DE2403055A1 - PHARMACEUTICAL MIXTURES OR SALT BASED ON BASIC QUINOLINE COMPOUNDS - Google Patents

Description

PATENT LAWYERS

DJpI-In ₀ -P-WIRtH - Dr. V. SCHMIED-KOWARZIK D »p» .- Ing. α DANNENBERG ■ Dr. P. WEfNHOLD Dr. D. GUDEL

2SH34 β FRANKFURTAM MAIM

^L * "2S7014 GH. ESCHENHEIMER STRASSE 3 ·

BA 3352/73
Wd / Sch

Fisons Limited
9 Grosvenor st.
London »Great Britain

Pharmaceutically usable mixtures or salts based on quinoline basic compounds

409830/1144

The present invention relates to new compounds, To their manufacture and to a new pharmaceutical one Mixture.

The object of the present invention is to provide a Pharmaceutical mixture containing a compound which contains an acidic group and a ketone carbonyl oxygen atom and from the group: benzopyrans, anthraquinones, iluorenones and xanthones is selected and is effective in the treatment of conditions caused by antigen-antibody reactions (e.g., asthma, allergic rhinitis or urtlkaria) together with an anti-inflammatory agent, being the anti-inflammatory agent and the compound are such that they have an additive effect in terms of the inhibition of the "reverse passive Arthus reaction" Rats have (see Goose J. and Blair A.M.J.N., Immunology, Volume 16, page 749).

The benzopyran compound can be a chromone-2-carboxylic acid or a chromone-2-tetrazole or a pharmaceutically acceptable one Be a derivative of these. Preferably the bensopyran compound is a compound disclosed in British U.S. Patent No. 1,144,905, i.e. a compound of formula I.

OXO

R ² .

R *.

R and R may be the same or different

where R,

can and in each case a hydrogen or halogen atom or an alkyl, hydroxy, alkoxy or substituted alkyl or alkoxy group (for example a hydroxyalkoxy, alkoxyalkoxy or carboxyalkoxy group) _t X is an optionally unsaturated, optionally substituted,

409830/1144

straight or branched hydrocarbon chain ₅ through a carbocyclic or heterocyclic ring or through, one or more oxygen atoms or carbonyl groups underfcroeb-sn, and Ex a carboxylic acid group * "means _c

Prevented the group of YerT) indications of the formula I, "at

12 5

where no "more than one of the best E, E and Br and no more than one of the rents R, R" * and R is not hydrogen and X is a 3- Ms 8-glieArigo ADkylenkettc, which is given.-falls through a Hydroxy groups is substituted. In particular, precaution is taken that all residues R bia RV / assca * stoff, elue precludes yer "binö." U ^ let 1 j.3 * -Biö (2-carbo3rychroiaon-5-yloxj) -2-ly drosy-propane »

A \ T3itö "ce Gruijpe of Bensopyranverbindungon are the Ben-^ odipyratiTor Mndungen British Patent ITr. 1,230,087 ie., The compounds of formula II aey

II

■ wherein an adjacent pair of the groups P, Q, R and T forms a chain -COCH-G (Rx) -O- and the remaining groups P, Q, R and T _1, which can be the same or different, each hydrogen, hydroxy , Alkoxy, alkyl, nitro, halogen, phenylalkoxy, alkenyloxy, alkenyl, alkoxyalkyl mean or- v / orin an adjacent pair of the groups P, Q, R and T together with the adjacent carbon atoms in the BenKol ring a 5- or 6-membered oxygen containing heterocyclic ring, and Rx is a cartonic acid group *.

A preferred compound is 4, Ip-dioxo ~ 5 ~ ethoxy-2,8-di ~

409830/1144

Another group of τοπ BariEopyranverbindungen are those in flor Belgian Patent Nos. 771 544 and 771 818 bencbriebciiän Compounds, from which compounds of the above formula I belong si where Rx is a 5H-Tetra £ o3 group, and that in the British Patent Hr. 56070/75 described connection he, to dt ^ .c Compounds of formula I include wherein Rx is a Garboxaniate.trazolgruppe is.

Other groups of JßensQpyr & nvw-'.ndungen are Konoebxon "<or.ivav bindings of Pornol II, before in P, Q, R and T joveils Y.'nssex · - otoff, Kydrorry, Alkoxy, AlVyI, Hnlogen, Alkoxy-allios; · /, / Jks / iyl Alkenylozy uciv «and Ej: a C; vi * lx« i.h; lure group for a Ttt: va «ol group (see see B. Eslricclie Patent No. 771,817) odor a carboxamide otetrusol group (sielie ".B", German Offenlegungsschrift ITr. 22 49 100).

As ΕβΙεφΙβΙβ for Anthrcohinonvorbiiidungen those can the Belgian Patcntcehrii't ITr. 770 937 and 775 586 mentioned i.e. compounds of the formula III

.0

OXH

III

wherein R ^ halogen ,. OH, OR ₉ or I ^ R ^ R / mean,

wherein R ₂ ^is alliyl C ^ - Cg, which is optionally substituted by OH, aryl, aryloxy, alkoxy or dialkylamine, and R ₇ and R. for H, alkyl C ^ - Cg, which is optionally substituted by OH , stand odea? viorin R., and R ^ Eusannsen form a heterocyclic Riijg with the H-Atora, which optionally contains a further Heteroatoai, for example Pip erid in, τ lcrpholin or K-Hethylpiperazin, (; arh oxy 1 r, rv] yp e

409830 / 114.4

or V χ: turns of the formula IT

IT

where X = 5 /, 1H7-! 2etrazole: R ₁ = H, halogen, OH, (with R ₂ = alkyl C ₁ - Cg or alkenyl C ₁ - Cg, both by one or more OH-Grαρρen or an aryl , Aryloxy-alkoxy or bialkylarairio group can be substituted.), Or HR _x R- (with _{-R 7.} And R. - H or alkyl C ₁ - C ^, which may also be substituted by OH, or with NR-R . = a heteroeyclisoher ring, which optionally contains a further heteroatom) mean.

