DE2006196A1 - Chromone and thiachromone compounds and processes for their preparation - Google Patents

Description

PATENT LAWYERS

DR. W. SCHALK DIPL.-ING. P.WlRTH · DI PL.-l NG. G. DAN N EN BERG DR-V / SCHMIED-KOWARZIK DR. P. WEI NHOLD DR, D. GUDEL

6 FRANKFURT AM MAIN

Often. ESCHENHEIMER STRASSE »9 _ "/" "

BA 7467/69 Fisons Pharmaceuticals Limited

12, Derby Road
Loughboroufth, Leicestershire,

England '. ₍

Chromone and thiachromone compounds and processes for their - production -

The present invention relates to new compounds, to methods for their manufacture and for new preparations containing them.

The present invention provides the new compounds of Formula I:

-CO ₂ H

in which P, Q, R and T, which can be the same or different, each represent hydrogen, halogen, an alkyl group with 1-10 carbon atoms, a hydroxy, alkoxy, hydroxyalkoxy, alkoxyalkoxy, acetoxy, carboxy, Amino, alkylamino, dialkylamino, alkenyl or aralkyl group with 1-10 carbon atoms, a phenyl, nitro, carboxy ester, alkenyloxy or acyl group or an adjacent pair of P ₁ Q, R and T can together with the adjacent carbon atoms in the benzene ring form a fused 5- or 6-membered carbocyclic or hafceroeyclieohen ring; '

V and W, which differ eind, each represent oxygen or sulfur nit provided that

0 0 9 8 4 5/1 9 2 ₁

i) not all of the substituents P, Q, R and T are hydrogen ; ii) when the substituents P, R and T are all hydrogen atoms, Q

is not a chlorine atom;
iii) when T is methoxy , Q and R are hydrogen, V is

Oxygen and W represent sulfur and P is not a Metfayl group; and the pharmaceutically acceptable derivatives thereof «

The present invention also provides processes for the preparation of the compounds of formula I or pharmaceutically acceptable derivatives thereof, which are characterized in that a) a compound of formula Ia:

Yes

R-

in which P, Q, R and T have the above meaning and the stated conditions apply, by cyclizing a compound of formula II:

II

T "Il _t

l-COOM

in which P, Q, R and T have the above meaning and the stated requirements apply and M stands for hydrogen or an alkali metal cation, manufactures, or

009845/192

b) a compound of the formula Ib:

I Il Ii

1-CO ₂ H

in which Pi Q, R and T have the above meaning and the stated conditions apply by treating a compound of formula III

or formula IV:

-COCH ₂ COCOOh
-OM ¹

where in formula III and IV P ₁ Q ₁ R ₁ T and M have the above meaning and the stated requirements apply and M ¹ Sr is hydrogen, an alkali metal cation or an alkyl group,
with phosphorus pentasulfide, and

optionally converting the compound of formula I formed into a pharmaceutical converts an acceptable derivative thereof.

The cyclization of process a) can be carried out by the Compound of formula II with a Cycüsationsmittel at room temperature or treated above. Suitable hydrating agents include dehydrating agents, such as phosphorus pentoxide, polyphosphoric acids, sulfuric acid, chlorosulfonic acid and other Lewis acids, In certain cases, glacial acetic acid can also be used with a small amount of hydrochloric acid or hydrobromic acid as

009845/1921

Cyclizing agents can be used. When using a dehydrating agent the reaction is preferably carried out under anhydrous conditions and the compound of Formula II becomes useful before use subjected to a drying stage.

Process a) can also be carried out by removing the -CCOH groups in formula II converted to acyl chloride groups, e.g., by treatment with PCI, PCI, - or SOCl, whereupon the acyl chloride obtained is an inner Friedel-Crafts reaction is subjected.

Process b) takes place in an inert under the reaction conditions Solvents such as benzene. The reaction is expediently carried out at elevated temperature

P-

temperature, e.g., at the reflux temperature of the reaction mixture. If the reaction product from process b) is an ester, this can be converted into the free acid by controlled alkaline hydrolysis.

