DE2142556A1 - New tetrazole derivatives and processes for their preparation - Google Patents

Description

dr. W. Schalk dipl.-ing. P-. Wirth dipl.-ing. G. Dan ν en berg DR. Y. SCHMIED-KOWARZIK · DR. P. WE I M HOLD · DR. D. G UDEL

6 FRANKFURT AM MAIN. B.A. 41 225/70

CR. ESCHENHEIMER STRASSE.

FISONS LIMITED ■: Harvest House Felixstowe , Suffolk 'England

New tetrazole derivatives and processes for their preparation

1 0 / T978

The invention relates to

:. new tetrazole derivatives of the general formula

and their pharmaceutically acceptable derivatives, wherein

1 "? 3 USB

R, R, R, R, R and R are identical or different and are each hydrogen, halogen, alkyl, hydroxy, alkoxy, substituted Alkyl or alkoxy (e.g. a hydroxy-alkoxy, alkoxyalkoxy or carboxyalkoxy group) and X is a saturated one or unsaturated, optionally substituted, straight or branched hydrocarbon chain replaced by a carbocyclic or heterocyclic ring or be interrupted by one or more oxygen atoms or carbonyl groups can mean; and a method for their production.

Generally it is preferred that no more than

12 3 one of the substituents R, R and R and not more than one

the substituents R, R and R are different from hydrogen. 'Preferred are compounds of the general

0 X..Ö

(Ia)

209810/1978

and their pharmaceutically acceptable derivatives prepared, where-

■ rin K and R are the same or different and each water

Alkoxy
substance, halogen, alkyl, hydroxy, / or substituted alkoxy

mean and X has the above meaning.

A OO h CC *

Meanings of R, ¹ R _t R., R, R and R are, for example, hydrogen, chlorine, bromine, lower. Alkyl, hydroxy, lower. Alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy and carboxy-lower alkoxy. '

The term "lower" as used herein, as applied to alkyl or alkoxy, for example, means that the group contains up to 6 carbon atoms ..

"Particularly preferred compounds produced according to the invention bonds are those in which R to R are hydrogen.

The group X can mean a large number of groups.

one
For example, it can be substituted or unsubstituted, straight or branched, saturated or unsaturated hydrocarbon chain. Furthermore, X can be a chain of this type which is formed by one or more oxygen atoms y. Carbonyl groups or interrupted by a carbocyclic or heterocyclic ring and substituted by one or more halogen atoms (for example chlorine or bromine atoms), hydroxyl or alkoxy groups. Specific examples of group X are groups of the formulas: - (CH ₀ ), .-, -CH ₀ -CH = CH-CH ₀ -, -CH ₀ CH ₀ CH- (CH.) -CH ₀ CH '-,

COCh ₂ -, <f3, "- CH ₂ -CH (OC ₂ H ₅ ) -CH ₂ -,

-CH, CH- ■ - / OH ₀ OH

-CH-C-CH ₀ - ,. - CH ₀ CIiOIlCIi ₀ -, -CH ₀ CPiOHCH ₀ OCIi ₀ CHOHCH ..-

CH Cl

2 and-CH ₂ CIiClCH. ₂ .

2 0 9'8TO / '

The group X is preferably a substituted or unsubstituted, straight or branched hydrocarbon chain which is interrupted by one or more oxygen atoms
can and contains 3 to 7 carbon atoms. If so desired
is such a chain through one or more chlorine or
Substituted hydroxyl groups; a particularly preferred chain is the 2-hydroxy-trimethylene chain (-CH ₂ CIlOHCH ₂ -).

According to one embodiment of the present invention are bis-benzopyranyl compounds of the formula

OH
t

OCH ₂ CH-CH ₂ O

(Ib)

and their pharmaceutically usable. Derivatives produced. The chain -0-X-O- can have different or corresponding positions

the .

connect to / benzopyrone cores.

Particularly preferred are compounds

wherein the -OXO- group connects the 5,5 'positions, e.g. Compound of formula

H"

OH f

0-CH ₀ CHCH ₀ -O

(Ic)

2098 10/197 8

2K2556

and their pharmaceutically acceptable derivatives. The inventive method for producing the new compounds of formula (I) consists άτίη that one a) a compound of the formula

, (II) R

R ¹⁰ OXO

wherein R, 'R, R and X have the above meaning, R

a group of the formula.
,1

, (III)

• 1 2 3
worm R, R and R have the above meaning, or a

Group R of the formula

-? > ^(IV)

is,

1 · 2 - £ 2

v; orin R, R and R have the above meaning, / Y is a group -CN or -CZ = NII and Z represent a / easily removable group, with an azide in a solvent, which under the reaction conditions is inert, treated;

209 810/197 8

2H2556

b) the group G in a compound of the formula

R-C

(V)

or

, (VI)

wherein R is a group of the formula

0X0

(VII)

represents in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X have the above meanings, E is a tetrazole group or ^{1 is} a group of the formula

or

G-N C

χ)

(VIII)

(IX)

209810/1978

represents and G is a group which can be replaced by hydrogen by hydrogenation, dealkylation, deacylation replaced by hydrogen under mild basic conditions, under acidic conditions or by reductive deamination; c) a compound of the formula

R ¹ OXO

■ ι Θ

(X)

or a salt thereof, wherein R, R, R and X have the above

have meaning and R 'is a group R defined above, or a group of the formula

(XI)

12 3
represents, wherein R, R and R have the above meaning,

cyclized; .

d) a compound of the formula

R ¹¹ OXO

209810/1978

, (XII)

4 5 6
wherein R ■, R, R and. X have the above meaning and R "a

Group R, as defined above, or a group of

Formula -.