Those of the Belgian patent specification can be used as xanthones ir. 759 292, i.e. a combination of the formula T.

where X = COOH or 5- / T "iH7-tetrazolyl and R ₁ and R ₂ = H, alkyl

- C

, Halogen, NR ₅ R ₄ , OR, or mean; with R ₅ and R ^ = E, phenyl, benzyl or alkyl, which can optionally be substituted by alkoxy C ₁ - Cg, phenoxy, phenyl, NH ₂ , NK-alkyl, N (alkyl) ₂ or one or more OH groups ? R ₅ = H, alkyl C ₁ - Cg and Rg = alkyl C ₁ - Cg. When X = COOH, both radicals and Ro = H are not.

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Other xanthones can be found in the Dutch declaration of action No. 72 09628 described compounds of the formulas VI and VII are mentioned:

and

wherein R is a group of the formula VIII or IX

VIII

OR ¹

-C

or

Il.

-C-R '

- C ₆ , tetra

wherein R ¹ is H, alkyl, O ₁ - C ₈ cycloalkyl, C ^ - C ₆ hydro-furan-2-yl, Ietrahydropyraii-2-yl, tetrahydro pyran - 4-yl 4 ~ Alkoxytetrahydropyran-4-yl or carboxyacyl C ₁ - ⁰ I? ¹ R ² for H, alkyl C ₁ - C _ß or cycloalkyl C ₃ - C ₅ , and R ⁵ for H, alkyl C ₁ - Cg, cycloalkyl C ₃ - C _gf Phenyl, optionally substituted by halogen, alkyl C ₁ - C «, Alkoxy C ₁ - C _n alkylthio C ₁ - C _Q , CF, or CIi or a 5- or 6-membered heterocyclic ring with 1 or 2 IT, 0 or S atoms can be para-substituted,

stand.

Further xanthones are the compounds of the formulas X and XI mentioned in Belgian Patent 843

409830/1 144

R-S (O)

COOH

wherein η = 1 or 2; if η = 1, E is the lower allcjl means; when η = 2, R is lower alkyl, hydroxy or Jiisino or Hono - or Pi-nie & ercs-allcylsinino means.

Other xanthones are included in the German patent application P 22 54 250 standardized compounds of the formula XII

0 ■ H

COOII

XII

where R = H or Al] JjI C, - C _r büöGUtet.

Then the xanthones of the German patent nni & el can fertilize P 22 34 252 and 22 34 253 and you? Dutch kit ent to message ITr. 72 09622 called v / erden, with v / olclien it sicIi about yer] undur <gon who acts Pormel XIII,

• COOIi

ΧΪΙΪ

viorin 1) R ₁ and R _? both lower alkoxy or both lower alkyl or one of the radicals R .. and, R ₂ lower alkoxy,

2) one of the radicals R ^ and Rp lower alkylthio and the other Remainder lower alkyl thio, lower alkyl or lower allrosy,

or 3) R ₁ and R _{2 are} hydrogen, chlorine, fluorine, lower alkyl, lower alkoxy or lower alkylthio.

Other · compounds used for the mixture according to the invention are those in the German patent application

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P 22 43 997 described fluorenone compounds and in the German patent application P 22 49 100 "described xanthone and other carbonamides» tetrazoles.

The above compounds can be in 3? Orm of a phsrma ~ an appropriately usable derivative of these can be used; ' preferably they are used in the form of a salt such as a sodium salt.

The second component (anti-inflammatory compound) is preferred effective in in-munologisclieij reactions of type 3, as with the "reverse paoeiven Arthus reaction", and can be of the steroid type, e.g. cortisone, hydrocortisone, prednisolone, Prednisone, 6i £ -MethylpredniBolon, Triaraeinolon, Paramethason, B -; - ta-methason, Dexamethason and 9. ^ ~ Fluorocortisol »If applicable Mixtures of steroids can also be used. However, the anti-inflammatory agent is preferably not steroid type, e.g., a 4-amino-quinoline compound such as Chloroquine (e.g. chloroquine diphosphate), hydroxychloroquine, Cycloquine or Amodiaquine, Chloroquine is preferably in the form of a relatively water-insoluble or flavor-free derivative, e.g. as a salt with emboxylic acid. More anti-inflammatory Agents that are not of the steroid type include indomethacin, phenylbutazone and aspirin.

The first compound and the anti-inflammatory agent are preferably in the composition in a ratio of about 1: 0.5 to 20, especially about 1: 5 Ms 20, especially about 1:10 by weight present.

The object of the present invention is also to provide a pharmaceutically acceptable salt of a basic quinoline compound, which has anti-inflammatory activity, with any of the compounds listed above. (I component)

409830/1144

Salts "which are unflavoured or unflavored are preferred have a pleasant taste.

The basic quinoline compound is preferably a 4-amino quinoline, e.g. chloroquine, i.e. 7-chloro-4- (4 ~ diethylainino-1 ~ methylbutyl-amino) -quinoline, Hydroxychiorοquine, Cycloquine i.e. 7-chloro-4- (3,5-di (d.iethylaminomethyl) -4-hydroxyaniline) ~ quinoline, or atnodiaquine.

If the first compound has two or more acid functions, so the salt can be a QaIz with one or more of these acid functions while the remaining acid functions either are free or in the form of pharmaceutically acceptable salts with other cations, e.g. with sodium ions.

