drugs which can be presented in different dosage forms.

Accordingly, the present invention also provides medicaments with an SRS-A activity inhibition a content of a compound of the general formula I, if appropriate together with pharmacologically acceptable excipients

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fen and / or diluents.

Examples and preferred definitions of R 1, R ₂ * A, Q, and R ₁ - have been discussed above.

The medicaments according to the present invention can be used as microfine Insufflation powder, the particles of the active compound advantageously having a diameter of less than 50 μm *, preferably below 10 µm - or in the form of an aerosol or a sprayable solution. You can also use the medicines with a sterile liquid carrier for injections or in an ointment, cream, lotion or solution for external use or as suppositories.

Compounds of general formula I that are effective when administered orally can be in the form of syrups, tablets, Capsules, pills and the like can be processed. Preferably the medicaments are in dosage units or in one Form before in which the patient can take and administer a single dose for himself, for example in the form of a Tablet, pill, linguet, powder or lozenge.

Any suitable ones can be used for the preparation of solid medicaments pharmacologically acceptable carrier materials used be, for example magnesium stearate, starch, lactose, glucose, Sucrose, rice flour, talc or chalk. The drugs can also be in the form of digestible capsules, for example from Gelatin capsules containing the compounds or in the form

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a syrup, liquid solution or suspension. Suitable pharmacologically acceptable liquid carrier materials are ethanol, glycerine, physiological saline solution and water together with flavorings and / or colorings to form syrups. A suitable dosage unit can contain 0.1 to 500 mg of active substance. The effective dose of the Compound of general formula I depends on the particular compound used, but is usually in the range of 0.01 to 100 mg per kg of body weight per day.

If necessary, small amounts of antiasthmatic drugs and Bronehodilators, for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine or ephedrine, Xanthine derivatives, such as theophylline or aminophylline, also corticosteroids, such as prednisolone, or adrenal stimulants such as ACTH, can also be used. In common practice, the drugs are provided with written or printed instructions for use regarding medical treatment, in this case as antiallergic agents for the treatment of, for example, asthma, hay fever or rhinitis.

The compounds of the general formula I can be prepared by nitrating the corresponding coumarin derivatives.

Accordingly, a further object of the present invention is a process for the preparation of the compounds of the general Formula I, which is characterized in that a compound of the general formula IV

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(IV)

in which A, ^ ₁ and R _{2 have} the meanings given above ", nitrated with a nitrating agent and then, if appropriate, the compound obtained is converted into a salt. The nitration can be carried out by means of customary nitrating agents, in particular with

(a) acetic acid and concentrated nitric acid or

(b) fuming nitric acid in chloroform.

The temperature at which the reaction is carried out depends on the nitrating agent used. To a nitration of the phenyl ring of the substituent A of the general formula II

X-Q

(II)

R,

to avoid v / ends most preferably a temperature Λ O

below 10 C and a reaction time of up to 90 minutes.

The preferred nitrating agent is fuming nitric acid in chloroform and the reaction is conducted at a temperature of -5 ° C to + 5 ° C, most preferably at 0 ⁰ C, for a period of 15 to 90 minutes conducted.

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- 18--

If appropriate, the compounds according to the invention can mile Except for those that have amino groups or substituted amino groups have, by nitrosating intermediate products of the general formula IV and then oxidizing the obtained Nitroso compound- be made.

Accordingly, a process for the preparation of a compound of the general formula also falls within the scope of the present invention I, which is characterized in that a compound of the general formula IV in which R ,, Rp, R ^, Rj, and R, - the at of the general formula I have given meanings, but with the proviso that the radicals R ^ to R ^ are not amino or substituted Represent amino groups, nitrosated mit.einem alkali metal nitrite in the presence of a lower alkanoic acid and then the Oxidized nitroso compound.

The nitrosation is carried out at temperatures between room temperature and 60 ° C. in a polar solvent. Appropriately the alkali metal nitrite is sodium or potassium nitrite and the lower alkanoic acid is acetic acid. Particularly suitable is the implementation of the oxidation stage in situ by rapid Stir in or rapidly passing air through the nitrosation product.

The present invention also provides intermediate products of the general formula IV ^ l |

in which L, R ₂ and A have the meaning given for general formula I.

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A suitable process for the preparation of the intermediates of the general formula IV consists in the condensation of a suitably substituted o-hydroxy-acetophenone of the general Formula V with diethyl carbonate in the presence of sodium hydride.

The desired substituent A is converted into a corresponding dihydroxyacetophenone of the general "formula VI by means of coupling with a halide, for example a chloride or bromide of the general Formula AY introduced in the presence of potassium carbonate in acetone, as indicated in Scheme 1. In this scheme 1 have the radicals R 1, Rp and A are those given for general formula I. Meanings, and Y represents a chlorine or bromine atom.

Scheme 1

AY + HO-J— I " ^{3 K} 2 ^C0 3 (V)

OH acetones

(VI)

7 0 9 8 13/1010

2BA22A8

(V)

(i) CO (OC ₂ H ₅ ) ₂ ; NaH
(ii) H ⁺

(IV)

Scheme 2

AO

AY

(VIII)

(IV)

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- sr -

JL *

Another suitable process for the preparation of the intermediates of the general formula IV can be seen in the above-mentioned scheme 2, wherein a halide AY is coupled with a hydroxy-4-imino-coumarin of the general formula VII using sodium hydride in dimethylformamide. The 4-imino-coumarin of the general formula VIII obtained is then hydrolyzed to the corresponding 4-hydroxy-coumarin of the general formula IV by means of a strong acid. The hydroxy-4-iminocoumarins of the general formula VII are prepared by customary processes. For example, 7-hydroxy-4-imino-coumarin is produced from ethyl cyanoacetate and resorcinol. This process is particularly valuable for the preparation of J-hryl oxy-alkyleneoxy-coumarins of the general formula IX

Q-

(IX)

in which Q, R ,, Rp, R ^ ₅ Rh and R ₁ - have the meanings given for the general formula I, especially if Q is substituted by a hydroxyl group.

Another process for the preparation of the intermediates of the general formula IV is illustrated in scheme j5. A Halide AY, for example a chloride, is coumarin with a hydroxy-4-benzyloxy-coumarin of the general formula X using

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coupled of sodium hydride in dimethylformamide. Optionally, when Y is a bromine atom, the reaction can be carried out using potassium carbonate in acetone or butanone. The H-llydroxy -coumarin of the general formula IV is obtained after the benzyl group has been split off by hydrogenating the compound XI in the presence of a palladium catalyst. In this scheme, R., Rp and A have the meanings given for general formula I, and Y is a halogen atom and Bz is the benzyl group

Scheme 3

(X)

OBz

rAY

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(χι)

H _o / Pd

(IV)

If appropriate, the intermediates of the general formula IV can be obtained by coupling an epoxide of the general formula XII either with a 4-imino-coumarin of the general formula VII or with 4-benzyloxy-coumarin of the general formula X. These two routes are illustrated in Scheme 4 below. The 4-hydroxy-coumarin of the general formula XIII is either by hydrolysis of the imino-coumarin of the general formula XIV or by hydrogenation of the benzyloxy-coumarin of the general formula XII. This 4-hydroxy-coumarin falls under the definition of general formula IV. In Scheme 4, the symbols have the definition given above, and η is a number from .1 to 4.

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The examples illustrate the invention.

example 1

2-hydroxy-4- (3-phenoxy propoxy) acetophenone

A mixture of 21.5 g (0.1 mol) of 1-bromo-jJ-phenoxypropane, 15.2 g (0.1 mol) of 2,4-dihydroxy-acetophenone and 20.8 g (0.15 mol) of anhydrous Potassium carbonate in 300 ml of anhydrous acetone is stirred under reflux for 24 hours until thin-layer chromatography shows that the reaction is complete. After cooling, the potassium salt is filtered off and the piltrate is evaporated to a pink solid substance which, when recrystallized from ethanol in the presence of activated charcoal, yields 21.94 g (= 77 % of theory) of a white solid of thin layer chromatography purity and a melting point of 82 delivers up to 82.5 ° C.

> ^ (Grid): I6l8, l600, 1595 cm " ¹ .

7.7 ^ (2H, quintet, J = 6.0 Hz); 7.48 (3H, s); 5.85 (2H, t, J = 6.3 Hz); 5.79 (JH, t, J = 6.3 Hz); 3.54 (2H, ra); 3.22 - 2.38 (5H, complex multiplet); 2.37 (IH, d, J = 9.5 Hz); 1 interchangeable proton in the low field.

analysis for C 71 C. 6th H 71 , 31 6th , 3 ^ , 28 , 58 L7 ^H l8 ° 4 ^: ber .: found:

The examples in Table I are carried out in the same way.

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Tabel

- 26 -

at
game 6th link 1 Pp., ° C yield
in % I. ^c l6 ^H l6 ° 5 analysis H (fo) 2 2-hydroxy-4- (2-phenylethoxy) aceto
phenone ■ 69 45 ber .: C (*) 6.29 7th found: 74.98 6.17 ^c l6 ^H l6 ° 5
ber .: 74.8o H (%)
6.29 3 2-hydroxy-5- (2-phenylethoxy) aceto
phenone 5β 21 found: C (fo)
74.98 6.55 ^c 17 ^H l8 ° 5 74.99 H (J *) 4th 2-hydroxy-4- (5-phenylpropoxy) aceto
phenone 74-77 85 ber .: C (fo) 6.71 found: 75.55 6.87 ^C 17 ^H 18 ° 5 75.47 H (Ji) 5 2-hydroxy-5- (5-phenylpropoxy) aceto
phenone 54-55 54 ber .: C (fo) 6.71 found: 75.55 6.90 ^C 18 ^H 20 ° 5
ber .: 75.82 H {%)
7.09 2-hydroxy-4- (4-phenylbutoxy) aceto
phenone 55 59 found: C (fo)
76.05 7, oo C ₁₈ H ₁₉ ClO
ber .: 75.95 H (fo) Cl (*) j
, 01 11.12 4- (4- / ^J T-chlorophenyl7-butoxy) -2-hydroxy-
acetophenone 75-75 71 found: C (fo)
67, Sl 6 , ^ 11.25 68.17 6

continuation

Table I.