(XIlI)

12 3
means, in which R, R and R have the above meaning,

selectively dehydrated or

e) a compound of the formula R ⁸ OXO

, (XIV)

wherein R, R, R and X have the above meaning and R

the group R defined above or a group of the formula

CN ₃ = NH

(XV)

12 3

represents, where R, Rz and R have the above meaning,

converted into a compound of formula (I),

2098 10/197 8

and, if desired or necessary, by one of the methods a) to e) prepared compound of formula (I) in a a pharmaceutically acceptable derivative thereof.

Suitable solvents under the reaction conditions of process (a) are inert, are those in which both reagents are soluble, e.g., N, N-dimethylformamide. Other Solvents are e.g. dimethyl sulfoxide, tetrahydrofuran, Diethylglycol and Ä'thylmethylglykoll The reaction is preferably carried out at a temperature of about 20 to 130 C for about Performed for 1 to 20 hours. The azide used in the reaction is preferably ammonium or an alkali metal azide, e.g.

if sodium or lithium azide, however, can /. if desired, others as well Azides, e.g. aluminum azide or the azides of nitrogenous bases, e.g. mono-, di-, tri- and tetramethylammonium, aniline, morpholine and piperidine azides can be used. if an azide other than an alkali metal azide may be used this produced in the reaction mixture by double conversion will. The reaction can be carried out in the presence, if desired an electron acceptor, e.g. aluminum chloride, boron trifluoride, Ethylsulfonic acid or benzenesulfonic acids are carried out. As an alternative to the reaction conditions described above, the reaction can be carried out using hydrazoic acid (Hydrogen azide) at a temperature of about 20 ° to 150 ° C

Pressure in a suitable solvent under higher / than atmospheric

carried out throw. If an azide other than nitrogen Hydrochloric acid is used, e.g. sodium azide, is that Reaction product is the corresponding tetrazole salt. This salt '

209 8 VO / 1978 ". '

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can easily be treated with strong acids, e.g. hydrochloric acid, be converted into the free acid. It is believed that process (a) via a compound of formula (XIV) as

detachable

Intermediate product runs. The easy / groupζ can be an alkoxy, Thiol or alkylthio group, e.g., a lower alkoxy or a lower alkylthio group.

In process b), the 'group G can, for example, be an aralkyl, for example a benzyl group; an aroylalkyl, for example a pheriacyl group; an acyl, for example acetyl group; be an amino group or a group -CCH ₉ ) ₉ A, where A represents an electron-withdrawing group, for example a nitrile, a carboxylic acid ester, for example a lower alkanol, or an acyl group, for example an acetyl group.

When G is an aralkyl group, the group can be converted into acetic acid by using hydrogen halide, e.g. HBr by catalytic hydrogenation using, for example, a palladium catalyst in a solvent containing is inert to the reaction conditions, e.g. ethanol.

When G is an acyl group, the group can under mild basic conditions, for example, with aniline or sodium bicarbonate be replaced.

If G is a group -CH ClLA, the group below can be mild basic conditions, for example with barium hydroxide be replaced.

When G is an amino group, the group can by reductive deamination with, for example, hypophosphorous Acid, stannous chloride or sodium in liquid ammonia can be replaced.

2 0 9 8 10/1978

The cyclization of process c) can be carried out by heating or under basic or neutral conditions will. However, it is preferred to have the cyclization in the presence an acid, e.g. hydrochloric acid, and in a solvent which is inert under the reaction conditions, e.g. ethanol, to perform. The reaction can take place at about 20 to 150 ° C be performed. It goes without saying that the compound of the formula (X) can also exist in the keto form, and these Shape is also included in the definition of formula (X). The compound of the formula (X) may, if desired, be in the form of Alkali metal salt thereof can be used.

can
In process (d) / dehydration by oxidation

using a mild oxidizing agent, e.g. selenium dioxide, Palladium black, chloranil, lead tetraacetate or triphenylline ethyl perchlorate, be performed. On the other hand, the dehydrogenation can also be carried out indirectly by halogenation and subsequent Dehydrohalogenation, e.g. by treatment with N-bromosuccinimide or pyridinium bromide-perbromide, can be carried out, whereby the 3-bromo derivative is obtained, which subsequently dehydrobrominates will. The reaction can be carried out in a solvent which is inert under the reaction conditions, e.g. a halogenated hydrocarbon, xylene or glacial acetic acid. The. The reaction can be carried out at an elevated temperature, for example from about 20 to 150 ° C.

The conversion of the process (e), by heating in a solvent which is inert under the reaction conditions ^1, be effected, for example, ethanol. The reaction can take

2098 10/1978

acidic or neutral conditions will be carried out, however preferably in the presence of a base, e.g. sodium hydroxide, in a solvent which is suitable under the reaction conditions is inert, e.g. water or ethanol. The reaction is preferably carried out in dilute, e.g., about 1% Solution carried out at about 15 to 3 5 C.

The compounds of the formula (II) in which Y is a group -CN can be obtained by dehydrating the corresponding compound the formula

R ⁹ OXO

CONH,

, (XVI)

4 5 6 '■ 9

wherein R, R, R and X have the above meaning and R the

η
Group R as defined above or a group of the formula

CONH,

, (XVII)

12 3
wherein R, R and R are as defined above, are prepared.

The reaction is preferably carried out using at least two equivalents of a dehydrating agent, for example POCl ₃ I, per mole of the compound of the formula (XVI). When the dehydrating agent is mixed with one of the sub-

2 0 9 8 10/1978 *.