Another object of the present invention is to provide a method for producing a pharmaceutically usable one Salt of a basic ohinoline compound which is a possesses anti-inflammatory activity, with a = ■ ·. of the first compounds listed above, which consists in that the basic quinoline compound and the other compound implemented together.

In the implementation, the basic quinoline compound and / or the other compound used in the form of another salt of these and a double conversion or double decomposition be applied.

The reaction can, in a solvent which is under the " Reaction conditions are inert, e.g. water. The reaction is preferably carried out using equimolar Ratios of the basic quinoline compound and the other compound were carried out. Preferably the starting materials subjected to a double reaction to obtain a by-product which is soluble in the reaction medium; even the starting materials themselves should be soluble in the reaction mixture For example, an alkali metal or amnionium

'"409830/1144

salt as the first compound and a salt of the basic quinoline compound with a strong acid, e.g. sulfuric or phosphoric acid, as starting materials in a double reaction be used.

The mixtures and salts according to the invention are valuable because they have a pharmacological effect in humans and animals "possess; 3They are particularly valuable because they reduce the release and / or effectiveness of pharmacological mediators * - inhibit which of the in vivo combination of certain species of antibodies and specific antigen, e.g. when combining reaginic and IgG antibodies with specific Antigen (see Example A below).

In humans, prior administration of the mixtures and salts according to the invention inhibits both subjective and objective changes which are caused by inhalation of specific antigen in sensitized persons. The mixtures and salts according to the invention are therefore suitable for the treatment of asthma, both allergic and non-allergic asthma. * The mixtures and salts are suitable. is also used to treat other conditions in which the disease is caused by antigen-antibody reactions, such as allergic. Rhinitis; certain eye diseases such as trachoma; Urticaria and other allergic skin diseases; and gastrointestinal allergies, especially "in children, eg milk allergy. The salts and mixtures according to the invention are also suitable for the treatment of conditions in which both inflammatory and antigen-antibody reactions are the cause of the disease, and are therefore suitable for the Treatment of "intrinsic" asthma ·

For the purposes listed above, the dose administered will of course vary depending on the composition used, the mode of administration and the treatment desired. In general , however, satisfactory results are obtained when the compounds are used in a dose of about 0.1 to 200 mg per kg

. »Mediators» 409830 / IU *

Body weight of the animals in that described in Example A " Attempt to be administered. In humans "the total daily dose is about 1 to 1000 mg, preferably about 5 to 200 mg, those in divided doses one to six times a day or as a preparation sustained release dosage forms suitable for administration (inhalation or Swallowing) therefore comprise about 0.17 to 1000 mg of the mixture or the .Salz, which is pharmaceutical with a solid or liquid usable diluents or carriers.

A pharmaceutical composition is also in accordance with the invention created a mixture according to the invention or a corresponding one Salt in conjunction with a pharmaceutically acceptable one Diluents or carriers. Suitable carriers are for example crystalline lactose or a solvent such as sterile water. A composition for oral use or Nasal inhalation may comprise, for example, a solution or suspension in sterile water, e.g., up to about 5 wt .- $, preferably about 2 wt .- $, the mixture according to the invention or the Salt and also preferably contains a preservative. Such an aqueous solution can also be a viscosity modifier (e.g. for rabbit drops) in order to increase the viscosity, and the pH value can be adjusted if necessary can be set to around 6.0. These aqueous solutions can be applied or with the help of a conventional nebulizer administered by pressure spray bottles or as nasal drops into the nose will.

If necessary, the composition can also be carried out with a pressure vessel, e.g. an aerosol can. For administration with an aerosol can, the composition dissolved or suspended in a liquefied propellant. Conventional propellants can be used for this purpose Spray from pressure vessels can be used. For example, halogenated hydrocarbons, such as fluorine or fluorine

409830/1 UA

- 12 - 2Ä03055

halogenated hydrocarbons, for example trichloromonofluoromethane, dichlorodifluoroethane, dichlorotetrafluoroethane, monochlorotrifluoroethane, monochlorodifluoromethane, and mixtures of these or mixtures with other propellants can be used. Typical suitable propellants are described, for example, in U.S. Patent Hi *. 2,868,691 and sold under the name Marlrennsraen "ireon". Preferably the propellant is of low toxicity, and difluorodiehloriaethane, dichlorotetrafluoroethane, or hybrids of these are preferably used. If he sgemliße Miseuimg or the corresponding Sals are not soluble in the propellant, it may be necessary to add a surfactant in order to suspend the mixture taw, the salt in the propellant f.-ίι, and for this purpose any of the customary surface-active gowns _5, for example a non-ionic surface-active agent, are used. Preferably, however, dialkyl sulfosuccinic acid ester or alkyl benzene sulfonate is used as the surfactant. The use of such surfactants and the benefit resulting from their use have been described in British Patent No. 1,063,512.

The mixtures and salts according to the invention can also be administered in the form of powders by means of an injection device such as that described in British Patent No. 1,122,284. For such an administration method, the active ingredient is preferably in extremely fine-grained form (that is, with a particle size of less than 10 microns, preferably about 0.1-10 microns). The finely divided powder of the active ingredient can be mixed with a coarser diluent material that has a size γοη about 60 to 120 microns, such as lactose, and this can be present in smaller, equal or larger amounts than the active ingredient, for example in about 50 to 150 wt .- ^ of the mixture according to the invention or the corresponding salt.

409830/1

2 ^ 03055

The mixtures and compositions according to the invention can be prepared by adding any of the active ingredients mixes other ingredients necessary to obtain a usable composition.When the active ingredients must be treated, for example by fine grinding, so this can be done with the individual constituent, while mixing ^ the ingredients or at a later point in time after mixing.