- 27 -

at link • "Cw ^ Γ ¹
X ¹ P. , Li yield ^C 19 ^H 22 ° 3 analysis H {%) 1 4 >> game 2-hydroxy-4- (4- / 4-methylphenyl / -
butoxy) acetophenone 69-70 in % about ,: C (*) 7.38 K) 8th 72 found: 76.57 7.59 K>
• J> ■ ^C l6 ^H l6 ° 4 76.22 H (*) 2-hydroxy-4- (2-phenoxyethoxy) -
acetophenone 133-134 ber .: C {%) 5.92 9 62 found: 70.57 6.00 ^C l6 ^H l6 ° 4 70.49 H {%) 2-hydroxy-5- (2-phenoxyethoxy) -
acetophenone. 133-114 ber .: C (fo) 5.92 10 43. found: 70.57 5.94 ^c l7 ^H i8 ° 4 70.58 ■ H (*) 2-hydroxy-5- (3-phenoxypropoxy) -
acetophenone 87-88 ber .: C {%) 6.34 11 70 found: 71.31 6.50 ^C 18 ^H 20 ° 4 71.34 H (*) 2-hydroxy-4- (4-phenoxybutoxy) -
acetophenone 95-96 ber .: C {%) 6.71 12th 87 found: 71.98 6.83 O ₁₉ H ₂₂ O ₄ 72.06 H (Ji) 2-hydroxy-4- (5-phenoxypentoxy) -
acetophenone 51-52 ber .: C {%) 7.05 13th 62.5 possibly.: 72.59 7.07 ^C 19 ^H 22 ° 4 72.3 ² I- H (*) 2-hydroxy-5- (5-phenoxypentoxy) -
acetophenone 45 about ♦: c (*) 7.05 14th 78 found: 72.59 7.21 ^C 20 ^H 24 ° 4
ber .: 72.77 H (%)
1.31 2-hydroxy-4- (6-phenoxyhexoxy) -
acetophenone 71-74 found: 75.15 7.16 15th 69 72.98

continuation

Tabel

- 28 -

CD CO OO

at link M.p., ⁰ ° C yield ^C 20 ^H 24 ° 4 analysis H ( %) ro game 2-hydroxy-5- (6-phenoxyhexoxy) -
acetophenone 78 in % about ,: C (Jg) 7.57 cn 16 45 found: 75.15 7.51 K) • C ₁₇ H ₁₇ ClO 71.80 η (ji) egg (ji) κ> 4- (5- / 5-chlorophenoxy_7-propoxy) -
2-hydroxy-acetophenone 82-85 ber .: 4 c. (ji) 5.54 11.05 co 17th 80 found: 65.65 5.41 10.99 C 0Hp ₀ O ₂ , 65.56 2-hydroxy-4- (5- / 4-methylphene 85-87 η (si) 18th oxyy-propoxy) -acetophenone 67 ber .: 6.71 found: 71.98 7.01 ^C IRHp _n Oh 72.52 2-hydroxy-4- (5- / 3-methylphene- 64 c (Ji) Xl \ / 0] 19th oxyy-propoxy) -acetophenone 80 ber .: 71.98 6.71 found: 7i, 95 6.95 0-ιθΗρ _η 0η c (Ji) 2-hydroxy-4- (5- / 2-methylphene 64 JU C. \ J ¹ T 71.98 η \ fo j 20th oxyy-propoxy) -acetophenone . 65 ber .: 72.28 6.71 found: 6.77 C (Ji) 2-hydroxy-4- (5 - ^ - methoxyphene- ^C 18 ^H 20 ° 5 68.54 η (ji) 21 oxyy-propoxy) -acetophenone 75-76 ber .: 68.14 6.57 59 found: C (%) 6.51 C ₁₇ H ₁₇ FO ₄ 67.11 η (si) 4- (5-Z ^ ~ ^I? I ^uo ^ P ^nenox yy ^r ~ P ^ro P ^o xy-
2-hydroxy) acetophenone 70-72 ber .: 67.24 5.59 22nd 59 found: 5.61

continuation

Tabel

O CO CXD

at
game link M.p., ⁰ ° C yield
in % ^c l8 ^H 17 ^NO 4
ber .:
found: analysis H {%) N {%)
5.47 4.50
5.67 4.22 25th 4- (5- / ^J f-cyanophenoxy _ / - propoxy) -
2-hydroxy-acetophenone 151-155 65 ^C 25 ^H 22 ° 4
ber .:
found .; C {%)
69.45
69.26 H {%)
6.08
6.44 24 2-hydroxy-4- (5-, A-phenylphen
oxy, / - propoxy) acetophenone I8I-I2I 72 C ₂₁ H ₂₂ O ₄
ber .:
found: C {%)
76.25
76.52 H {%)
7.06
7.11 25th 2-hydroxy-4- (5- / 5,6,7,8-tetra-
hydro-2-naphthyloxyy-propoxy) -
acetophenone 80-82 59 ^C 20 ^H 24 ° 4
ber .:
found: C {%)
74.12
74.11. H (*)
7.37
7.57 26th 2-hydroxy-4- (5-phenoxypropoxy) -
5-n-propyl-acetophenone 67-68 84 C ₁₉ H ₂₂ O ₄
ber .:
found: C (Ji)
73.15
75.05 H (%)
7.05
7.20 27 5-ethyl-2-hydroxy-4- (5-phenoxy
propoxy) acetophenone 60.5-61 , 5 ■ 74 C {%)
72.59
72.45

Example 28

1-chloro-3-phenoxy-2-propanol

A mixture of 94 g (1.0 mole) phenol and 138.8 g (1.5 mol) of epichlorohydrin is stirred at 100 ⁰ C for 6 hours in the presence of 2.0 g of piperidine hydrochloride vigorously, then cooled and then under reduced pressure at 100 ⁰ C of excess epichlorohydrin freed. The residue is cooled, dissolved in the same volume of chloroform and stirred vigorously with excess concentrated hydrochloric acid for 30 minutes. After separating into phases, the organic layer is washed with water, dried and evaporated to a colorless oil. After distillation of 112 ⁰ C to obtain 116.4 g (= 62.5% of theory) of l-chloro-3-phenoxy-2-propanol, bp. At 0.6 Torr (purity due to the gas chromatography).

^ _mov (film): 3310, I603, 1590, 1495, 1245 cm " ¹ , max

"£ (CDC1,): 7.40 (broad, exchangeable singlet); 6.25 (2H, J = 3.5 Hz); 5.90 (2H, s) j 5.90 (IH, m); 3.21-2.56 (5H, m)

The compounds of Table II are prepared in the same way.

709813/1010

T a b e 1 link 1 e II 1.5 ²² ° yield
in % analysis - 51 - at
game l-chloro-5- (2-n-propylphenoxy) -
2-propanol Fp. or
Kp. In C 0.5 W- ¹ ^ ² 44 29 1- (4-acetyl-2-n-propylphenoxy) -
5-chloro-2-propanol Kp. 2.0 ¹ ^ ⁶ " ¹⁴⁰ 100 ^C l4 * ⁱ 19 ^C "'" ^O 5
ber .:
found: 50 1- (4-acetyl-5-hydroxyphenoxy) -
5-chloro-2-propanol oil 60 C (Ji)
62.10
61.52 η (*) approx. W
7.07 15.10
7.01 14.02 51. 1- (4-acetyl-5-hydroxy-2-raethyl-
phenoxy) -5-chloro-2-propanol 'Oil 6l> 52 1- (4-aoetyl-5-hydroxy-2-n-propyl
phenoxy) -5 ~ chloro-2-propanol Pp 112-116 89 1- (4-acetyl-2-allyl-5-hydroxy-
phenoxy) -5-chloro-2-propanol oil 61 ^G l4% 7 ^C ' ¹ ' ^ 4
ber .:
found: 54 1- (2-allyl-5-hydroxy-4-proprio-
nyl-phenoxy) -5-chloro-2-propanol Fp. 100-104 100 ^C 15 ^H 19 ^C1O 4
ber .:
found: C (Ji)
59.05
58.78 H {%) Cl (#)
6.02 12.45
6.08 15.19 35 1- (4-acetyl-6-ethyl-5-hydroxy-
phenoxy) -5 ~ chloro-2-propanol oily-solid 74 C ^ Hj ^ ClQ ^
ber .:
found: C {%)
60.50
60.17 H {%) Cl (^)
6.41 11.87
6.44 12.25 56 1- (4-carbomethoxyphenoxy) -5-
chloro-2-propanol Kp. 75 C-qH-j ^ CIO ^
ber .:
found: c W
57.25
57.66 H {%)
6.28
6.50 57 Kp. C (J6)
54.05
54.50 H (fo) Cl (Jg)
5.56 14.49
5.51 14.17

Example 38 «« * ♦ *

^^ 4-Dihydro-7- (2-hydroxy ~ 3-phenoxypropoxy) -4-imino-coumarin To a warm, stirred suspension of 17 * 7 g (OjI mol) of 3,4-dihydro-7-hydroxy-4-imino coumarin in 75 ml of anhydrous dimethylformamide, 2.4 g (0.1 mol) of sodium hydride are added in portions. The mixture is refluxed for 90 minutes until the sodium salt is completely formed. A solution of 18.7 (0.1 mol) of 1-chloro-3-phenoxy-2-propanol in 10 ml of anhydrous dimethylformamide is then added dropwise while refluxing and the mixture is stirred under reflux for a further 4 hours. The solvent is then removed under reduced pressure and 200 ml of water are added to the residue. The yellow solid is filtered off, washed well with water and dried under reduced pressure over Pp ° C. 30 * 0 g (= 92 % of theory) of a crude product which was suitable for most purposes are obtained. After recrystallization from ethyl acetate, the compound is obtained with a mp. 213 to 214 ° C.

"ν * ν (grid): 3320, 3200, complex carbonyl range

I690-I590 cm " ¹ .

X (DMSO): 5.82 (5H, m) j 5.35 (2H, broad exchangeable singlet); 4.85 (IH, s); 3.20-2.52 (8h, multiplet with 1 proton, which is removed after DpO exchange); 2.02 (IH, d) ..

Analysis for C ₁₈ H ₁₇ NO ₅ 0.5H ₂ OC (%) H (#) N {%)

calc .: 64.28 5.39 4.16 found: 64.52 5.26 3.78

The compounds of Table III are prepared by the same procedure.