1 G
substituents R bis.R or with X Cz.B. reacts with a group containing the -OH group), sufficient dehydrating agent should be used that both the side reaction and the main reaction proceed satisfactorily, or the reactive group should be protected. If desired, the reaction can be carried out in the presence of an acid binder, for example triethylamine. The reaction can be carried out in the presence of a solvent, for example N, N-dimethylformamide, dimethyl sulfoxide, pyridine, benzene or hexamethylphosphoramide; an excess of the dehydrating agent can also be used as the reaction medium. The reaction can be carried out at a temperature of about 0 to 200 ° C. depending on the dehydrating agent used. When phosphorus oxychloride is used, a temperature of 0 to 100 ° C. is preferred.

The compounds of the formula (XVI) can be prepared in that a compound of the formula

R ¹⁵ OXO 1-_ υ υ _{9 (XVIII)}

■ COOR *

wherein R, R, R and X have the above meaning, R ^X one

• 5 7

lower alkyl group and R is a group R defined above or a group of the formula

2098 1 0/197 8

coQir

, (χΐχ.)

1 2 3 χ

wherein R, R, R and R have the above meaning, with ammonia using in "the manufacture of amidone common methods from esters, e.g. using alkanol as solvent at a temperature of 0 to 120 ° C, is implemented.

Compounds of the formula (II) in which Y is the group -CZ = NH represents, can be prepared in a manner known per se from compounds of the formula (II) in which Y is a group -CN, for example by reaction with an alkanol, a thiol or HS, in the presence can be produced by HCl.

Compounds of the formula CV) can be prepared in this way be that a compound of the formula

R ¹² OXO

, (XX)

wherein R, R, R, X and G have the above meaning and R

a group R defined above or a group the formula

, (XXI)

2 09810/1978

12 3 · '· where R, R, R and G have the above meaning? represents is reacted with an azide. The reaction can essentially under the same conditions as for procedure, a) described, be performed.

The compounds of the formula (XX) can be prepared in that a compound of the formula

R ¹³ OXO

COMHG

, (XXII)

wherein R, R, R, X and .G have the above meaning and R a group R defined above or a group the formula.

R ¹

CONHG

12 3
wherein R, R, R and G have the above meaning, is reacted with phosphorus pentachloride.

The compounds of the formulas (V) and (VI) can also be prepared from a compound of the formula (I) in a manner known per se be prepared, for example by reaction with a compound G. Hai, where G has the above meaning and Hai a Represents halogen atom using in the like

209810/1978

2 U 25 56

Reactions usual procedures. Compounds of the formulas (V) and (VI) ", in which G is an amino group, can be prepared by reacting a compound of the formula (I) with hydroxylamine-O-sulfonic acid in a weakly aqueous alkaline solution, and compounds of the formulas ( V) and (VI), in which G is a group -CH ₂ CH A, can also be obtained by a Michael addition of a compound CH = CHA to form a compound of the formula (I). *.

The compounds of the formula (X) can be prepared by reacting a compound of the formula

R ¹⁴ OXO

COCIL

, (XXV)

wherein R, R, R, X and M have the above meaning and R a group R as defined above or a group of the formula

COCH

, (XXVI)

12 3
wherein R, R, R and M have the above meaning - represents, with a compound of the formula

2098 10/197 8

- ■■ ι? -.

R ^X OOC ~ C - N - H

N- "

are obtained in which R ^{X has} the above meaning, is reacted, / the reaction can be carried out under conditions which are customary for a Claisen condensation. The compounds of the formula (X) can also be prepared by the action of a mild alkali on a compound of the formula (I).

Compounds deir formula (XII) can by selective Hydrogenation of a compound of the formula (I) or -, by analogues Procedure like procedure (a) using the appropriate Chromanone-2-carboxylic acid (via the nitrile) as the starting material getting produced.

The starting materials for the above processes are either known compounds or can be made from known compounds using known compounds or those described above Process are produced.

12 3 4 5 6 Some of the groups R, R, R _v R, R, R and X can

can be attacked by the reaction conditions (either in the final stages or during the preparation of the intermediate products). Therefore, if necessary or desired, those to be carried out should Reactions can be carried out using protected derivatives of the reagents. So can any existing free -OII groups are protected, for example by Acylation j and the protecting group subsequently, e.g. Hydrolysis, can be removed. . .

2098 10/197 8

It goes without saying that although the above is the urisubstituted Tetrazole group shown in delocalized form. other representations of the same group generally used.

The compounds of formula (I) and the intermediates for this you can apply from their reaction mixtures common methods can be obtained.

the .

According to the method described above, connections

of formula (I) or their derivatives are prepared. However, it is also within the scope of the present invention to each to treat derivative so prepared to release the free compound of formula (I), or one derivative into another convict. Pharmaceutically usable derivatives are, for example, pharmaceutically usable salts and in particular water-soluble salts. Examples of salts are basic addition salts, e.g. ammonium, amine, alkali metal and alkaline earth metal salts, especially the sodium salt.

The present invention also relates to a process for the preparation of pharmaceutically acceptable salts a compound of formula (I) which consists in that a compound of formula (I) or another salt thereof with a compound, e.g. a base or an ion exchange resin, which contains a pharmaceutically acceptable cation, e.g. sodium, potassium, · calcium, ammonium and suitable nitrogenous cations. In general, the pharmaceutically acceptable salt is preferably through Treatment of the free acid of formula (I) with a suitable one

209810/1978

Base, for example with an alkaline earth or alkali metal hydroxide, carbonate or bicarbonate in aqueous solution or by a metathetic process. When a strongly basic compound used wird-, care must be taken for example by _s, the temperature is kept sufficiently low * that is the compound of formula (I) not hydrolyzed or otherwise degraded. The pharmaceutically acceptable salt can be obtained from the reaction mixture, for example, by solvent precipitation and / or removal of the solvent by evaporation, such as freeze-drying.