For the compositions according to the invention, those are preferred the 1,3-bis (2-carboxyohroüion-5-yloxy) -2 "hydroxypropane or 7 ~ (2-Hydro3ryäthoxy) ~ xanthone-2 ~ carboxylic acid or a pharmaceutical useful (e.g. sodium) salt of either of the two.

The invention also provides a preparation preferably for Inhalation, especially for asthma, containing an effective amount of 4-aminoquinoline.

The same dosage levels as indicated above are possible.

The following examples serve to explain the invention in more detail.

example 1

5 »5 '- (2- (Hydroxytrimethylene) -dioxy) -bis- (5- (4-O3CO-4H-1-benzo pyra n-2-carboxylic acid) -6-chloro-4- (4-diethylamino-1 methylbutylainino) ohtnoline salt

Chloroquine diphosphate (5.52 g; 0.0107 mol) was added to water (20 ml). An aqueous sodium hydroxide solution containing 10%. Shot was added and the chloroquine free base was released in the form of an oil. This oil was extracted with ether, and the ether layer was washed over with water Magnesium sulfate dried, filtered and the piltrate in vacuo

409830/1 U4

evaporated to dryness to obtain Cb.loroq.uine in the form of a colorless oil. Then a solution of disodium 5,5 ¹ - (2- (hydroxy-trimethylene) -dioxy) -bis- (5- (4-oxo-4H-1-benzopyran) -2-earboxylate) in water (60 ml) added to the Chloroqui = ie, and. the mixture was on the steam bath until complete. Dissolution heated. Then, the solution was cooled and άηπ desired salt came out der.Lösung as an oil which formed a lower layer of. This layer was decanted and the oil was rubbed with acetone to give a white solid which was filtered off and washed with acetone and ether. The product was dried in vacuo at 90 ° C for 48 hours (6.1 g).

Analysis: Found: C = 60.8, H = 5.4, N = 5.1 £

Calculated: C = 60.8, H = 5.5, N "= 5.2 1 ° for C ₄₁ H ₄₂ OlN ₅ O ₁₁ with 2.7% water content

The nuclear magnetic resonance spectrum (HiIR) in Hsxadeuterodimethylsulfoxyd showed peaks "" T3ei 8.75 '^ for 3 methyl groups in chloroquine and a sharp two-proton siriglette at 3 for the 3 and 3 'protons of the Bis-Ehromon part.

Example 2

5.5 ^t '((5 _t 5 ^t (2-hydroxytrimethylene) -dioxy) ~ bis- (5- (4 "Oxo-4II-1 ~ " benzopyran-2-yl)) -bia ~ tetrazole ~ 7-chloro ~ 4 - (4 - diethylamino - 1- i | t ^ hylbutylamino) -quinoline salt-monohydra t

The procedure of Example 1 was repeated, except that 4.5 g of chloroquine diphosphate were used to prepare the chloroquine and that with 5.5 ^f - / "(5.5 ^t - (2-hydroxy-trimethylene) ~ dioxy) -bis- ( 5- (4-oxoHH-1-benzopyran-2 ~ yl) _7-bis-tetrazole (4.5 g) in 75 ml of water was reacted to obtain 4.1 g of the above-mentioned compound.

* Peaks

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Analysis:

Found: C - 57.8, H = 5.6, Cl - 4.5, N - 17.8 %

Calculated: C = 57.8, H «5.2, Cl = 4.2, N = 18.1 # for C _A1 H ₄₂ ClTi ₁₁ O ₇

The nuclear magnetic resonance spectrum in hexadeuterodimethylsulfoxide showed peaks at 8.75t for 3 methyl groups in chloroquine and a sharp two-proton singlet at 3, for the 3 and 3 'protons of the bis-chromone part.

Example 3

The following compounds can also be made by the procedure described above:

a) 7-Methoxy-2-1H (tetrazol-5-yl) -xanthene-9-one-7-chloro-4- / JK- (ethyl (2-hydroxyethyl) amino) -1-methylbutylamino_7-quinoline salt

b) 7-Methoxy-xanthen-9-one-2-carboxylic acid 4- (7-chloro-4-quinolylamino) -oi-diethylamino-o-cresol salt

c) 7- (2-Hydroxyethoxy) -9-oxoxanthene-2-carboxylic acid cycloquine salt

d) 4,10-Dioxo-5-methoxy-2,8-dicarboxy-4H, 10H-benzo- (1,2-b: 3,4-b ' ) Dipyran-7-chloro-4- (4-diethylamino-1-methylbutylainino) -quinoline salt

Example A.

"Reverse Arthus Passive Reaction" in Rats *

In this test procedure, Dutch rabbits weighing 2-3 kg are sensitized by giving them 2 intramuscular injections every 5 weeks , each 0.5 mg of egg albumin dissolved in 0.5 ml Reversed Passive Arthus Reaction "

A0983C / 1UA

an emulsion of saline with an adjuvant ("Freunds Complete Adjuvant "). After this treatment, the rabbits are given 10 mg of egg albumin at weekly intervals in 0.1 ml of saline solution is injected intradermally into the shaved back until a noticeable Arthus reaction developed.

The rabbits are blood drawn by cardiac puncture 3-6 days after the last injection and the blood samples are taken for 15 minutes centrifuged at 4000 rpm for a long time to remove the blood cells from the Separate serum. Several sera are then mixed together and used as a source of rabbit anti-egg albumin antibodies used.