70981 3/1010

Table III

- 33 -

CD CO OO

CD CD

at link Pp., ⁰ C yield C ₂₀ H _lq N0 ₆ analysis 59.55 tr fet \ N {%) game 7- (3- / i-acetyl-3-hydroxyphenoxy_7- I58-I59 in % C * f csi \ 58.98 Xl \ ya J 3.79 39 propoxy} -5,4-dihydro-4-imino-coumarin 60 ber .: \ S I JQ J 5.18 3.49 found: 65.03 5.54 N {%) C ₂₀ H ₁₉ NO ₅ 64.90 H (%) 3.96 7- (3-Z4 "-Acetylphenoxy_7-propoxy) -3,4-
dihydro-4-imino-coumarin • I65-I68 ber .: C {%) 5.42 3.92 40 94 found: 67.98 5.54 N {%) C ₁₉ H ₁₉ NO ₄ 67.59 H {%) 4.30 3,4-dihydro-5-methyl-7- (3-phenoxy-
propoxy) -4-imino-coumarin 164-167 ber .: C {%) 5.89 3.96 41 91 found: 70.14 6.12 N {%) ^C 20 ^H 19 ^N0 6 ^I. 69.81 H {%) 3.62 7- (3-Z ^ -Carbotnethoxyphenoxy_7-
propoxy) -3,4-dihydro-4-imino- 155 ber .: ^ ⁰ c (%) 5.46 3.39 42 coumarin 100 found: 62.01 5.49 N {%) 62.4θ ) H {%) 3.47 7- (3-Z4 ~ -CarbomethoxyphenoxyJ7-2-
hydroxypropoxy) -3,4-dihydro-4- 212-215 C ₂₀ H ₁₉ NO ₇ H ₂ O _{c {%]} 5.25 3.58 43 imino-coumarin 94 ber .: 5.04 found:

JZ

Example 44

4-benzyl oxy-7-hydroxy-coumarin

A solution of 1.78 g (0.01 mol) of 4,7-dihydroxycoumarin in 7.5 ml of anhydrous dimethylformamide is stirred with the addition of 0.24 g (0.01 mol) of 100 percent sodium hydride. The mixture is stirred ^{at 100 °} C. for a further hour. A solution of 1.27 g (0.01 mol) of benzyl chloride in 1 ml of anhydrous dimethylformamide is then added dropwise and stirring is continued at 100 ^° C. for a further 4 hours. After the solvent has evaporated off under reduced pressure, water is added and the oily solid which separates out is separated off. After recrystallization from ethanol (23% of theory =) gives 0.623 g of the aforementioned compound of mp. °

( ^Glfcter ) ^: 5150, 3050, 1710, I630 cm " ¹ .

X (DMSO): 4.67 (2H, s); 4.19 (IH, S); 3.28 (IH near s);

3.20 (IH, dd., J = 2.0 Hz; 5.0 Hz); 2.66-2.26 (6H, m); 1 exchangeable proton wide in the low field.

Analysis for Cj ^ H- ^ O ^ C (%) H

calc .: 71.64 4.51

found: 71.51 4.70

Example 45

4-Benzyloxy-7- (2- ^ T-fluorophenyl7-ethoxy) -coumarin A mixture of 5.36 g (0.02 mol) of 4-benzyloxy-7-hydroxy-coumarin, 4.0 g of anhydrous sodium carbonate and 4, 06 g of l-bromo-2- (4-fluorophenyl) propane in 100 ml of acetone is refluxed for 20 hours

70981 3/10 10

touched. Inorganic substance is then filtered off. Evaporation of the filtrate under reduced pressure gives an oil which solidifies rapidly on scratching. After 200 ml of chloroform have been added, the mixture is filtered in order to remove unreacted 4-benzyloxy-7-hydroxy-coumarin. After renewed evaporation of the piltrate, 3.34 g (= 43 % of theory) of a white solid of melting point are obtained . 120 ⁰ C.

( ^Grid ) ^{: χ} 715, 1675, 1β20 cm " ¹

t (CDCl ₃ ): 6.93 (2H, t, J = 6.7 Hz); 5.8θ (2H, t, J = 6.7 Hz); 4.87 (2H, s); 4.38 (IH, s); 3.29-2.49 (βΗ, m); 2.32 (IH, d, J = IO Hz).

Analysis for C ₂ ^ H ₁₉ FO ₄ C {%) H

her.-. 73.84 4.91

found:

Example 46

7- (3-Z ^ r-Acetylphenyl7-propoxy) -4-benzyloxy-coumarin The alkylation process; of Example 45 is mixed with 2.68 g (0.01 mol) of 4-benzyloxy-7-hydroxy-coumarin and 2.4l g (0.01 mol) of 1- (4-acetylphenyl) -3-bromopropane repeated. After recrystallization from ethanol, 3.28 g (= 77 # of theory) of the above-mentioned compound with a melting point of 117 ° C. are obtained

_me (grid): 1725, 1682, 1620 cm " ¹ , max

7098 13/1010

7.92 (2H, m) j 7, ^ 8 (JH, s); 7.18 (2H, m); 5.94 (2H, t, J = 6.4 Hz); 6.69 (2H, X); 6.16 (IH, s); 3.17-2.00 (12H, m).

analysis for C ₂₁ H ₂₄ O ₅ 75 C {%) H {%) ber .: 75 , 68 5.65 found: , 14 5.52

Example 47

2-Hydroxy-3-n-propyl-4- (tetrahydropyran-3-yloxy) -acetophenone 3 drops of concentrated hydrochloric acid are added to a mixture of 10 g of 2,4-dihydroxy-3-n-propyl-acetophenone and 25 ml of dihydropyran . The mixture heats up to form a solution. After standing overnight at room temperature, ether and then a 2.5 N sodium hydroxide solution are added. After separation into phases, the aqueous phase is extracted with ether. The combined organic phases are washed with water, dried over magnesium sulfate and evaporated to an oil which is distilled. 12.05 g (= 77 %) of the ether with a boiling point of 152 to 172 ° C. at 0.4 torr are obtained.

>? (Film): 2680 (wide), I725, I630 / I59O, 1494 cm " ¹ .

Example 48

4-Hydroxy-8-n-propyl-7- (tetrahydropyran-3-yloxy) -coumarin A solution of 12.05 g (0.043 mol) of 2-hydroxy-3-propyl-4- (tetrahydropyran-3-yloxy) - acetophenone in 100 ml of anhydrous benzene is added to a stirred suspension of 2.40 g (0.1 mol) of sodium hydride in 100 ml of anhydrous benzene over a period of 30 minutes while refluxing. After another 10 minutes will

709813/1010

a solution of 10.7 g (0.087 mol) of diethyl carbonate in 100 ml of benzene was added over the course of 1 hour. The mixture is then stirred under reflux overnight. Then water is added to the cooled solution and the brown aqueous phase obtained is washed with ether, cooled to below 5 ° C. and carefully acidified. A pale yellow solid precipitates out, which is filtered off and washed well with water / water. After recrystallization, 6.986 g (= 53 % of theory) of the compound of B ⁿ p mentioned in the title are obtained. I6j5 to I65 C.

> (Grid): 2710, 2600, I66O, I63O, I6OO cm " ¹ max

X (DMSO): 9, 08 (3H, t, J = 7.0 Hz); 8.34 (BH, m); 7.25 (2H, m); 6.36 (2H, broad)] 4.50 (IH, exchangeable sharp singlet); 4.33 (IH, broad singlet); 2.62 (2H, AB-quartet, J = 9.0 Hz); £ v> 35 Hz). 1 exchangeable proton wide in the low field.

analysis for C 17 ^H 20 ° 5 C. , 09 6th H (*) ber .: 67 , 49 6th , 62 found: 67 , 89

Example 49

4-benzyloxy-7-hydroxy-8-n-propyl-coumarin

0.528 g (10 percent excess) of sodium hydride are added to a solution of 6.08 g (0.002 mol) of 4-hydroxy-8-n-propyl-7- (tetrahydropyran-3-yloxy) coumarin in 10 ml of anhydrous dimethylformamide and the mixture is heated the stirred mixture to 100 ⁰ C. Then is added a solution of 2.76 g (corresponding to 2.5 ml; lOprozentiger

709813/1010

Excess) of benzyl chloride in 2 ml of anhydrous dimethylformamide over the course of 30 minutes added and the mixture is kept 6 stood at a temperature of 100 to 110 ⁰ C.

After cooling, the solvent is removed under reduced pressure and water is added. The precipitated sticky solid is taken up in chloroform, washed with dilute sodium hydroxide solution and then with water and dried. After evaporation, a pink-colored solid is obtained which, after recrystallization from ethanol 1.533 S (= 19.5 % of theory), gives white crystals of the tetrahydropyranyl ether of the compound mentioned in the title with a melting point of 146 ° to 147 ° C.

"max ( ^Gitfcer ) ^: 3-735, 1625, 1615 cm" ¹

: 9.11 (3H, t, J-7.5 Hz); 8.36 (Sn, m); 7.28 (2H, t, J = 7.5 Hz); 6.44 (2H, m); 4.70 (2H, s); 4.40 (IH, s); 4.18 (IH, s); 2.94 (IH, d, J = 9 Hz); 2.58 (5H, m); 2.40 (IH, d, J = 9Hz).

analysis for ^C 24 ^H 26 ° 5 C. (*) 6th H {%) ber .: 73, 08 6th , 64 found: 73, 14th , 78

The alkaline wash water after acidification gives a brown tar which, after dissolving in hand, gives a further 0.905 g (= 15 % of theory) of the compound mentioned in the title when left to stand. Their melting point is 213 to 214 ⁰ C.

70981 3/1010

max ( ^Gitfcer ) ^: 3050 (wide), 1675, I605, 1570 cm " ¹ .

'C (DMSO): 9.09 (3H, t, J = 7.5 Hz); 8.46 (2H, s); 3.15 (IH, d,

J = 9 Hz); 2.56 (OH, m) f1 in the low field interchangeable Proton.

Analysis for C ₁₉ H ₁₈ O ₂ ^ C (j6) H (j6) calc .: 73.53 5.85 found: 73.54 6.07

When the tetrahydropyranyl ether isolated from the ethereal phase is cleaved with methanolic acid, the compound mentioned in the title is obtained in a yield of 71 % and a pp of 212 ° C. after recrystallization.

Example 50

7- (3 "/ 4-acetyl - 3-hydroxy-2-n- propylphenoxyy ^r -2-hydroxypropoxy) -4-benzyloxy-c umarin

A solution of 5.36 g (6.02 mol) of 4-benzyloxy-7-hydroxy-coumarin in 30 ml of anhydrous dimethylformamide 0.48 g of (0.02 mol) lOOprozentigem Natriuranydrid treated and about 1 hour at 100 ⁰ C. touched. To this solution is added a solution of 7 S 1- (4-Acetyl-3-hydroxy-2-n-propylphenoxy) -3-chloro-2-propanol in 2 ml dimethylformamide and stir the resulting mixture for a further 4 hours at 100 ⁰ C. After removing the solvent under reduced pressure, add water and extract with chloroform. After the extract has been chromatographed on 300 g of silica gel and eluted with chloroform, the compound mentioned in the title is obtained after recrystallization from etha

709813 / 101Q

nol as a white crystalline solid with a melting point of 172 ° to 173 ° C. and a boiling point of 0.38. Yield: 4.38 g (= 42 % of theory).

^ _Qv (grid): 1715, I630, I620 cm " ¹ , max

IT (DMSO): 9.19 (3H, t, J = 7.0 Hz); 8.58 (2H, sextuplet, J = 7.0 Hz) 7.48 (3H, s + 2H, m); 6.71 (IH, sharp, interchangeable); 5.80 (5H, s); 4.68 (2H, s); 4.50 (IH, broad, interchangeable); 4.13 (IH, s); 3.32 (IH, d, J = 9 Hz); 3.12-2.15 (12H, m); IH in the low field interchangeable, sharp).

Analysis for C 30 ^H 30 ° 8 C {%) H (fo) ber .: 69.49 5.83 found: 69.30 5.80

Using analogous methods, although chromatography is not always necessary, the following table IV listed compounds.