• The compounds of formula (I) and their pharmaceuticals

-vate
Usable Deri / are valuable because they have a pharmacological activity in animals. In particular, they are useful because the release and / or action of pharmacological amboceptors that result from the in vivo combination of certain types of antibodies and specific antigens, e.g. the combination of reactive antibody with specific antigen (see Example A). In humans, both subjective and objective changes resulting from inhalation of a specific antigen by sensitized individuals are inhibited by prior administration of the compounds. Thus, the compounds can be used for the treatment of asthma, for example allergic asthma. The compounds are also suitable for the treatment of so-called "intrinsic" asthma (in which no sensitivity to extrinsic antigen can be demonstrated). The compounds are also valuable in treating other conditions,

209810/1978, "

2U2556

which antigen-antibody reactions are responsible for the disease are, e.g. hay fever and urticaria. For the purposes mentioned above, the dose administered will of course vary depending on the compound used and the mode of administration and the desired treatment. In general, however, satisfactory results are obtained when the compounds in a dose of 0.1 to 50 mg per kg of animal body weight in the experiment described in Example A. For humans, the total daily dose is around 1mg to 350Q mg, divided into individual doses of 1 to 6 times a day or in can be administered in a sustained release form. Appropriate administration doses (by inhalation or esophageal) is about 0.17 to 600 mg of the compound in admixture with a solid or liquid pharmaceutically acceptable diluent or carrier. The compounds of the formula (I) and their .. · pharmaceutically usable derivatives can be prepared in a customary manner administered, preferably in admixture with a larger amount of a pharmaceutically acceptable diluent, Adjuvant or carrier. In particular, the compounds can be inhaled as a liquid, e.g. as an aerosol composition, or as a powder composition, e.g., a powder composition containing a diluent such as lactose and possibly in combination with a bronchodilator, e.g. isoprenaline, or given esophageally as a tablet or capsule.

For administration by inhalation is preferred

the end
a powder used which / particles of the compound of formula (I)

20 9 8 10/1 97 8

2U2556

or a pharmaceutically acceptable derivative thereof an effective particle size of 0.01 to 10 microns, preferably in connection with a coarse-grained carrier »for example having an effective particle size of 30 to 80 microns. The fine particles of the compound of formula (I) or the pharmaceutically acceptable derivative thereof can be prepared by grinding. ·

The invention also encompasses compounds of the formulas -II ■

R ¹⁰ OXO

II

wherein R, R, R are the same or different and each for Hydrogen, a halogen atom or an alkyl ,, hydroxy, alkoxy,

10 substituted alkyl or alkoxy group, R denotes a

Group of formula ₁ '

R ¹

III

1 2 '6

wherein R, R and R can be the same or different and each represent hydrogen, a halogen atom or an alkyl, hydroxy, alkoxy or substituted alkyl or alkoxy group or a group R ^{1 of} the formula IV ■ ·

209810/1978

IV

Ί 2 3 wherein R, R and R ^ have the above meaning, Y stands for the groups -CN or -CZ = NH and Z denotes an easily cleavable group; . And the formula XIY

R ⁰ OXO

XIV

CN ₃ = NH

wherein R, R, R and X have the above meaning, R for one

Group R as defined above or for a group of the formula

XV stands

CN ₃ = NH

XV

"12 3 where R, R and R have the above meaning,

20981 0/1978

"CD

The following examples are provided to the present invention . explain in more detail without, however, being restricted to this < target. All parts are based on weight.

Example 1: 5,5'-jY2-hydroxytrimethylene) -dioxyJ-bis- | j> - (4-oxo-mi-l-ben2opyran-2-yl) -tetrazolj

a) 5,5'- £ (2-hydroxytrimethylene) -dioxy] -bis- [jt-Oxo-MH-l-benzopyran-

2-carboxamidj -

A suspension of 25 parts of 5,5'-Jj2-hydroxytrimethylene) -dioxyj-bis- [( ^l i-oxo- ¹ 4H-l-benzopyran-2-carboxylic acid i-diethyl ester in 250 parts of N, N-dimethylformamide and 250 parts 0.88 ammonium hydroxide solution was stirred for U hours at room temperature The reaction mixture obtained was filtered, the residue washed with water and then dried to give 23 parts of a white powder, mp 288-29 ° C. (decomp.). Crystallization of this product from aqueous N, N-dimethylformamide would give 20 parts of ^{5,5 1} - £ (2-hydroxytrimethylene) -dioxyjbis- | _ ^l i-oxo-iiH-1-benzopyran-2-carboxamido as white crystals, m.p. 293 - 295 ° C (dec.),

Spectral determination: The I.R. Spectrum (Nujolmull) contained bands at 1700 and 16U0 cm because of the Amidearbοny! group and the Benzo-

20981.0 / 137 8

- * β - 2Κ2556 it

pyran ring carbonyl group. In addition, it contained bands

_ -ι
3150 and 3280 cm because of the amide N-Hs. The NMR spectrum showed peaks at 1.56 and 1.90 T because of the 2 NH protons of the amide group and also a singlet at 3.38 T because of the benzopyran ring 3-proton '(solvent dimethyl sulfoxide - d _fi ) . b) 5,5'- [(Formyloxy trimethylene) -dioxy] -bis- p4-oxo-4H-l-benzojjyran-2-carbon itrilj

250 parts of N, N-dimethylformamide were slowly added 10 parts of phosphorus oxychloride added with stirring and ice cooling,

* Then 20 parts of 5, 5'- |] (2-hydroxytrimethylene ) - 'dioxyJ-bis- £ M-oxo-4H ~ 1-benzopyran-2 ~ carboxamideJ to the solution added and the reaction mixture stirred for 72 hours at room temperature. The dark solution obtained was in 1000 parts of ice water poured and the precipitated solid filtered, washed with water and dried, with 16 parts of a light brown powder. By crystallizing this product from a mixture of ethanol and N, N-dimethyl 14 parts of 5,5'- [. (2-formyloxytrimethylene) -dioxy] to ~ 4-oxo-4Ii-l-benzopyran-2-carbonitrile were formulated obtained as white crystals, melting point 214-216 ° C. (decomp.).