A sensitivity test is now carried out to determine the smallest amount of serum necessary to obtain a reaction 2-3 cm in diameter in a comparison group of rats using the test described below. It has been found that optimal sensitivity is obtained in rats weighing 100-120 g if a serum is used which has been diluted with 3 parts of a physiological saline solution. This diluted rabbit serum is called Antibody Serum A.

The antigen to be reacted with the antibodies in serum A is produced by adding dried egg albumin in physiological saline solution at a concentration of 1 w / v. -% is solved. This solution of egg albumin is called solution B.

Rats with a body weight of 100-120 g of the Charles River France / Fisons v / erden breed are sensitized by injected 0.1 ml of serum A intradermally into the shaved right flank. One lets the sensitivity 4 Develop for hours, after which the rats are given 1 ml / 100 g body weight for a mixture of solution B (0.25 ml), Evans

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Blue dye solution (0.25 ml) and either saline (0.5 ml) or a solution of table salt (0.5 ml) with an effective Portion of the first compound oder.der mixture according to the invention or the corresponding salt injected.

Between 0 and 4 hours before the injection of solution B is given the rats by the oral route through a gastric tube either distilled water (1 ml) or a solution or Suspension (1 ml) with an effective proportion of the anti-inflammatory compound or the mixture according to the invention or the salt administered.

The animals are left 4 hours before this oral administration starve. In each case 5 rats are treated and 5 rats serve as comparison animals in each experiment.

30 minutes after injection of Solution B and Evans Blue dye the rats are killed and their skin examined. The intensity of the reverse passive Arthus reaction will be determined by the size of the blue areas, which are caused by the spread of the Evans blue dye from the sensitized Position is compared with the size of the blue areas in the comparison animals. By the treatment-induced inhibition, expressed as a percentage, is calculated as follows:

Size at size in treated _{animals of the same # 1 β} "" th animals χ 100 '

Size in comparison animals

To the additive effect when treating with different Identifying combinations of benzopyran and anti-inflammatory drugs will determine the inhibitory effects of the two Compounds - once individually and once combined - compared to the Passive Arthus reaction.

40983Q / 1U4

2Λ03055

- 18 Example B

A composition was prepared by using the following Ingredients mixed and the mixture poured into a gelatin capsule:

Sodium Cromoglycate 20 mg

Chloroquine embonate 20 mg

Lactose 40 mg

The disodium cromp glycate and chloroquine embonate were micronized to have a particle size between 0.01 and 10 microns, and the lactose was reported to have a particle size of 30 to 80 microns.

Example C

Typical composition of a nasal spray:

Mixture according to the invention or salt 2.0 #

Disodium edetate BP 0.01 #

Sodium Phosphate BP -. 0.24 %

Sodium Hydrogen Phosphate BP 0.94 %

Benzalkonium chloride solution BP 0.02 %

Purified water BP to 100 %

(Note: Sodium Chloride BP can be added to make the solution isotonic; it can also be soluble Cellulose derivatives are added to increase viscosity).

preparation

The solid components are in part of the purified

A09830 / 1144

Dissolved in water. The benzalkonium chloride solution is under slight JRirring added. The volume is made with purified water filled up, and it is stirred for 10 minutes. Then the mixture is clarified by filtration.

In a sterile tree, the solution is sterilized by filtration and filled into sterilized nasal spray bottles.

Example D

Preparation for a pressure aerosol:

Gew./Wew.-#

Title compound of Example 1 0.500

liatric dioctyl sulfosuccinate 0.002

Propellant (Propellant 114 BPC) 4.4-98

Propellant ^{Mixture "4} " 95,000

⁺ Propellant mixture consisting of: Propellant 12 BPG =

60 w / w -% Propellant - 114 BPC =

40 w / w-#

The title compound of Example 1 was finely comminuted to to obtain a particle size between 0.01 and 10 microns.

Manufacturing method:

The liatrium dioctyl sulfosuccinate is in a small amount of the propellant 114, which is at a temperature below -15 ° C has been cooled, and the solution is placed in a ball mill cooled to below -15 ° C. Now the Title compound of Example 1 and about one third of the total amount of propellant 114, which is cooled to below -15 ° C has been admitted. The mixture is ground for 15 minutes at a temperature below -15 ° C and then placed in a ta

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The mill is washed twice with each half of the remaining propellant 114, which has been cooled to below -15 ° C, and the washing liquids are collected in the container. Finally, a sufficient amount of propellant 114, cooled to below -15 ° C., is added to obtain the desired weight and mixture. The mixture is cooled to O ⁰ C -4-cooled .and directed into an aerosol iHillanlage. Now, cooled to -40 ⁰ C a blowing agent mixture is added and the mixture into suitable cans filled.

Id the case that the compounds described in this application Alkyl, alkenyl, alkoxy or alkenyloxy groups or these Have groups containing radicals, then these are groups preferably low molecular weight, i.e. they contain about 1 to 6 .B. 1 - 4, carbon atoms. As carbocyclic or heterocyclic Rings are preferred with 5 or 6 ring members. In the case that an aryl substituent or an aryl containing When the remainder is present, such an aryl group is preferred Phenyl.