709813/1010

tab link Hurry 153-155 IV analysis - 41 - - H {%) ci (si) at yield C ₂₃ H ₁₇ ClO _{5 c (} ^. 6.02 8.67 game M.p., ⁰ ° C in % calc .: 67.57 6.05 8.64 51 4-benzyloxy-7- (4-chloro-phenoxy- \ 146-147
methoxy) coumarin \ found: 67.69 H (Si) 190 4.19 4.33 H (#) 52 7- (2-Z4-acetyl-2-hydroxy-3-n- C ₂₇ H ₂₄ O _{7 c} ^ 5.45 propylphenoxy_7-ethoxy) -4-benzyl
oxycoumarin calc .: 70.43 5 ^,; +4 53 4-Benzyloxy-7- (3-Z ^ - ^cari koniethoxy- IO9-IIO 69 found: 70.42 Tr (rf \ phenoxyJ7-propoxy) - coumarin C W Π. ^. Π \ / 0 y 192-195 5.25 ber .: 71.70 5.60 54 7- (3 - /? - acetyl-3-hydroxy-2-n- 154 found: 71.77 V! (of. \ propylphenoxy_7-propoxy) -4-benzyl ^C 28 ^H 28 ° 6 C {%)
calc .: 73.04 JZ oxy-coumarin found: 73.04 6.02 - raw product 6.29 55 4-benzyloxy-7-v (2-hydroxy-3 -, / 2-n-
propylphenoxyj ^ -coumarin 157 26th H {%)
6.13 ^C 30 ^H 30 ° 7 C {%) 6.05 56 7- (3- / 4-acetyl-3-hydroxyphenoxyy-
2-hydroxypropoxy) -4-benzyloxy- 33 ber .: 71.70 coumarin found: 71.85 57 7- (3T / 5-acetyl-2-n-propylphenoxy_7- OqO JTIq ^: VJQ VJ. > i ₂ U / "Tl 2-hydroxypropoxy) -4-benzyloxy- ^ (ν / £ 1U W CZ. Oil coumarin C (si) K) calc .: 67.32 K) 58 7- (3-Z5-acetyl-3-hydroxy- & ethyl- 30th found: 67.24 co phenoxy _ / - 2-hydroxypropoxy) -4- benzyloxy coumarin

Port setting

b e 1 1 e IV

- 42 -

at
game link M.p., ° C yield
in % analysis 59
60
61
62
63
64 7- (3- / £ -acetyl-6-ethyl-3-hydroxy-
phenoxy _ / - 2-hydroxypropoxy) -4-benzyl-
oxy-coumarin
7- (3- _< /2-allyl-3-.hydroxy-4-propionyl-
phenoxy_7-2-hydroxypropoxy) -4-benzyl-
oxy-coumarin
7- OZ ^ -Acetyl-O-hydroxy - ^ - n-propyl-
phenoxy_7-2-hydroxypropoxy) -8-methyl-
4-benzyloxy-coumarin
7- (3-Z ^ r ^ ^ce ^ yl ~ 5- ⁿ ydroxy-2-n-propyl-
phenoxyJ7-2-hydroxypropoxy) -8-allyl-
4-benzyloxy-coumarin
7- (3-Z ^ -acetyl-3-hydroxy-2-n-propyl-
phenoxjrj- 2 -hy dr oxy pr ο poxy) - 8 -n-propyl-
4-benzyloxy-coumarin
6- (3-Z ^ - ^Ace tyl-3-hydroxy-2-n-propyl
phenoxyJ7-2-hydroxypropoxy) -4-benzyl-
oxy-coumarin 195
200
201-203
foam
foam 37
25th
37
41
38 ^C 29 ^H 28 ° 8 C {%) H {%)
calc .: 69.04 5.59
Found: 68.98 5.67
^C 31 ^H 30 ° 8 C {%) H {%)
calc .: 70.17 5.70
found: 70.19 5.54 '
C ₅₁ H ₃₃ O ₈ 0.5H ₂ O _c ^ _{o) H} ^
ber .: 68.6l 6.31
Found: 68.83 6.04
R _f (CHCiySiOg) 0.50
R _f (CHCWSiO ₂ ) 0.43

Example 65

4-Hydroxy-7- (3-phenoxypropoxy) coumarin in

A solution of 14.35 g (0.0509 mol) of 2-hydroxy-4- (J> - phenoxypropoxy) acetophenone in 100 ml of anhydrous benzene is added to a refluxing, stirred 60 percent suspension of 4.60 g (0.115 mol) Sodium hydride in mineral oil in 100 ml of anhydrous benzene was added within J> 0 minutes. After a further 10 minutes, a solution of 12.02 g (0.102 mol) of diethyl carbonate in 100 ml of anhydrous benzene is added over the course of 1 hour under reflux and the solution is kept under reflux for a further 19 hours. After cooling, the mixture is poured into 550 ml of ice-cold 2N hydrochloric acid. The solid precipitate is filtered off and washed well with water. After recrystallization from ethanol in the presence of activated carbon is obtained 10 ^ 5 g (= 65 / o of theory) of the above title compound as a white in Peststoff mp. I90 to 192 ⁰ C (decomposition).

Λ (grid): 3270, 2600 (wide), 1715, I65.O, ΐβΙΟ cm " ¹ .

t (DMSO): 7.7 ^ (2H, quintet, J = 6.5 Hz); 5.8θ (2H ₅ t, J = 5.5 Hz);

5.68 (2H, t, J = 7.0 Hz); 4.28 (i _H , s); 3.17-2.48 (7H ₅ m);

2.20 (IH, d, J = 9.0 Hz); 1 interchangeable in the NiederfeM Proton.

Analysis for ^c x8 ^H l6 ° 5

ber .: found .:

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

709813/1010

C. (*) 5 H ( 69 22nd 5 , 16 69 22nd , 21

Table V

- 44 -

at ¹ 71 link M.p., ⁰ ° C yield C ₁₇ H ₁₄ O ₄ analysis H (*) - <. C51 game 4-hydroxy-6- (2-phenylethoxy) -
cumärin 189 in % ber .: c (%) ■ 5.00 4> » 66 71 found: 72.33 4.95 ro
K) 72 C ₁₇ H ₁₄ O ₄ 71.95 H (*) -P- 4-hydroxy-7- (2-phenylethoxy) -
coumarin 203 ber .: c (%) , 5, oo egg (*) OD 67 49 found: 72.33 4.98 10.28 ^c l8 ^H l6 ° 4 72.34 H (%) 10.46 4-hydroxy-6- (3-phenylpropoxy) -
coumarin 212 ber .: C (fo) 5.44 68 83 found: 72.96 5.62. ^C l8 ^H l6 ° 4 73.02 H (fo) 4-hydroxy-7- (3-phenylpropoxy) -
coumarin 255 ber .: C (fo) 5.44 69 56 found: 72.96 5.70 ^C 19 ^H 18 ° 4 72.77 H (Ji) 4-hydroxy-7- (4-phenylbutoxy) -
coumarin I92 ber .: C (fo) 5.85 70 42 found: 73.53 5.87 C ₁₉ H ₁₇ ClO 73.62 H (fo) 7- (4- / 4-chlorophenyl / butoxy) -4-
hydroxy-coumarin 209-210.5 ber .: 4 c (fo) 4.97 63 found: 66.19 4.95 ^C 20 ^H 20 ° 4 66.05 H ($>) 4-hydroxy-7- (4- / 5-methylphenyl / -
butoxy) coumarin - I98-2OI ber .: C (%) 6.17 57 found: 74.07 6.14 73.80

Port setting link T a b e 1 I. L e V - analysis C (fo) 45 - C73 at 4-hydroxy-6- (2-phenoxyethoxy) -
coumarin yield C ₁₇ H ₁₄ O ₅ 68.45 ro game Pp., ⁰ C in % ber .: 68.67 73 211 39 found: C (fo) H (%) co 4-hydroxy-7- (2-phenoxyethoxy) -
coumarin C ₁₇ H ₁₄ O ₅ 68.45 4.73 ber .: 68.50 4.79 74 244 39 found: C (fo) H (%) 4-hydroxy-6- (3-phenoxypropoxy) -
coumarin ^C l8 ^H l6 ° 5 68.45 4.73 ber .: 69.18 4.84 75 204-205 71 found: C (fo) H (fo) 4-hydroxy-7- (4-phenoxybutoxy) -
coumarin ^C 19 ^H 18 ° 5 69.93 4.73 ber .: 69.92 5.35 76 194 70 found: ⁰ c (% H (%>) 4-hydroxy-6- (5-phenoxypentoxy) -
coumarin ^C 20 ^H 20 ° 5 ^H 2 67.03 5.56 ber .: 66.61 5.61 77 163-164 40 found: C (%) ) H (%) 4-hydroxy-7- (5-phenoxypentoxy) -
coumarin ^C 20 ^H 20 ° 5 70.57 6.19 ber .: 70.54 5.83 78 180 49 found: C (fo) H (fo) 4-hydroxy-6- (6-phenoxykexoxy) -
coumarin ^C 21 ^H 22 ° 5 71.17 5.92 ber .: 70.37 6.00 79 I62-I63 58 found: 5H _Q 0 _p H (fo) 4-hydroxy-7- (6-phenoxyhexoxy) -
coumarin ^C 21 ^H 22 ° 5 ⁰ * 69 6.26 ber .: 69 6.47 80 170 22nd found: (fo) H (*) , 41 6.38 , 36 6.12

Port setting Table V

,,
at link Mp-, ° C yield Anal ^ se C (fo) H (fo) Cl (fo) game 7- (5 - / ^ - chlorophenoxyJ7-propoxy) -
4-hydroxy-coumarin 25O-254 in % C ₁₈ H ₁₅ ClO ₅ 62.35 4.36 10.22 -81 71 . about ,: 62.00 4.76 10.22 found: c. (Ji) H (fo) 4-hydroxy-7- (3- <A-methylphenoxy_7-
propoxy) coumarin 209-212 ^C 19 ^H 18 ° 5 69.93 5.56 82 69 ber .: 69.99 5.86 found: C (fo) H (%) 4-hydroxy-7- (3- / 3-methylphenoxy7-
propoxy) coumarin I90 ^c 19 ^H l8 ° 5 69.93 5.56 83 26th ber .: 69.75 5.62 found: c (%) HW 4-hydroxy-7- (3- / 2-methylphenoxy_7-
propoxy) coumarin 203 ^C 19 ^H 18 ° 5 69.93 5.56 84 24 ber .: 69.82 5.80 found: C (%) H (*) U 4-hydroxy-7- (5- / 5-methoxyphenoxy_7-
propoxy) coumarin I93-I96 ^C 19 ^H 18 ° 6 66.66 5.50 85 73 ber .: 66.66 5.52 found: C (%) H (fo) 7- (3- / 4-fluorophenoxy_7-propoxy) -
4-hydroxy-coumarin 2O5-2O6 ^c l8 ^H 15 ^FO 5 65, ^ 5 4.55 86 58 ber .: 65.67 4.84 found:

Table V continued

- 47 -

O CO OO

Bel- link M.p. ,, ⁰ ° C yield analysis 5 \ Λ * J H {%) N {%) game 7- (5-Z4 ~ cyanophenoxy_7-propoxy) ~
4-hydroxy-coumarin 180-184 in % ^C 19 ^H 15 ^NO 5 ber .: 67.66 4.45 4.15 87 50 about ,: found: 67.81 5.05 5.92 found .; ^C 20 ^H 20 ° 5 ρ- (af \ 4-hydroxy-7- (5 -, / 4 * -pneny! Phen 240-242 CoiiHpoOc ber .: 88 oxy / propoxy) coumarin 76 found: 74.25 5.15, ber .: ^C 21 ^H 22 ° 5 74.10 5.52 found: ber .: c {%) tr (rf \ 4-hydroxy-7- (5- / 5,6,7,8-tetra- I99-2OI CHO found: 72.15 π \ / o J 89 hydro-2-naphthyloxyJ7-propoxy) - 42 72.12 6.01 coumarin C {%) 6.07 70.58 H (*) 6-ethyl-4-hydroxy-7- (5-phenoxy-
propoxy) coumarin 255-254 70.29 5.92. 90 75 C {%) 6.12 ^ . 71.77 H (%) ■ ^ 4-hydroxy-7- (5-phenoxypropoxy) -
8-n-propyl-coumarin 149-I5O 70.88 6.26 91 95 6.56

Example 92

4-Hydroxy-7- (2-hydroxy-3-phe noxypropoxy) -coumarin A solution of 6.5 g (0.02 mol) of 3,4-dihydro-7- (2-hydroxy-3-phenoxypropoxy) - 4 ~ imino-coumarin in 80 g 50gewichtsprozentiger sulfuric acid is stirred for 3 to 6 hours at 100 ⁰ C. A yellow solid precipitates out of the initially pale red solution, which is separated off by decanting after cooling and diluting with water. After several decantings with water, the oily solid is taken up in warm ethanol, treated with activated charcoal, filtered and the filtrate gradually diluted with water. The precipitated oily solid crystallizes overnight and gives 2.934 g of a yellow-brown solid with a melting point of 145 to 175 ° C. After recrystallization from aqueous methanol, 2.275 g (= 34 % of theory) of the compound of melting point 18I bis mentioned in the title are obtained 183 ⁰ C.

^ (Grid): 3250, 3060, I705, I610 cm " ¹ .

X (DMSO): 5.85 (5H, m); 4.75 (IH wide, interchangeable); 4.50 (IH, exchangeable sharp singlet); 3.19-2.50 (TH, complex multiplet); 2.22 (IH, d, J = 9.0 Hz); i singlet interchangeable in the low field.

Analysis for C ₁₃ H ₁₆ O ₆ C {%) H {%)

calc .: 65.85 4.91 found: 65.48 5.19

The compounds listed in Table VI are prepared in the same way.

709813/10 10

Table VI

at link M.p., c yield (Foam * analysis game 7- (3- ₍ / T-acetyl-3-hydroxyphene- 220-222 in % 0 93 oxy / propoxy) -4-hydroxy-coumarin 71 calc .: 64.86 4.90 Found: 65.02 5.08 7- (3- ^ i-acetylphenoxyJ7-propoxy) -
4-hydroxy-coumarin 202-204 ^C 20 ^H 18 ° 6 C (fa) H (%) 94 55 calc .: 67.79 5.12 Found: 67.39 5.26 4-hydroxy-5-methyl-7- (3-phenoxy-
propoxy) coumarin 218-219 ^C 19 ^H 18 ° 5 C (%) H (%) 95 65 calc .: 69.93 5.56 Found: 70.31 5.43 7- (3- (A-carboxyphenoxy_7-propoxy) - 275-276 96 4-hydroxy-coumarin 80 97 7- (3- / 5-carboxyphenoxy _ / - 2-hydroxy-169-172 95 propoxy) -4-hydroxy-coumarin

Example 98

7- (3-; ffi-acetyl-3-hydroxy-2-n- propylphenoxy7-2-hydroxypropoxy ) -4-hydroxy-cui-narin

The hydrogenation of 5.42 g (0.0066 mol) of 7- (3- / 4 -acetyl-3-hydroxy-2-n-propylphenoxy-2-hydroxypropoxy) -4-benzyloxy-coumarin in 60 ml of dimethylformamide under normal pressure and using 10 percent palladium-charcoal catalyst gives 2.86 g of the compound named in the title with a thin-layer chromatography grade.

-C (DMSO): 9.13 (3H, t, J = 6.7 Hz); 8.59 (2H, m); 7.4o (3H, s); 7.40 (2H, m); 6 ^ 30 (IH, wide, interchangeable); 5.75 (5H, s); 4.75 (IH, broad, interchangeable); 4.50 (IH, s, interchangeable); 3.30 (IH, d, J = 9.3 Hz); 3.01 (2H, m); 2.23 (IH, d, J = 9, ö'hz); 2.15 (IH, d, J = 9.3 Hz); IH interchangeable in the low field, sharp.

The molecular ion has the m / e ratio 428.

The compounds listed in Table VIl are prepared by the same procedure.

70981 3/1010

Table VII

at link Fp ., ⁰ C phenoxy / -2-hydroxyproρoxy) -4-hydroxy- yield 75 ^C 20 ^H 18 ° 5 analysis H {%) game 7- (2- / ² i-fluorophenyl7-ethoxy) - coumarin in % ber .: 5.36 99 4-hydroxy-coumarin found: 5.66 7- (3- / 5-acetylphenyl7-propoxy>
4-hydroxy-coumarin 205 C ₁₆ H _n ClO C {%) • υ (ei \ ■ m (of \
JrI \ / o) UJ. \/O) 100 ber .: 70.99 3.48 11.13 found: 71.25 3.76 11.17 7- (3- / 4-chlorophenoxymethoxy_7) -
4-hydroxy-coumarin 218 5 c (ji) 101 60.24 60.63 7- (2-2? F-acetyl-3-hydroxy-2-n- 83 ^C 20 ^H 18 ° 7 H (#) 102 propylphenoxy_7-ethoxy) -4- ber .: 4.90 hydroxy-coumarin found: 5.08 7- (3-Z ^ -Carbomethoxyphenoxy_7-
propoxy) -4-hydroxy-coumarin 218 89 C Hp 0 ^ 0 C (fa) (fa) H {%) 103 20th 64.86 48 6.11 , ber .: 64.51 87 5.86 4-hydroxy-7- (2-hydroxy-3- / 2-n- 197 ' found: .5HpO _r 104 propylphenoxyJZpropoxy) coumarin S. 60 Cm W 66 66 CJ)
Tj (af \ J ^. 7- (3-Z ^ -acetyl-3-hydroxyphenoxyJ7-
2 ~ hydroxypropoxy) -4-hydroxy-coumar: LXl approx. 205 64 Cp-ι Hp _n On η \ p) 105 7- (3-Z4-acetyl-2-n-propylphenoxy_7- CX CU O 5.04 K io6 2-hydroxypropoxy) -4-hydroxy-coumarin ber .: 5.23 -j>.
CO 7 - (> - Zi-Acetyl-3-hydroxy-2-methyl _T 230 found: 107 \ j \ yo) 62.99 - 62.78

Table VII continued

CD OO

CO

O O

At- link I. Pp., ⁰ C phenoxy_7-2-hydroxypropoxy) -4- I yield C H Oo ber .: analysis TT (cf \ t So much 7_ (5_ / J-acetyl-6-ethyl-3- 240 hydroxy-8-n-propyl-coumarin in % 22nd found: C * (öf \ H \ Jo) 108 nydrOxyphenoxy_7-2-hydroxypropoxy) - 7 - ^ - Zi-acetyl ^ -hydroxy ^ -n-propyl- 166
phenoxyy ⁷ -propoxy) -4-hydroxy-coumarin 87 \ j \ J0) 5.35 4-hydroxy-coumarin 63.76 5.50 63.47 4-hydroxy-7- (3- / 3-hydroxy-4-propi- 109 onyl-2-propylphenoxji7-2-hydroxy- propoxy) coumarin 6- (3- ^ i-acetyl-3-hydroxy-2-n-propyl- 7- (3-Z 1-4 acetyl-3-hydroxy-2-n-propyl phenoxyJ ⁷ -2-hydroxypropoxy) -4- 110 phenoxy _ / - 2-hydroxypropoxy) -4- hydroxy-coumarin hydroxy-8-methyl-coumarin 7- (3-Z? F-acetyl-3-hydroxy-2-n-propyl - Foam C ₂₃ H ₂₄ O ₇ 111 100 ber .: found: H {%) c (si) 5.86 112 66.98 6.03 66.74 115.

CP

N) CD -P - NJ ro

CO

Example 114

7 ~ (3-Z ^ -Ac e tyl-3-hydroxy-2-n - propylphenoxyJ7-2-hydroxypr opo xy) -4 ~ hydroxy -> - nitro-coumarin

9 ml of fuming nitric acid are added to a mixed suspension of 2.8 g of 7- (3- / 5-acetyl-3-hydroxy-2-n-propylphenoxy-7-2-hydroxypropoxy) -4-hydroxy-coumarin in 300 ml of chloroform 0 ⁰ C within 1 hour and the dark mixture is stirred for a further 30 minutes at this temperature. Then there I50 ml of diluted hydrochloric acid and evaporate the chloroform at 0 ⁰ C under reduced pressure. The solid which separates out is filtered off and recrystallized from ethanol. 2.42 g (= 78 % of theory) of a yellow pesticide with a pp. 201 to 2 (JJ ⁰ C (decomposition)) are obtained.

V> (grid): 3350 (wide), 1770, 1620, l6l0, 1540 cm " ¹ , max

t (DMSO): 9.17 (3H, t, J = 6.9 Hz) j 8.55 (2H, m, J = approx. 7 Hz); 7.43 (3H, s + 2H, m); 5.78 (5H, s); 3.20 (3H, m) j 2.16 (2H, exchangeable s); 2.16 (2H, near doublet); IH interchangeable in the low field, wide.

Analysis for C ₂₅ H ₂₅ NO ₁₀ C {%) H (fo) N {%)

calc .: 58.35 4.90 2.96 found: 58.49 5.07 3.04

The sodium salt prepared in the usual way melts at 262 ^° C. with decomposition.

^ o ^ (grid): 1720, 1620, I605 cm " ¹

Analysis for C ₂₅ H ₂₉ NNaO ₁₀ C (^) H {%) N {%) Na

calc .: 55.76 4.48 2.83 4.64 found: 56.01 4.77 2.80 4.73

709813/1010

The compounds listed in Table VIII are prepared by the same procedure.