Spectral determination: The IR spectrum (Nujolmull) contained a doublet at 1735 cm because of the formate carbonyl group and a band at 1655 cm because of the benzpyran ring carbonyl group. The NMR spectrum showed sharp singlets at 1.32 and 2.7If because of the proton of the formate group and the benzopyran ring ~ 3-proton (solvent dimethyl sulfoxide - d.). c). 5.5 ^l - [(2-Hydroxytrimethylene) dioxy] bis [5- (4-oxo-MH-1benzopyran-2-yl) tetrazole]

2 0 9 810/1978

<Ζ $ 2,2556

A mixture of 18 parts of 5,5'- £ (2 * -Formyloxytrimethylene) -dioxy "] -bis - ^ - oxo ^ Hl-benzopyran ^ carbonitrile ^], 7.5 parts of sodium azide, 6 parts of ammonium chloride and 200 parts of N. , H-dimethylformamide was stirred and heated on a steam bath for 48 hours, most of the solvent ^, was distilled off under reduced pressure and 200 parts of water was added to the residue, the suspension thus prepared was filtered and the filtrate with 20% Hydrochloric acid acidified to give a precipitate which was filtered, washed with water and dried to give 15 parts of 5,5 '- [(2-hydroxytrimethylene) -dioxy3 -bis- [ β- (4-oxo-4H-1 -benzopyran-2-yl) tetrazo].] as a yellow solid.

A portion of this product was purified by converted with aqueous sodium bicarbonate to the disodium salt, and then this salt was converted with hydrochloric acid again in the free tetrazole, leaving a solid yellow material was obtained. Mp. 300 ⁰ C (dec.).

Analysis: '

Calculated for C ₂₃ II ₁₆ HgO ₇ : C 53.49, H 3.12, N 21.71% found: C 53.22, H 3.56, N 21.01%.

Spectral determination: The IR spectrum (Nujolmull) contained a Band at 1655 cm because of the benzopyran ring carbonyl group.

The NMR spectrum contained a broad absorption at 4.49 Z due to the protons of the 2 NH and 0-H groups and also a singlet at 3.2 3 T cars of the benzopyran ring 3-proton (solvent dimethyl sulfoxide - d _fi ).

d) 5,5 '- £ (2-hydroxytrimethylene) -dioxy] -bis- [s- (4-oxo-4H-1benzopyran-2-yl) tetrazole] -disodium salt

20981 0/1978

2H2556

17.45 parts of 5, 5 '- [(2-Hydroxytrimethylene) -dioxy] -bis - [_ 5 ~ (4-oxo-4H-1-benzopyran-2-yl) -tetrazalj were heated in a solution of 5, 11 parts of sodium bicarbonate dissolved in 400 parts of water. The water was azeotroped from the resulting solution using isopropyl alcohol until a solid precipitated. This solid was filtered "wash overall with cold water and dried to give 8 _S, 5 parts of 5,5'-£ (2-IIydroxytrimethylen) -dioxy] J-bisjj> - (4-oxo-4H-l-benzopyr3n- 2-yl) tetrazol / disodium salt sesquihydrate were obtained as a pale yellow powder.

Calculated for C ₂₃ H ₁₄ NgO ₇ Na _2. ! 1/2 H ₃ O: C 47.02, H 2.97, N 18.36% found: C 46.74, II 3.18, N 18.32%.

Spectral determination: The IR spectrum (IJujolmull) contained a Peak at 1658 cm because of the benzopyran carbonyl group. The NMR spectrum contained an Sd-Glett at 3.28 T because of the Benzopyran ring-3-protons (solvent dimethyl sulfoxide - d_).

Example 2: 5,5'-jjC2-chlorotriniethylene) -dioxy] -bisr5- (4-oxo-4H-1-benzopyran-2-yl) tetrazole]

a) 5,5'- [_ (2-Chlortrime thy len) -dioxy [| -bis- J] 4-oxo-4H-1-benzopyran-2-carboxylic acid J-diethyl ester

A mixture of 24.5 parts of 5, 5 '- f (2-Hydroxytrii; iethylene) dioxy] -bis- [4-oxo-4H-1-benzopyran-2-carboxylic acid I-diethyl ester and 4 7.6 "parts of thionyl chloride in 40 parts of dry 1,2-dichloroethane were refluxed for 16 hours. Then the solvent was evaporated, the residue triturated with petroleum ether and the solid obtained from ethanol crystallized, with 15.6 parts of 5,5'-F (2-chlorotrimethylcn) -

209 8 10/1978

BATH ORIGINAL

_- ■ ". .. 2H2556

dioxy] -bis - ^ - oxo-MH-1-benEopyrari-Z-carboxylic acid J-diethyl ester were obtained in the form of white crystals, m.p. 14 4 - 144.5 ° C, Analysis:

Calculated for C ₂₇ H ₂₃ O ₁₀ Cl: C 59.74, H 4.27%

found: C 60.08, II 4.33%.