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Claims (1)

Claims (M) A process for producing a pharmaceutically usable salt of a basic quinoline compound, characterized in that a first compound which comprises an acidic group and a ketonic carbonyl oxygen atom from
of the group: benzopyrans, anthraquinones, fluorenones and
Xanthones is chosen and is effective in treating conditions caused by antigen-antibody reactions
caused, is reacted with the basic quinoline compound with anti-inflammatory activity with salt formation. Method according to claim 1, characterized in that
the basic quinoline compound and / or the first compound can be used in the form of another salt and a double reaction is carried out. 3. The method according to claim 1-2, characterized in that the implementation using equimolar proportions the quinoline compound and the first compound is carried out, 4. The method according to claim 1 - 3 * characterized in that a compound of the formula I as the first compound is used, wherein R, R, Er, R, IT and R ^{6 are} identical or different. are and in each case a hydrogen or halogen atom or an alkyl *, hydroxy, alkoxy or substituted alkyl 409830/1144 ... 2Λ03055 or alkoxy group; X is an optionally unsaturated, optionally substituted, straight or branched hydrocarbon chain, which is replaced by a carbocyclic or heterocyclic ring or be interrupted by one or more oxygen atoms or carbonyl groups can; , and Rx is a carboxylic acid group, a 5H-tetrazole " group or a carboxamidetrazole group. 5. The method according to claim 4-, characterized in that a compound of the formula I is used as the first compound 1, in which no more than one of the radicals R, R and R and no more than one of the radicals R, έΡ and R is not hydrogen and X is a 3- to 8-membered alkylene chain , which is optionally replaced by a hydroxyl group is substituted. 6. The method according to claim 4-, characterized in that the first compound is a compound of formula I , 1 6 wherein all of R to R is hydrogen and Rx represents a carboxylic acid group turns. 7. The method according to claims 1-3 "characterized in that as © etting compound is a compound of the formula II II ■ is used, wherein an adjacent pair of groups P, Q, R and T a chain -GOCH-C (Rx) -O- forms and the rest 409830/1144 . ORiGlNAL INSPECTED ~ 25 - Groups P, Q, R and T, which may be the same or different can, in each case hydrogen, hydroxy, alkoxy ,. Alkyl, nitro, halogen, phenylalkoxy, alkenyloxy, alkenyl or Alkoxy-alkyl, or wherein an adjacent pair of the groups P, Q, R and T together with the adjacent carbon atoms in the benzene ring form a 5- or 6-membered one oxygen-containing heterocyclic Sing, and Rx is a carboxylic acid group. 8. The method according to claim 1 - 3 _t, characterized in that the first compound is a compound of formula III GOQH wherein R ,, halogen, OH, OR ₂ or with R ₂ -alkyl O, - C ₆ , which is optionally substituted by OH, aryl, aryloxy, alkoxy or dialkylamino, and R ^ and R ^ = H, alkyl C ^ - C ₆ , which is optionally substituted by OH, or with R ₅ and R ^, which together with the N atom form a heterocyclic ring which optionally contains a further heteroatom; mean,
or a compound of the formula IV 409830 / 1U4 INSPECTED where X = 5 / ~ 1H_7-2etrazole; R ₁ = H, halogen, OH, OR ₂ , (with R ₂ = alkyl C ₁ - Cg or alkenyl C ₁ - C ₆ , both by one or more OH or an aryl, aryloxy, alkoxy or dialkylamino group (η) can be substituted), or NR-R. mean, (with R-, and R. = H, alkyl C ₁ - Cg, which is optionally substituted by OH, or NR ~ R, is a heterocyclic ring, which optionally contains another heteroatom), is used. 9. The method according to claim 1-3, characterized in that a xanthone of the formula Y as the first compound is used, where X = COOH or 5 - / "~ 1H7-tetrazolyl; R ₁ and R ₂ = H, alkyl C ₁ -C., NO ₂ , halogen, NR ₅ R ₄ , OR ₅ or NR ₅ SO ₂ R ₆ ; with R, and R. = H, "phenyl, benzyl or alkyl, optionally substituted by alkoxy C ₁ - Cg, phenoxy, phenyl, NH ₂ , NH-alkyl, N- (alkyl) ₂ or one or more OH-groups (n ) is substituted; R ₅ = H, alkyl C _{1 -C 6} and R 6 = alkyl C ₁ -C ₆ ; mean, however, when X = COOH, R ₁ and R ₂ are not both = H. . . 409830/1144 10. The method according to claim 1-3 »characterized in that the first compound is a compound of the formulas VI or VIl and wherein R is a group of the formulas VIII or IX VIII OR ¹ -C - -IV or ¹¹ 3 means, in which R ₁ = H ₁ alkyl C ₁ - C _Q , cycloalkyl C ₅ - Cg tetrahydrofuran-2-yl, tetrahydropyran-2-yl, tetra-hydropyran-4-yl »4-alkoxytetrahydropyran-4-yl or carboxyaeyl C ₁ - C-jg *
R ₂ = H, alkyl C ₁ -C ₉ or cycloalkyl C ~ - Cg, and R- = H, alkyl C ₁ - Cq, cycloalkyl C ₅ - Cg, phenyl, optionally _{substituted by halogen, alkyl C 1} - Cg, alkoxy C ₁ - Cg, alkylthio C ₁ - C _ß . CF ₅ or CU or a 5- or 6-membered heterocyclic ring with 1 or 2 N, 0 or S atoms is para-substituted j represent;