709813/1010

T a b e 1 link 1 e VIII yield C ₁₇ H ₁₅ NO ₆ analysis C (fo) C (%) c {%) - 55 - N (fo) N (%) At- 4 ~ Hydroxy-5-nitro-6- (2-phenyl-
ethpxy) coumarin in % ber .: C (f>) 62.59 65.54 65.72 4.28 4.10 So much M.p., ° C 75 found: 62.59 62.59 ■ 65.54 65.98 4.55 4.51 115 166 62.09 c {%) H {%) N (%) Sodium salt, 62.66 4.00 N (%) 5.65 4-hydroxy-5-nitro-7- (2-phenyl-
ethoxy) coumarin C ₁₇ K ₁₅ NO ₆ C (%) 62.56 5.86 4.28 5.52. 85 ber .: 65.54 Sodium salt, Pp. 250 ⁰ C 4.14 116 I54 found: 65.58 C ₁₉ H ₁₇ NO ₆ H {%) N (%) 7- (2- / 4 ~ -fluorophenyl-7-ethoxy) -4 ~ Sodium salt, ber .: 4.00 5.94 hydroxy ~ 5-nitro-coumarin O ₁₈ H ₁₅ NO ₆ found: 4.12 N (%) 4.05 117 4-hydroxy-5-nitro-6- (5-phenyl-
propoxy) coumarin C ₁₈ H ₁₅ NO ₆ ber .: 4.10 79 ber .: found: 4.17 118 I57-I58 found: C ₂₀ H ₁₇ NO ₇ H (Jg) Mp. 226-227 ⁰ C ber .: 4.45 H {fo) 4-hydroxy-5-nitro-7- (5-phenyl-
propoxy) coumarin found: 4.51 4.45 • 75 4.57 119 I92-I95 H (fo) 7- (5-Z5-acetylphenyl7-propoxy) -
4-hydroxy-5-nitro-coumarin 4.47 70 4.66 120 155 M.p. 200 ^° C H {%) 4-hydroxy-5-nitro-7- (4-phenyl-
butoxy) coumarin 4.82 88 4.89 121 I52

-J O CD OO

CO

Continuation of tab hurry VIII 138-140 yield - 56 - C ₁₀ H ₁ ^ ClNO ;; C. (%) H (%) N (fo) Cl (%) • C (*) H (fo) 9.10 Bel- in_ $ ber .: 52 y , 54 4.14 3.59 (fo) H (%) N (%) 59.48 3.81 9.00 game link M.p., ⁰ ° C 62 analysis C. found: 52. , 81 4.16 3.91 »83 2.77 3.85 59.57 3.80 N (%) 122 γ- (4- / 4 "-chlorophenyl7-butoxy) - 157-160 ber.:. 58. C (*) H (fo) , 92 2.69 3.86 C (%) H (fo) 3.79 4-hydroxy-3-nitro-coumarin found: 58 y 65.04 5.15 Sodium salt, mp. 229-230 ⁰ C 59.48 3.81 3.73 ^C 20 ^H 19 ^N0 6 64.52 x 5.09 C ₁₇ H ₁₅ NO ₇ 59.70 4.14 ber .: ber .: 88 found: found: egg (*) 123 4-hydroxy-7- (4- / ¥ -methylphenyl7-
butoxy) -3-nitro-coumarin 145-147 C ₆ H _1O C1N ( C ₁₇ H ₁₅ NO ₇ 9.75 D U ber .: C (fo) H (fo) 9.97 70 found: 60.51 4.23 124 7- (4-chlorophenoxymethoxy) -4- 130 60.57 4.31 N (fo) hydroxy-3-nitro-coumarin 4.08 3.86 C ₁₈ H ₁₅ NO ₇ N (%) ber .: 4.08 45 found: 3.72 125 4-hydroxy-3-nitro-6- (2-phenoxy-
ethoxy) coumarin 164-165 69 126 4-hydroxy-3-nitro-7- (2-phenoxy-
ethoxy) coumarin 188 N ($>) 3.92 3.65 127 7- (2- _< / 5-acetyl-3-hydroxy-2-hydroxy- 2-n-propylphenoxy_7-ethoxy) -4- hydroxy-3-nitro-coumarin 43 128 4-hydroxy-3-nitro-6- (3-phenoxy-
propoxy) coumarin

ro co

continuation

Table VIII

- 57 -

CD OO GJ

at
game link M.p., ⁰ ° C Yield!
in fo ! ber
found 88 C ₁₈ H ₁₅ NO ₇ analysis H (£) C (fo) H {%) N W) 129 4-hydroxy ~ 5-nitro-7- (5-phenoxy-
propoxy) coumarin 148-150 82 ber .:
found: C (*) 4.25
4.12 54.54
54.19 5.84
5.80 3.92
4.01 60.51
60.59 DN-methylglucamine salt,
Mp. 150 to 132 ⁰ C C (%)
61.45
61.49 H (fo)
4.61
4.62 C ₂₅ H ₅₂ NO ₁ , Fp. 223-225 N {%) ber .:
found: C {fo)
63.15
63.35 H (fo)
5.30
5.54 5.07
4.82 C ₁₉ H ₁₇ NO ₇
ber .:
found: , Fp. 186 ⁰ C N (*)
3.77
4.11 150 4-hydroxy-5-methyl-5-nitro-
7- (5-phenoxypropoxy) coumarin 154-157 67 Sodium salt ⁰ C C ₂₁ H ₂₁ NO ₇
ber .:
found: H {%) N (*) N {%)
3.51
3.54 151 4-hydroxy ~ 5-nitr0-7- (5-phenoxy-
propoxy) -8-n-propyl-coumarin 156-157 84 Sodium salt 4.78
4.85 3.32
2.99 C ₂₁ H ₅₀ NNaO ₇ C (fa)
62.35
62.02 H (*)
4.97
5.08 C {%) , Fp. 257-258 Na (%) .: 59.86
.: 59.88 5.45
5.90 C ₂₀ H ₁₉ NO ₇
ber .:
found: N (%)
3.65
3.77 I52 6 ~ ethyl-4-hydroxy-5-nitro-7-
(3-phenoxypropoxy) coumarin 154-155 Sodium salt ⁰ C

O CD OO

continuation link T a b e 1 1 e VIII C ₁₈ H ₁₄ ClNO ₇
C {fo) - 58 analysis ) N {fo) Cl {fo) C. N {fo)
5.51 C. at
game 1- (5-Z ^ -chlorophenoxyJZpropoxy) -
4-hydroxy-5-nitr0-coumarin Pp., ° C yield
in % ber: 55.18
found: 55.18 H {f> 5.58
5.55 9.05
9.20 N ifo)
6.75
6.78 155 159-145 72 ^C 19 ^H 15 ^NO 9
ber .:
found: 5.60
5.55 ) H {fo)
'4 ^ 08 N {%)
5.49
5.27 N {%) 7- (5-Z ^ -Carboxyphenoxy_7-propoxy) -
4-hydroxy-5-nitro-coumarin C ₂₀ H ₁₇ NO ₉
ber .:
found: C {fo
56.86
57.61 ) H {%)
4.15
4.11 N (*)
5.57
5.41 154 7- (5- / 4 ~ carbomethoxyphenoxy_7-
propoxy) -4-hydroxy-J-nitro-
coumarin 259-240 55 Sodium salt C {%
57.85
57.80 255-257 ° 155 164-168 87 ^C 20 ^H 17 ^N0 9
about ,:
found: , Pp. ) H (*)
4.29
4.67 7- (5- / 4-acetylphenoxy_ / propox ^ -
4-hydroxy-5-nitr0-coumarin C ₁₉ H ₁₆ N ₂ O
ber .:
found: C {f>
60.15
60.44 ) H {fo)
5.87
4.18 156 4-hydroxy-7- (5-Z4-methyl-2-nitro-
phenoxy _ / - propoxy) -5-nitro-
coumarin 159-161 52 C ₂₀ H ₁₇ NO ₉
ber .:
found: C {fo
54.81
54.97 N TJ (of \
j ίϊ. \, 'ΰ J
4.15
4.28 157 7- (5- / 4- aoetyl-5-hydroxyphenoxy_7-
propoxy) -4-hydroxy-5-nitro-
coumarin I85-I85 20th Sodium salt C if
57.85
57.55 265-267 ° 158 199-200 75 , Pp.

Table VIII continued

- 59 -

at link M.p., c yield - C H NO analysis M.p. 254 ^° C ) N (%) 5.56 game 7- (5- _/ / ¥ -acetyl-5-hydroxy-2-n- 148 in fo η (ct \ tr (c * 3.06 5.68 159 propylphenoxy_7-propoxy) -4- 74 υ \ / o) η \ jo 2.87 S) N (fo) hydroxy-5-nitro-coumarin calc .: 60.59 5.07 3.75 found: 60.56 5.15 C (fo) H (%) N (%) 3.85 Sodium salt 54.68 5.62 hydroxypropoxy) -4-hydroxy-5- 220-221 ^c i9 ^H i5 ^NO io 54.54 5.87 I4o nitro-coumarin 49 ber .: C (fo) H ( found: 57.91 4.05 H (fo) N (£) 4-Hydroxy-7 ~ (2-hydroxy-3-phenoxy-
propoxy) -3-nitro-coumarin 179-180 C ₁₈ H ₁₅ NO ₈ 57.89 4.05 4.12 3.18 141 50 ber .: 4.15 3.51 found: (Decomposition) 7- (5- / ² I-AOe tyl-2-n-propylphenoxyy ^r - H (%) N (f.) 142 2-hydroxypropoxy) -4-hydroxy-3- .5HpO _{r (af} . 4.45 5.0ö nitro-coumarin 54.54 4.64 2.94 7- (3- _< / ³ T-acetyl-3-hydroxyphenoxyJ7-
2-hydroxypropoxy) -4-hydroxy-5- 120 C ₂₀ H ₁₇ NO ₁₀ O 54.74 (Decomposition) 145 nitro-coumarin 49 ber .: , M.p. 235 ° C found: • ^5H 2 ° C (%) Sodium salt. '55.50 7- (3-Z? -Acetyl-3-hydroxy-2-methyl-
phenoxy_7-2 ~ hydroxypropoxy) -4- 204 C ₂₁ H ₁₉ NO ₁₀ O 55.49 144 hydroxy-5-nitro-coumarin 67 ber .: , M.p. 185 ° C found: Sodium salt.