Spectral mood: the IR spectrum contained Olujolmull)

-1
Bands at 1730 and 1670 cm due to the ester carbonyl group and the benzopyran ring carbonyl group, respectively. The HHR spectrum contained a peak at 5.30 T-because of the tri-ethylene protons and also a singlet at 3.13f because of the benzopyran ring-3-proton (solvent deuterochloroform). The mass spectrum showed a molecular ion at m / e 54 2 with an isotopic peak at jn / e 544 due to the presence of the chlorine atom.

b) 5,5'- j_ (2-chlorotrimethylene) -dioxy3 * -bis- [4-oxo-4H-1-benzopyran-2-carboxamide] »

A suspension of 15 parts 5, 5 '- [(2-Chlortrimethylen) -dioxy3 ~ bis - [(4 ^ oxo ^ Hl-benzopyran-2-carboxylic acid 1 -diäthylester in 150 parts of N _S N-dimethylformamide and 150 parts of 0, 88 Ammonium hydroxide solution was stirred for 5 hours at room temperature. The reaction mixture obtained was filtered, the residue was washed with water and then dried, whereby 11 parts of a white powder were obtained. By crystallizing this product from aqueous N, N-dimethylformamide, 8 parts of 5, 5'- £ (2-chlorotrimethylene) ~ dioxyl-bis ^ L4-oxo-4H-1-benzopyran-2-carboxamidi obtained as white crystals, melting point 175 ° C. (decomp.) The Beilstein halogen test was positive.
Spectral determination.:. The IR spectrum (Hujolmull) contained bands

209810/1978

-1
at 1705 and 1655 cm because of the amide carbonyl and benzopyran ring carbonyl groups. In addition, it contained bands at 3200 and 3320 cm because of the amide N-Hs.

c) .5,5 '- [(2-chlorotrimethylene) -dioxyJ-bis- [| f-oxo-4H-1-benzopyran- 2- carbon itril]

120 parts of N, N-dimethylformamide were added slowly Rein 5 parts of phosphorus oxychloride while stirring and cooling with ice puts. Then 10 parts of 5,5 · '-J_ (2-chlorotrimethylene) -dioxyJ -bis- r4-oxo-4H-1-benzopyran-2-carboxamide] was added and the reaction mixture lasted for 60 hours stirred at room temperature. The dark solution obtained was poured into 500 parts of ice water and the precipitated solid was filtered, washed with water and dried, whereby 6.8 parts of a brown powder were obtained. By crystallizing this product from a mixture of ethanol and. N, N-Dimethylformamide were 4.6 parts of 5,5'- £ (2r-chlorotrimethylene) -dioxyj-bis - [(4-oxo-4H-1-benzopyran-2-carbonitrile | obtained as white crystals, melting point 185 ° C. (decomp.). The Beilstein halogen test was positive.

Spectral determination: The IR spectrum (Nujolmull) contained a Peak at 1660 cm because of the benzopyran ring carbonyl group.

d) 5,5 '- [(2-chlorotrimethylene) dioxy] bis [5- (4-oxo-4H-1benzopyranr2-yl) tetrazole

A mixture of 6 parts of 5,5'- [(2-chlorotrimethylene) -dioxyj-bis-r4-oxo-4H-1-benzopyran-2-carbonitrile , 2.2 parts of sodium azide, 1.8 parts of ammonium chloride and 60 parts of N, N-dimethylformamide were stirred and for 30 hours on a steam

209810/1978

. 4S

bath heated. Most of the solvent was then under distilled off under reduced pressure and 60 parts of water were added to the residue. The insoluble material was filtered and the filtrate acidified with 20% hydrochloric acid, with a precipitate which was washed with water and dried became. There were 4.8 parts of 5,5'- [C2-chlorotriniethylene) -dioxyJ - bisf5- (4-oxo-4H-1-benzopyran-2-yl) tetrazole] obtained as a yellow solid.

A portion of this product was purified by converting it to the disodium salt with aqueous sodium bicarbonate and then this salt was reconverted to the free tetrazole with hydrochloric acid to give a yellow solid .wurde, M.p. 245 C (dec.). The Beilstein analog test was positive.

Spectral determination: The IR spectrum (Nujolmull) contained a

-1
Band at 1658 cm away from the benzopyran ring carbonyl group.

The NMR spectrum contained a broad absorption at 3.40f because of the protons of the 2N-H groups, a multiplet at 5.27T because of the trimethylene protons and also a singlet at 3.12T because of the benzopyran ring 3-proton (solvent dimethyl sulfoxide - d _R ).

e) 5,5'- [(2-Chlorotrimcthylen) -dioxyJ-bis- {5- (4-oxo-4H-1-

benzopyran-2-yl) tetrazole] disodium salt

3 ^ 20 parts of 5, 5 '- [i 2-chlorotrimethylene) -dioxy] -bis- [5- (4-oxo-4H-1-benzopyran-2-yl) -tctrazolj were heated in a solution "of 1 , 01 parts of sodium bicarbonate dissolved in 60 parts of water. The water was removed from the resulting solution using isopropyl alcohol until azeotropiort

2098 10/197 8

Solid has precipitated; This solid was filtered, Washed with cold water and dried, leaving 1.8 parts of 5,5'- £ (2-chlorotrimethylene) -dioxyJ-bis-j5- (4-oxo-4H-1-benzopyran-2-yl) tetrazole disodium salt were obtained as a yellow powder.

Spectral determination: The IR spectrum (Nujolmull) contained a

- 1
Peak at 1655 em because of the benzopyran ring carbonyl group.