or a compound of the formulas X or XI 409830/1144 R-S (O), CO) ₁₁ p COOH where η = 1, or 2, where, when η = 1 iat, R is lower alkyl, and when η = 2, R is lower alkyl, hydroxy or amino or mono- or di-lower-alkylamino is; or a compound of the formula XII HIGH COOH XII where R = H or alkyl means; or a compound of the formula XIII COOH XIII wherein 1) R ₁ and Rg both lower alkoxy or both lower alkyl or one of the radicals R ₁ and R ₂ lower alkoxy, 2) one of the radicals R ₁ and R _{2 is} lower alkylthio and the other is lower alkylthio, lower alkyl or lower alkoxy ,, or 409830/1144 3) R ₁ and R _{2 are} hydrogen, chlorine, fluorine, lower alkyl, lower alkoxy or lower alkylthio, is used. 11. The method according to claim 1-10, characterized in that a 4-aniinoquinoline is used as the "basic quinoline compound will. 12. The method according to claim 11, characterized in that the quinoline compound is chloroquine, hydroxychloroquine, Cycloquine or Amcdiaquine is used. 13. A method for preparing a pharmaceutical mixture, characterized in that a first compound, the one acidic group and a ketonic carbonyl oxygen tone » and is selected from the group: benzopyrans, anthraquinones, pluorenones and xanthones and in the treatment of conditions effective through antigen-antibody reactions caused, is mixed with an anti-inflammatory agent, being de ^ anti-inflammatory Agent and the first compound are such that they are useful in inhibiting the reverse passive Arthus reaction have an additive effect in rats. 14. The method according to claim 13, characterized in that .the first compound in the form of a pharmaceutically acceptable Salt is used. 15. The method according to claim 13-14 »thereby marked, that the anti-inflammatory compound is effective in a type 3 immunological response. 16. The method according to claim 13-15, characterized in that the anti-inflammatory agent cortisone, hydrocortisone, , Prednisolon, Prednison, 6- ££ -Methylprednisolon, IDriamcinolon, Paramethason, /?> ~ Methason, Dexamethason or 9- oc -Fluorkort isol is used. 409830 / 1U4 17. The method according to claim 14-16, characterized in that that as an anti-inflammatory agent a 4-amino-quinoline is used. 18. Terfahren according to claim 17, characterized in that as anti-inflammatory agent chloroquine, hydroxychloro- • quine, cycloquine or amodiaquine is used. 19. The method according to claim 13-15 _9, characterized in that . that as an anti-inflammatory agent indomethacin, phenylbutazone or aspirin is used. 20. The method according to claim 13-19, characterized in that that the first compound and the anti-inflammatory agent in the ratio of about 1: 0.5 to 20, preferably about 1: 5 to 20 can be mixed. 21. The method according to claim 13-20, characterized in that a compound of formula I as the first compound is used, - wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , X and Rx have the same meaning as in claim 4. 22. The method according to claim 21, characterized in that at most one of the radicals R,, 4 R ² and R- and at most one the radicals R ¹ * ", R ⁵ and R ^{6 are} not hydrogen and X is a 3 to 8-membered alkylene chain which is optionally substituted by a hydroxyl group. 409830/1144 23. The method according to claim 21, characterized in that all radicals R to R are hydrogen and Rx is a carboxylic acid group. 24. The method according to claim 13-20, characterized in that that the first compound is a compound of the formula II is used, where P, Q, R and T and Rx have the same meaning as in Claim 7. '. · 25. The method according to claim 13-20, characterized in that the first compound is a compound of formula III. COOH wherein R ^ has the same meaning as in claim 8, or a compound of the formula IV wherein X_ and R ^ have the same meaning as in claim have, 409830/1144 240305S is used. 26. The method according to claim 13-20, characterized in that a xanthone of the formula V as the first compound is used, where X, IL- and R 9 are close. same meaning as in claim 27. The method according to claim 13-20, characterized in that that the first compound is a compound of the formula VI. or VII CO ₉ HR it or wherein R has the same meaning as in claim 10j a compound of the formula X or XI 0 : ooh or R-SCO) wherein η and R have the same meaning as in claim; 409830/1144 a compound of the formula XII 0 H COOH XII wherein R has the same meaning me in claim 10; or a compound of the formula XIII COOII XIII where R .. and R «have the same meaning as in claims Have 10; is used. 28. Pharmaceutically usable salt of a basic ghinolin compound with anti-inflammatory activity and a first compound that is an acidic group and a leetonian Carbonyl oxygen atom, is selected from the group: benzopyrans, anthraquinones, fluorenones and xanthones and is effective in treating conditions caused by antigen-antibody reactions. 29. Salt according to claim 28, characterized in that the first compound a compound of formula I. 409830/1144 OXO is where R "to R, X and Rx have the same meaning as to claim 4. 30 ,. Salt according to claim 29, characterized in that at most one of the radicals R ', R and R and at most one of the radicals R ⁴ ", R ⁵ and R ^{6 is} not hydrogen and X is a 3- to 8-membered alkylene chain, which optionally is substituted by a hydroxyl group. 31. Salt according to claim 29, characterized in that all radicals R to R are hydrogen and Rx is a carboxylic acid group mean. 32. Salt according to claim 28-30, characterized in that the first compound is a compound of the 3? Ormel II is where P, Q, R, T and Rx have the same meaning as in Claim 7. 33. Salt according to claim 28-30, characterized in that the first compound is a compound of the formula III 409830/1144 CXX) H wherein R _{1 has} the same meaning as la claim 8, or a compound of the formula IY O is wherein X and R _{1 have} the same meaning as in claim. 34. Salt according to claim 28-30, characterized in that the first compound is a xanthone of formula V is wherein I, -R ₁ and R _{2 have} the same meaning as in claim 9. 35. Salt according to claim 28-30, characterized in that the first compound is a compound of formula VI or VII 409830/1144 VI l \ 1 J <SS or I ^ IL Ji ^) VII wherein R has the same meaning as in claim 10; a compound of the formulas X or XI .