4> » CO

Continuation from T a be 11 e VIII

- 60 -

at Connection _s foam ■ 4-hydroxy-7- (2-hydroxy-3- / 3-hydroxy- I52-I54 yield Cp ₆ H, analysis ) N {%) game 7- (3- / 5-acetyl-6-ethyl-3-hydroxy- 4-propionyl-2-n-propylphenoxyy- in % 2.65 145 phenoxy_7-2-hydroxypropoxy) -4- 4-hydroxy-3-nitro-8-n-propyl-coumarin propoxy) -3-nitro-coumarin 2.61 hydroxy-3-nitro-coumarin 4-hydroxy-3-nitro-7- (4-phenoxy-
butoxy) coumarin ber. 6- (3-Z ^ -acetyl-3-hydroxy-2-n ^; -propy] gef * 146 phenoxy_7-2-hydroxypropoxy) -4- {%) Na {%) hydroxy-3-nitro-coumarin 56 4.21 55 4.68 147 _3Q N0 _lo .0.75Hp0 148 98 N (Si) 'C (si) H' (Ji 4.61 : 59.03 5.81 3.59 : 59.00 5.42 7- (3- / i-acetyl-3-hydroxy-2-n-propyl- Sodium salt; foam phenoxy_7-2-hy dr oxy pr opoxy) -4- ^C 26 ^H ; hydroxy-8-methyl-3-nitro-coumarin 7- (3- / 5-acetyl-3-hydroxy-2-n- ber. propylphenoxy_7-2-hydroxypropoxy) - found .. 149 ^C 19 ^H ! 150 96 - ber. found .; JgNNaO ₁ Q.0.5H ₂ O C (%) H {%) N : 57.14 5.35 2, : 57.21 5.61 2, ■ IIV ^ \ jv J JtI \ / o J 61.45 4.45 61.45 4.69 Sodium salt, bp 195 ^° C

€ O

Table VIII continued

- 61 -

CD OO χ co

O O

at
game j link Ports. Pp., ⁰ C yield
injö analysis TJ (0t \
Il \ / 0 y N (%) Well (fo) 150 C ₁₉ H ₁₆ NNaO 4.38
4.01 3.41 5.60 C (fo) Pp. 192 ⁰ C calc .: 55.47
found: 55.80 C (*)
62.33
62.02 H (%)
4.87
5.02 N (%)
3.62
5.43 151 110 20th Sodium salt, C (Ji)
63.15
62.61 H (%)
5.50
5.45 N (%)
5.51
5.65 152 143-145 77 C ₂₀ H ₁₉ NO ₇
ber .:
found: C (fo)
63.15
63.18 H (fo)
5.50
5.41 N (fo)
5.51
5.27 153 90-91 37 ber .:
found: 154 110 66 C ₂₁ H ₂₁ NO ₇
ber .:
found: 4-hydroxy-3-nitro-6- (5-phen-
oxypentoxy) coumarin 4-hydroxy-3-nitro-7- (5-phen-
oxypentoxy) coumarin 4-hydroxy-3-nitro-6- (6-phen-
oxyhexoxy) coumarin 4-hydroxy-3-nitro-7- (6-phen-
oxyhexoxy) coumarin

K) OO

Example I55

4-Hydroxy-7 ~ (3- / 2-methylphenoxy.7-propoxy) -3-nitro-coumar in Man add 0.24 g (0.003 mol) of sodium nitrite all at once to a suspension of 1 g of 4- Hydroxy-7- (j5- / 2-methylphenoxy7 ~ propoxy) -coumarin in 30 ml glacial acetic acid. After 2 hours at room temperature, the reddish solution is poured into 150 ml v / ater. The yellow solid which separates out is filtered off and recrystallized from aqueous ethanol. 0.815 g (= 70 % of theory) of the yellow 3-nitro derivative with a melting point of 146 ° C. are obtained.

V ^. _ev (grid): 1750, I615, I600, I600, 1525 cm " ¹ , max

T (DMSO): 7.85 (3H, s); 7.82 (2H, quintet); 5.88 (2H, t,

J = 7.2 Hz); 5.72 (2H, t, J = 7.2 Hz); 3.23-2.73 (6h, m);

2.13 (IH, d, J = 9.3 Hz); 1 sharp, interchangeable in the low field Proton.

Analysis for C ₁₉ H ₁₇ NO ₇ C {%) H ($) ' N {%)

calc .: 61.45 4.61 3.77 Found: 61.25 4.56 3.58

The sodium salt melts at 225 ° C.

Analysis for C ₁₉ H ₁₆ NNaO ₇ C {%) H {%) N {%) Na {%)

calc .: 58.02 4.10 3.56 5.86 found: 57.80 4.38 3.38 5.96

The compounds listed in Table IX are prepared by the same procedure.

7098 13/1010

Table IX

- 63 -

CD CO OO

CO

—A

at
game link M.p., ⁰ ° C yield
in fo analysis / * s f rff \
\ u \ / OJ
61.45
61.83 H (%) N (%)
4.61 3.77
4.50 3.67
210 ⁰ C
(fo) H (56) N (%)
48 4.41 3.41
50 4.59 3.55 N (fo)
3.77
3.62 156 4-hydroxy-7- (3- / 3 ~ methylphenoxy _> 7-
propoxy) -3-nitro-coumarin 142 64 C ₁₉ H ₁₇ NO _{7 c} ^
calc .: 61.45
found: 61.12
Sodium salt, m.p.
C ₁ 0H ₁₆ NNaO.H ₂ O _c
ber .: 55,
found: 55, C {%)
58.91
59.21 H (fo)
4.61
4.76 N (fa)
3.62
3.36 157 4-Hydroxy-7- (3-Z ^ ~ ^me ^ ⁿ ylPh ^enox 3l7-
propoxy) -3-nitro-coumarin 170-172 21 C ₁₉ H ₁₇ NO ₇
ber .:
found: c (%)
57.60
57.49 H (%)
4.42
4.82 N {%)
3.75
3.57 I58 4-Hydroxy-7- (3-Z ^ - ^me thoxyphenoxy_7-
propoxy) -3-nitro-coumarin 167-175 52 C ₁₉ H ₁₇ NO ₈
ber .:
found: C (fo)
59.69
59.43 H (%)
3.73
4.10 N (%)
7.33
7.04 159 7- (3- / 4-fluoro phenoxy ^ ⁷ -propoxy) -
4-hydroxy-3-nitr0-coumarin 173-176 24 C ₁₈ H ₁₄ FNO ₇
ber .:
found: H (%)
3, '92 I60 7- (3-Z ^ "- cyanophenoxy_7-propoxy) -4-
hydroxy-3-nitro-coumarin 204 40 ber .:
found:

rsj Kj -t> OO

Table IX continued

- 64 -

at
game Connection ^ ■ _ ■■. ', M.p., ⁰ ° C yield
in fo C ₂₄ H ₁₉ NO ₇
ber .:
found: Analysis, H (fo)
4.42
4.60 N (fo)
3.23
3.14 161 4-hydroxy-7- (3-Z4 "-phenylphenoxy_7-
propoxy) -3-nitro-gumarin I8O-I82 76 C ₂₂ H ₂₁ NO ₇
ber .:
found: C {%)
66.51
66.40 H (%)
5.11
5.44 N {%)
3.41
3.10 162 4-hydroxy-3-nitro-7- (3- / 5,6,7,8-
tetrahydro-2-naphthyloxy _ / - prop-
oxy) coumarin 127-134 40 ber .:
found: C (fo)
64.23
63.85 TT (of \
5.10
5.18 N (fo)
3.37
3.62 163 4-hydroxy-7- (2-hydroxy-3- / 2 ~ n-
propylphenoxy_7-pr.opoxy) -3-nitro-
coumarin 125-126 87 C (Jg)
60.72
60.43

Biological data
(I) SRS-A antagonistic activity

The compounds according to the invention are used as immediate antagonists a slowly reacting anaphylactic substance, namely SRS-A, through an experiment on isolated guinea pig Ileum has been assessed.

SRS-A of rats is obtained from the peritoneal space after passive peritoneal anaphylaxis by a method based on the remarks by RP Orange, DJ Stechschulte and KF Austen in "J. Immunology" 105 (1970), p. IO87, as they are by BA, Spicer, JW Ross, and H. Smith in Clin.exp. Immunol. 2_1 (1975) , p. 419. The sensitizing serum containing the reagentic antibody is produced in rats as described by BA Spicer (loc. Cit.).

2 ml of sensitizing serum that is diluted with five different degrees of dilution, is injected peritoneally into the recipient rats. After 2 hours, the same way 5 ml Tyrode's solution with a content of 0.4 mg / ml ovalbumin (Sigma grade III) and 50 µg / ml heparin are injected. The rats are anesthetized 5 minutes after the immunity test. Blood is then drawn from the rats and the peritoneal fluids are collected in ice-cooled polycarbonate Tube. After centrifuging at 150 g for 5 minutes the supernatant solutions are combined, heated for 5 minutes in a boiling water bath, then cooled and stored at -20.degree. The combined peritoneal fluids contain SRS-A and

7098 13/1010

are used in the antagonistic studies.

The experiments with SRS-A are carried out on isolated strips of guinea pig ileum in a Tyrode 'see solution with a content of 5 χ 10 -m atropine and 10 -m pyrilamine, namely 2 - / (2-dimethylaminoethyl) - (p-methoxybenzyl ) -amino / -pyridine, carried out _} as it has been described by WE Brocklehurst in ¹¹ J. Physiology "151 (1960), p. 416.

The effectiveness of the antagonists is determined by their ability to reduce submaximal irritant effects induced by SRS-A. The antagonists are added to the 4 ml bath in 0.1 m volume in aqueous solution half a minute before the addition of SRS-A and are present during the induced contraction. Two or three antagonist concentrations are applied and the percentage inhibition of the SRS-A stimulus response is plotted against the bath concentration of the antagonist. The best fit curve is then drawn and the concentration of 50 percent inhibition, IC ₁ -Q, is read graphically.

(II) Passive skin anaphylaxis test

In rats, it becomes a heat-labile homocytotropic antibody containing Serum in crystallized ovalbumin XOA using Bordettela pertussis vaccine as adjuvant after the I. Mota "Immunology" method ?. (1964), p. 681.

The passive skin anaphylaxis test (PCA) is after the procedure by A. Ovary and O.G. Beer in "Proc. Soc. Exp. Biol. Med." 8_1_

709813/1010

(1952), p. 58 ¹ I-, in the modified form according to J. Goose and

A.M.J.N. Blair in "immunology" 1β (19β9)> P. 769 *.

0.1 ml each of 6 samples from a twofold serum dilution series of the combined antiserum in 0.9 percent sodium chloride solution is 250 to ^ 00 g heavy Wistar rats on different Injected intradermal sites of the shaved back. 72 hours later the animals are given 0.5 ral one percent strength intravenously Injected ovalbumin solution in isotonic sodium chloride solution, the buffered with 0.5 m Sorensen buffer solution (PBS) of pH 7.2 and with 0.2 ml of a 5 percent solution of the dye "Pontamine Sky Blue 6BX "(CI. 24410; manufacturer: Raymond A. Lamb, London) is present mixed in isotonic saline solution. After 20 minutes the rats are killed, and the diameters of the blue ones Spots at the antibody injection sites on the outer skin surface are measured. The serum dilution series will be like this scheduled that after vaccination at the injection site at the at the highest dilution there is no reaction and at the lowest dilution there is a maximum reaction. Generally will 6 samples of a 2-fold serum dilution series from 1/4 to I / 128 were used.