Example 3: 5,5 '- j_ (2-Hydroxytrimethylene) -dioxy ^ -bis-T5- (U-oxo-4H-1-benzopyran-2-yl) -tetrazoi]

A solution of 0.52 parts of 5.5 ^l -i (2-hydroxytrimethylene) -dioxyj-bis-Γδ- (2,3-dihydro ~ 4-oxo-4H-l-benzopyran-2-yl) -tetrazoIj and 0 88 parts of selenium dioxide in 10 parts of N, N-dimethylformamide were heated to 85 to 90 ° C. for 3 hours with stirring. After cooling, the reaction mixture was filtered and the filtrate poured into water. The suspension produced in this way was filtered, washed with water and dried, with 5,5'- [C2-hydroxy-trimethylene) -dioxyj-bis- rs-Ci- oxo-ifH-1-benzopyran-2-yl) tetrazole was obtained as a yellow solid, melting point 300 ° C. (decomp.).

2 098 10/197 8

2U2556

t * (I I

Be i s ρ i e 1 U: 5,5'- [(2-Hydroxytrimethylene) -dioxy] -bis - [_ 5- (4-oxo-4H-l-benzopyran-2-yl) tetrazole]

A solution of 0.69 parts of 5,5'- Γ (2-Hydroxytrime thy lendioxy]} - bis- [5- (4-oxo-ifH-1-benzopyran-2-yl) -N-benzyltetrazol2 in 10 parts N, N-dimethylformamide was stirred in a hydrogen atmosphere for 12 hours with 0.028 parts of 5% palladium αμΓ carbon at 60 ° C. After cooling, the reaction mixture was filtered and the filtrate poured into water. The suspension thus produced was filtered, washed with water and dried wherein 5,5 '- [(2-hydroxytrimethylene) -dioxyj bis [5- (4-oxo-HH-l-benzopyran-2-yl) -tetrazolJ was obtained as a yellow solid, mp 300 ⁰ C (. Decomp.).

Example A: The procedure described below can be used to increase the effectiveness of a compound in inhibiting the release of pharmacological Determine amboceptors of anaphylaxis.

In this experiment the effectiveness of the compounds in the inhibition of passive cutaneous anaphylactic Reaction determined in rats * It has been proven that this form of experiment is reliable qualitative indications about the ability

209810/1978

the to. compounds to be tested are the antibody-antigen. inhibit reaction in humans.

In this test procedure, Charles River France " Rats bred by Fisons (male or female) and weighing between 100 and 150 g, at weekly intervals with N. brasiliensis larvae in increasing doses from around 2000 larvae per animal to 12,000

^. Larvae infected subcutaneously per animal to cause infection. After 8 weeks, the rats were bled by cardiac puncture and collected 15 to 20 ml of blood from each animal. The blood samples were then rotated at 3,500 revolutions per minute for 30 minutes centrifuged to remove the blood cells from the blood plasma. The serum was collected and used to prepare a serum, containing the N. brasiliensis antibody was used. A sample sensitivity test was performed to determine the minimum amount of serum to determine which is necessary in order to be able to develop a skin bruise in control animals in the experiment described below

^w 2cm in diameter. It has been found that the optimum sensitivity in rats with a body weight of 100 to 130 mg is obtained when using a serum which is diluted with 8 parts of a physiological saline solution. This ver. thin solution was called antibody serum A.

DAS _antigen: to react with the antibodies in serum A is prepared by N.brasiliensis-worms from the intestine of the affected Ratten'entfernt, the homogenate is centrifuged and the supernatant liquid is collected. This liquid is diluted with a saline solution to achieve a protein content of 1 mg / ml and is available as solution B.

20981 0/1978

•known.

2142558-

Charles River France rats made by the Fisons company were bred and had a body weight of 100 to 130 g, were sensitized by intradermal injection of 0.1 ml of serum A into the right flank. The sensitivity allowed to develop for 24 hours and then the rats were given intravenous 1 ml / 100 g body weight of a mixture from 0.2 5 ml of solution B, 0.2 5 ml of a blue dye solution (Evans Blue) and 0.5 ml of the compound to be tested (with varying percentages of active ingredient). Insoluble compounds were given as a separate intraperitoneal injection 5 minutes before intravenous administration of solution B and of the blue dye administered. For each 'percentage Active substance in the solution which was tested was injected into 5 rats. In each experiment, 5 rats became controls used. The doses of the compounds to be tested were chosen to give a range of inhibitory values.

Thirty minutes after the solution B was injected, the rats were sacrificed and the skins removed and turned over. The intensity of the anaphylactic reaction was determined by the size of the characteristic blue welts that by spreading the blue dye from the sensitization point with the size of the welts was compared in the control animals. The size of the welts is rated from 0 (no welt found, i.e. 100% inhibition) to .4 (no difference - in the size of the welt, i.e. none Inhibition) and the percent inhibition for each dose is calculated as follows:

2098 10/1978

- a *

St.

(Control group evaluation - evaluation of the treated

"" 3rd group) x 100

% Inhibition = -

Control group evaluation

The percent inhibitions for the various dosages were plotted for each compound. the end
The curves can be used to determine the dose required to achieve 50% inhibition of the anaphylactic reaction (ID _Q ).

The connections were also made in the above manner

ψ Application of intestinal and gastric administration of the compound assessed.

Example B: Contained an inhalation composition
a mixture of 20 mg of a compound of formula I, e.g.
5,5'- [(2-Hydroxytrimethylene) -dioxy3-bis- [5- (4-oxo-HII-benzopyranl-yD-tetrazole-disodium salt with a particle size of 1 to 10 microns and 20 mg of crystalline lactose with a particle size of 32 to 63 microns The composition can be contained in a gelatin capsule.