Ό0ΙΙ (O) _n S. or : ooH R-S (O) wherein η and R have the same meaning as in claim; a compound of the formula XII COOH XII . H. * wherein R has the same meaning as in claim 10; or a compound of the formula XIII XIII 409830/1144 is wherein R ₁ and R ₂ ^ have the same meaning as in claim 10. 36. Salt according to claim 28-35 »characterized in that the hasische quinoline compound is a 4-amino quinoline, 37. Salt according to claim 36, characterized in that the Quinoline compound Chloroquine, Hydroxyohloroquine, Cycloquine or Amodiaquine is. 38. SaIs according to claim 28, 36 and 37, characterized in that that the first compound is 1,3-Ms- (2-carbo>: yehromon ~ 5-yloxy) -2-hydroxypropane is. ^{39.5.5 f} - (2 ~ Hydroxytri! Nethylene) ~ dioxy) -his- (5- (4-oxo-4H-1-benzopyran-2-carboxylic acid) -7-chloro ^ - (4-diet hylaraino -1 methyl (butylamino) quinoline salt. 40.5,5 '- (5,5'-C2-Hydroxytriinethylene) -dioxy) -his- (5- (4-oxo-4H-1henzopyran-2-yl)) - his ~ tetrazol-7-chloro- 4- (4-diethylaiaino-1-Taethylhutylamino) quinoline salt. 41.7-Methoxy-2-1H- (tetrazol-5-yl) ~ xanthene-9-one-7-chloro-4- £ ~ 4- (ethyl- (2-hydroxyethyl) -amino) -1 - me thylhut ylainino_7-quinoline salt. 42, - 7-Methoxy-xanthen-9-one-2-carboxylic acid-4 ~ (7-chloro-4-quinolylamino) ~ ta diet hylamino-o-creole salt z . 43. 7- (2-Hydroxyethoxy) -9-oxo-xanthene-2-carboxylic acid _T cycloquine salt. 44. 4,10-Dioxo-5-methoxy-2,8-dicarhoxy-4H, 10H-henzo- (1,2-h: 3,4- "b ') -dipyran-7-chloro-4- (4 -diethylamino-1-methylhutylamino) ~ c.hinoline salt. 409830 / 1U4 45. Pharmaceutical mixture, characterized in that it a first compound containing an acidic group and a ketonic carbonyl oxygen atom from the group: Benzopyrans, anthraquinones, pluorenones and xanthones are selected and is effective in treating conditions caused by antigen-antibody reactions and comprises an anti-inflammatory agent, the first compound and the anti-inflammatory agent are such that they have an additive effect in inhibiting the reverse passive Arthus reaction in rats to have. 46. Mixture according to claim 45 »characterized in that it has the first compound in the form of its pharmaceutically acceptable salt. 47. Mixture according to claim 45-46, characterized in that the anti-inflammatory compound is effective in a type 3 immunological response. 48. Mixture according to claim 45-47, characterized in that the anti-inflammatory agent is cortisone, hydrocortisone, prednisolone, prednisone, 6- oo-methylprednisolone, triamcinolone, paramethasone, β- methasone, dexamethasone or 9-oc-fluorocortisol. 49. Mixture according to claim 45-47, characterized in that the anti-inflammatory agent is a 4 ~ aminoquinoline. 50. Mixture according to claim 49, characterized in that the anti-inflammatory agent chloroquine, hydroxychloroquine, Cycloquine or Amodiaquine is. 51. Mixture according to claim 45-47, characterized in that the anti-inflammatory agent indomethacin, phenylbutazone or is aspirin. 409830 / 11U 52. Mixture according to claim 45-51, characterized in that · they the first compound and the anti-inflammatory agent in a ratio of about 1: 0.5 to 20, preferably about 1:10. 53. Mixture according to claim 45-52, characterized in that it is a compound of formula I as the first compound 0X0 1 fi comprises, wherein R to R, X and Rx have the same meaning as in claim 4. 54. Mixture according to claim 53, characterized in that 12 3 at most one of the radicals R, R and R and at most one the radicals R ⁴ ″, R ⁵ and R ^{6 are} not hydrogen and X denotes a 3 to 8-membered alkylene chain which is optionally substituted by a hydroxyl group. 55. Mixture according to claim 53, characterized in that all radicals R ¹ bi
group mean. 1 6 all radicals R to R hydrogen and Rx a carboxylic acid 56. Mixture according to claim 45-52, characterized in that siss as the first compound a compound of the formula II II wherein P, Q, R and T and Rx have the same meaning as in claim 7. 409830 / 1U4 57. Mixture according to claim 45 -.52, characterized in that it is a compound of formula III as the first compound COOH wherein IL has the same meaning as in claim 8, or a compound of the formula IV wherein X and R. have the same meaning as in claim,
includes. 58. Mixture according to claim 45-52, characterized in that it is a xanthone of the formula V as the first compound comprises, wherein X, R .. and Rp have the same meaning as in claim 9. 409830/1144 59. Mixture according to claim 45-52, characterized in that the first compound is a compound of the formulas VI or VII COJl R or VII wherein R has the same meaning as in claim 10; a compound of the formulas X or XI COOH XI. R-SCO) wherein η and R have the same meaning as in claim; a compound of the formula XII 0 H COOH XII wherein R has the same meaning as in claim 10 ; or a compound of the formula XIII 409830/1 144 COOH xii: wherein R ₁ and R ₀ have the same meaning \ iie in Anaj: ra eh includes. 60. Mixture according to claim 45-52, characterized in that it is the first Verbirour-g 1 _f 3 ~ bis «(2-csr'boxyohroino2i'-5 - ylc> r _f Y) -" 2-hyc.v- oxypr-opari or a pharmaceutically vervencHbr-roü S & lz of this, 61. Pharmaceutical composition characterized in that it comprises a SbIr according to claim 20-44 or a mixture according to claim 45-60 as active ingredient _f p: G _f if necessary, rcufiaromen with a pharmaceutically usable diluent or carrier 62. Zu s ara τπ cn settlement according to claim 61, characterized in that that it comprises about 0.17 to 1000 mg of active ingredient per unit dosage. 40983 0/1144