The compounds of the invention are tested for their ability investigated reducing the diameter at those intradermal sites that were less than the maximum in the control animals Show reaction. Each dose of the compounds of the present invention is given to a group of 6 rats in an amount of 2 ml / kg Body weight in isotonic saline solution, which has been adjusted to pH 7 with sodium bicarbonate if necessary, and

709813/1010

administered intravenously immediately before the intravenous vaccination with ovalburnin. The control group of 6 animals receives at the same time the same volume of carrier liquid.

The results are calculated according to the following formula: % Inhibition of Passive Skin Anaphylaxis Test = 100 χ (1-a / b).

a = the sum of the diameters of the blue spots in the Test group arise at the sites of antibody injections, such as they are used in the control group}

b = the mean sum of the diameters of the bruises that

the places with
in the control group at / those antibody injections

arise in which at least 5 of the 6 animals show no maximum reaction. A typical variation in the control animals was SEM + 6 %. ■

The required dose of the compound that has the passive skin anaphylaxis irritant effect to $ 50 inhibits, becomes from the logarithm the dose-stimulus-effect curve determined.

70981 3/10 10

Biological results

- 69-

a- "game

10 " ⁸ M.

Formula SRS-A antagonism on guinea pig ileum

approximate concentration that
a 50 percent inhibition
a lesser than the highest
Effect of the SRS-A causes stimuli

Passive Skin Anaphylaxis Test (PCA) Rats

Concentration administered intravenously to achieve 50 percent Inhibition of the response to the PCA stimulus

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709813/1010

70981 3/10 10

709813/1010

toxicity

During biological evaluation, none of the compounds described in the preceding examples reveal any toxic effect.

acute toxicity

The following compounds 4-hydroxy-3-nitro-7- (2-phenylethoxy) -coumarin, 7- (5- / 2-n-propylphenoxy_7-2-hydroxypropoxy) _4-hydroxy-j> nitro-coumarin,

7- (^ - / i-acetyl-phenoxyJ / '- propoxy) -ty-hydroxy - ^ - nitro-coumarin, 7- (3-Z ^ -acetyl-3-hydroxy-2-n-propylphenoxy _ / - 2-hydroxypropoxy) -

4-hydroxy-5-nitro-coumarin and

7- (j5- / i-acetyl-3-hydroxy-2-n-propylphenoxy_7-2-hydroxypropoxy) -

4-n-propyl-; 5-nitro-coumarin

are given intravenously in an amount of 100 mg / kg body weight administered to mice. No toxic effects were observed over the course of 5 days.

709813/1010

Claims (1)

Claims (D in which R _{1 and H 2 are} identical or different and denote hydrogen atoms or 1 to 6 carbon atoms having alkyl, alkenyl, alkynyl or alkoxy radicals or, when R 1 and R p are on adjacent carbon atoms, 1,4-buta -l, 3-dienylene group or an alkylene radical with 3 to 5 carbon atoms, A for a substituent of the general formula II .R, X-Q (II) is in the 6- or 7-position of the coumarin ring, in which X is a Is an oxygen atom or the methylene group, Q is a straight-chain alkylene radical having 1 to 8 carbon atoms, where a different methylene group in the radical Q than the methylene group that is covalently bonded to the oxygen atom, may be substituted by a hydroxyl group, and R- *, R ^ and Rc are the same or different and are hydrogen or halogen atoms, the nitro, hydroxy, cyano, carboxyl, amino, phenyl, phenoxycarbonyl or benzyloxycarbonyl group or 1 to 6 Carbon atoms on ferrous alkyl, alkenyl, alkynyl, alkoxy, Alkoxycarbonyl, acyl, acyloxy, mono- or dialkylamino, mono- 709813/1010 _οτππ ORIGINAL INSPECTED or diacylamino or alkylphenyl radicals, with two on R ,, Ru and Rrauch radicals bonded to adjacent carbon atoms an alkene radical having from J5 to 5 carbon atoms, inclusive of the 1,4-buta-l,> - dienylene group, and their pharmacologically acceptable salts. 2. Derivatives according to claim 1, in which R 1 and Rp are hydrogen atoms or are alkyl radicals having 1 to 6 carbon atoms. 3. Derivatives according to claims 1 or 2, characterized in that R, and Rp are hydrogen atoms or alkyl radicals having 1 to 6 carbon atoms, R is a hydrogen or halogen atom or the nitro, hydroxy, cyano, carboxyl, amino -, phenyl or the phenoxycarbonyl group or an alkyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, mono- or dialkylamino or a mono- or diacylamino radical or an alkyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, or a mono- or diacylamino radical, Rh is an alkyl having 1 to 6 carbon atoms -, alkoxy, alkoxycarbonyl, acyl or acyloxy radicals, and R, - stands for a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms or that two radicals R,, R ₂ , or R ^ is an alkylene radical having 2 to 5 carbon atoms, including the 1,4-buta-1,3-dienylene group. H. Derivatives according to at least one of Claims 1 to 3, characterized in that R 1 and R ₂ ^ are hydrogen atoms and Rp. Denotes an alkyl radical having 1 to 6 carbon atoms. 5. Derivatives according to claim 4, characterized in that 709813/1010 R, - denotes the methyl, ethyl or n-propy! Group. 6. Derivatives according to claims 4 or 5 *, characterized in that that R, - is in the 2'-position of the phenyl ring. 7. Derivatives according to at least one of claims 1 Ms 3 *, characterized in that R ^ is a fluorine atom and R ^ and R _{1 are} hydrogen atoms. 8. Derivatives according to claim J _} characterized in that R- is in the 4 ¹ -position of the phenyl ring of the A substituent. 9. Derivatives according to at least one of claims 1 to 3 *, characterized in that R _{2 is} a hydrogen atom, R is a fluorine atom and in the 2 ¹ position and R ₁ - an alkyl radical with 1 to 6 carbon atoms in 4 ' Position of the phenyl ring of the substituent A means. 10. Derivatives according to claim 9 * characterized in that R, -die n-Propy! group is. 11. Derivatives according to at least one of claims 1 to 3, characterized in that R is the hydroxyl group, Rh is a lower acyl radical and R ₁ - is a lower alkyl radical. 12. Derivatives according to claim 11, characterized in that the radicals R ₁ - are in the 2'-position, R-, in the 3'-position and R ₁ , in the 4 ¹ -position. 709813/1010 13. Derivatives according to claim 1, characterized in that all radicals R ,, Rp, R- ,, Ru and R ₁ - are hydrogen atoms. 14. Derivatives according to at least one of claims 1 to IJ _3, characterized in that R and Rp are hydrogen atoms. 15. Derivatives according to claims 1 or 2, characterized in that R _v , R ^ and R ₁ - are hydrogen atoms. 16. Derivatives according to at least one of the preceding claims, characterized in that the radical AO is in the 7-position of the 3-nitro-coumarin ring. 17. Derivatives according to at least one of the preceding claims, characterized in that X is the methylene group. 18. Derivatives according to at least one of the preceding claims, characterized in that X is an oxygen atom. 19. 4-Hydroxy -> - nitro-7- (2-phenylethoxy) -coumarin and its pharmacologically acceptable salts. 20. 7 ~ (2- / i-fluorophenyi / ethoxy) -4-hydroxy-3-nitro-coumarin and its pharmacologically acceptable salts. 21. 7- (2- / 2-n-Propyl-4-f-Iuophenyl-7-ethoxy) - ^ - hydroxy-jj-nitrocoumarin and its pharmacologically acceptable salts. 22. 7- (j5- / i-acetyl-3-hydroxy-2-n-propylphenoxyJ7-propoxy) -4- 70981 3/10 10 - ST - C hydroxy-3-nitro-coumarin and its pharmacologically acceptable Salts. 23. 7- (3- / i ~ acetyl-3-hydroxy-n-propylphenoxy_7-2-hydroxypropox34-4-hydroxy-3-nitro-coumarin and its pharmacologically acceptable salts. 24. 7- (3- / 4-acetyl-2-n-propylphenoxy_7-2-hydroxypropoxy) -4-hydroxy-3-nitro-coumarin and its pharmacologically acceptable salts. 25. 7- (3- / 5-Acetyl-3-hydroxy-2-n-propylphenoxy-7-2-hydroxypropoxy) -4-hydroxy-8-n-propyl-2-nitro-coumarin and its pharmacologically acceptable salts. 26 ". 7- (3 - ^ - n-Propylphenoxy_7-2-hydroxypropoxy-4-hydroxy-3> nitro-coumarin and its pharmacologically acceptable salts. 27 x 7 - (^ - ZS-methylphenoxyZ-propoxy) -4 ~ hydroxy-3-nitro-coumarin and its pharmacologically acceptable salts. 28. 7- (3- / 5-fluoro-phenoxy-7-propoxy) -4-hydroxy-j5-nitro-coumarin and its pharmacologically acceptable salts. 29 · 7- (3 - ^ - n-Propyl-4-fluorophenoxy_7-propoxy) -4-hydroxy-j5-nitro-coumarin and its pharmacologically acceptable salts. 30. 4-Hydroxy-3-nitro-6-phenoxy-hexoxy-coumarin and its pharmacological properties compatible salts. 7 0 9 8 13/1010 - 88 -, 31. Derivatives according to claims 1 to 30 in the form of their alkali metal salts. 32. Derivatives according to claims 1 to 30 in the form of their sodium salts. 33 · Derivatives according to Claims 1 to 30 in the form of their N-methyl-D-glucamine salts. Process for the preparation of the 3-nitro-coumarin derivatives of the general formula I according to Claims 1 to 33 * thereby characterized in that a compound of the general formula IV in which R., Rp and A have the meanings given in claim 1 possess, nitrated with a nitrating agent and then optionally converted the compound into a salt. 35. The method according to claim 3 ^> characterized in that the nitrating agent used is a mixture of acetic acid and concentrated Nitric acid used. 36. The method according to claim 3 ^ * characterized in that fuming nitric acid in chloroform is used as the nitrating agent. 70981 3/1010 2ΒΑ2248 'in derivatives 37 · Process for the preparation of the 3-nitro-coumarin general formula I with the proviso that the radicals R- to Rc are not amino or substituted amino groups, according to at least one of claims y \ - to Jo, characterized in that one a compound of the general formula IV is nitrosated in the presence of an alkali metal nitrite and a lower alkanoic acid and then the nitroso compound obtained is oxidized and the compound of the general formula I obtained is optionally converted into a salt. 38. The method according to claim 37 *, characterized in that sodium nitrite is used as the alkali metal nitrite. 39 · The method according to claims 37 or 38, characterized in that that acetic acid is used as the lower alkanoic acid. 40. Medicinal products, characterized by a content of at least a 3-nitro-coumarin derivative of the general formula I, optionally together with pharmacologically acceptable carrier materials and / or diluents. 709813/1010