209810/1978

Claims (1)

2H255-.6 Claims 1) Compounds of the formula wherein R _1, R, R, R, R- and R- can be the same or different and each represent hydrogen, a halogen atom or an alkyl, hydroxy, alkoxy, substituted alkyl or alkoxy group, X is a saturated or unsaturated, substituted one or unsubstituted, straight or branched hydrocarbon chain which can be interrupted by a carbocyclic or heterocyclic ring or by one or more oxygen atoms or a carbonyl group. 2) compounds according to claim 1, characterized in that 12 3 no more than one of the radicals R, R and R and no more as one of the radicals R, R and R has a meaning other than Has hydrogen. 3) Compounds according to claim 1 or 2, characterized in that R ¹ , R ² , R ⁵ , R ^, R ⁵ and R are hydrogen, chlorine, bromine, lower alkyl, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy mean lower alkoxy and carboxy-lower alkoxy. 209 8 10/197 8 2U2556 3 * 4) Compounds according to claim 1 to 3, characterized in that all radicals R ¹ , R ² , R ⁵ , R ⁴ , R ⁵ and R ^{6 are} hydrogen. 5) compounds according to claim 1 to 4, characterized in that that X is a hydrocarbon chain having 3 to 7 carbon atoms which can be substituted by one or more chlorine atoms or one or more hydroxyl groups. 6) compounds according to claim 1 to 5, characterized in that that the group -0X0- the 5,5'-positions of the benzene nuclei connects. 7) 5,5 '- / j ^ -hydroxytrimethylene) dioxv7 ~ bis- / 5- (4 - o: x.o-4H-1-benspyr8n-2-yl7-tetrazole. 8) 5.5 ^? - / r2-chlorotrimethylene) dioxy_7-bis- / 5- (4-oxo-4H-1-benzpyran-2-yl7-tetraaol. ι . . ■ ■ ■ ■ 9) Compounds according to claim 1 to 8 in the form of pharmaceutical acceptable salts. 10) compounds according to claim 9, characterized in that the salt is a sodium salt. 11 ") connections according to claim 1 to 10, characterized in that that they have an effective particle size of about 0.01 to 10 microns. 209810/1978 'i2) / process for the preparation of "compounds according to formula 1, as defined in claim 1, characterized in that one a) a compound of the formula II OXO II wherein R-, R, R and λ have the meaning given in claim 1 10
have processing, R- is a group of the formula III III K- R 12 3 '' " wherein R, R and R have the meaning given in claim 1 own or for a group R of the formula IV -N - H IV 12 3
wherein R, R and R have the meaning given in claim 1, Y is one of the groups -CN or '-CZ = NH and Z is an easily split off group, 2 0 9810/1978 with an azide in one under the reaction conditions converts inert solvents, b) with hydrogen, the group G in a compound of the formulas V or VI VI wherein R is a group of the formula VII VII wherein R ¹ , R ² , R ³ , R 1, R ⁵ , R ⁶ and X each have the meaning given in claim 1, E stands for a tetrazole group or a group of the formula VIII or IX G — N — C- / W 209810/1978 VIII IX 21425.58 -V-. " and G represents a group which replaces with hydrogen v / can earth, durch.'Hydrierung, Dealkylierung, Deacylierung under light basic or acidic conditions or by reductive Deam in ic; tion, replaced c) a compound of the formula X or its salts are cyclized R'OXO- ^JJ - '' ^ * ^{v X} ' wherein R, R, R and X have the meaning given in claim 1 have and R 'for the group R as defined above or a compound of the formula XI XI 12 3 wherein R, R and R are those given in claim 1 ·. Significant. possession d) subjecting a compound of the formula XII to selective dehydrogenation 209810/1978 HO XII R ' wherein h -, R r% R 'and X have the meaning given in claim 1 and R ^{n stands} for the group R $ which is defined as above or a group of the fo fin el Χϊϊί ΧΪΙΙ - ■ 1-2 3
wherein R, R tuid R as defined in claim 1 have the meaning · or e) a connection of the Forinel XI? R ⁸ OXO XIV v / orjn R, R, - R and X have the meaning given in claim 1 own and 8 '- 7 R for the group R as defined above or a group of the formula XV 209 6 10/1978 7U2556 xv 1 2 3 ■ wherein R ₅ R and R are those given in claim 1. Have meaning into a compound according to claim. 1 transferred. 3) Connections of the Foröiel '. : '' "; ':' v / orin R, R ^-3 , R and X have the meaning given in claim 1 10
R stands for a group of the formula III III R- R 12 '6 v. ^r orin R, R and R have the meaning given in claim 1 own, .. '", -.- ■;. 2 0 9 810/1978 2U2556 - € 1 - η or represents a group R 'of the formula IV IV wherein R ,, R ^ and, R have the above .. "" meaning _; ^;; X stands for one of the groups -CN or -CE-NH; and: / Z means an easily split off group. 14) compounds of formula R ⁸ OXO XIV CN_ = MI wherein R, R, R and X have the meaning given in claim 1 own and ■ · 8 V R for the group R as defined in claim 13, or is a group of the formula XV XV R 'R. 209810/1978 2U2558 wherein R, R "and R- have the meaning given in claim 1 own. . --- .. .. 15) Pharmaceutical preparation containing a compound according to Claim Ij or a phara & aeütis & h usable derivative thereof, as an active component in conjunction with a pharmaceutically acceptable diluent, adjuvant or carrier! 16) preparation iiäch claim "15, characterized gelcenhaeiclinet» that it 0.1? "up to βόο mg of active Kömporierite per dosage unit contains. " The patent attorney 1 / ^ / c ■, 209810/1978