The compounds of formula II can be prepared by reaction of compounds of the formula V:

P.
V.

R- ^ '-SM

in which P, Q, R, T and M have the above meaning and the above Conditions apply

with acetylenedicarboxylic acid or an ester or salt thereof under alkaline conditions to form a product which is either the desired product or which can be hydrolyzed to it. If an ester is used, one is preferred, which is from a C to C ₁₀ ,

009845/1921

- .5 - ■ ". '■

preferably a C. to C ^, alcohol is derived. The alkaline conditions can by an organic base, such as benzyltrimethylaninonium hydroxide, by an alkali metal hydroxide or expediently by using an alkali metal salt, such as a sodium salt, the formula V can be created. The acetylenedicarboxylic acid or salt thereof and the compound of formula V are preferably used in approximately stoichiometric amounts excess alkali reacted in aqueous solution. The reaction is preferably carried out at about 50-150 °.

In the above reaction, the acetylenedearboxylate ester may be replaced with an ester of a monohalofumaric acid or a precursor thereof. In this case, the reaction is a condensation and takes place with elimination of halogen acid or alkali metal halide between the halogen fumarate and the compound of formula V. The reaction is therefore preferably carried out in the presence of an acid binding agent, if M stands for H, although possibly also other methods of eliminating the halogen acid can be used. It can also be a precursor of the halogen fumarate ester. for example a halogen maleate or a dihalosuccinate ester can be used. In this case, additional alkali must be provided to ensure conversion of the precursor to the desired halofumarate ester.

The compounds of formulas III and IV are either known or can be prepared by methods analogous to methods for the preparation of known compounds. .

The compounds of formula I and the intermediates thereof can be according to those customary in the recovery and purification of similar known compounds Process can be obtained and purified.

The above processes can provide the free acids of Formula I or derivatives thereof. According to the invention, the product from any of the above processes can also be treated, if appropriate after isolation and purification, to liberate the free acid or to convert one derivation into another. The usual methods can be used to isolate and clean the products. Thus, the salts can be produced by applying alkaline conditions during the extraction and purification of the compound. Or you can win the free acid and. followed by neutralization with an appropriate base, for example an »organic amine, or any alkali, such as an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, preferably a mild base or alkali, such as sodium carbonate or bicarbonate, to convert into the desired salt. Where the compound is obtained in the form of a salt, this can be converted into a more suitable salt, for example by a metathetic process. * The esters are obtained by reacting a corresponding alcohol, alkyl sulfate or halogen compound with free carboxyl groups in the compound of formula I. ; or by reacting an appropriate alcohol kit with an acyl halide of the compound of formula I. Transesterification processes can also be used to replace one ester group with another. The amides are easily obtained by dehydrating the ammonium salt or by reacting an ester or aoyl halide with a corresponding amino compound, such as ammonium hydroxide, or a primary or secondary amine or an amino acid. The free acid of Formula I can also be condensed into a mixed anhydride with an alkyl halogenate (see, for example, chloroformate) in the presence of an organic base such as triethylamine

009845/1921

an amino acid or an ester thereof in the presence of a suitable one Solvent is treated to an N-carbojyalkyl-substituted amide. The mixed anhydride takes from the reaction mixture in which it is produced was not to be isolated, but can be treated in situ will. ,

According to the invention there is also a pharmaceutical preparation made from a compound of the formula Ic: · ■ PV

Ic

in which P, Q, R, T, V and ¥ have the meanings given above and none Conditions apply, or a pharmaceutically acceptable derivative of the same i-n compound with a pharmaceutically acceptable diluent or Carrier created. - * - '

Pharmaceutically acceptable derivatives of the compounds of Formula Ic at ° n pharmaceutically acceptable salts (especially water-soluble salts), esters and amides with one or more 2-carboxylic acid groups. Suitable salts include Ammonium salts, alkali metal salts, e.g. sodium, potassium and lithium salts, Alkaline earth metal salts, e.g. magnesium and calcium saltsj and salts with organic Bases, e.g. amine salts derived from mono-, d.i- or tri-lower alkyl or lower alkanolamines (e.g. triethanolamine or triethylamine) and salts with heterocyclic amines such as piperidine or Syridin.

009845/1921

As esters can be mentioned simple alkyl esters, those of alcohols with 1-10 carbon atoms are derived (e.g. methyl, ethyl, propyl or pentyl esters) and alkylamino alkyl esters (e.g. those of the general formula

-COO-H ¹ W ¹¹ B ¹¹¹¹

in which R stands for a straight or branched alkylene chain, e.g. with 1- ^ 4 · Carbon atoms; K and R, which are the same or different can each represent hydrogen or an alkyl group (e.g. a lower Alkyl group, such as methyl, ethyl, propyl or butyl) or form, together with the nitrogen atom, a heterocyclic ring, such as a piperidine or morpholine ring. Such basic esters are e.g. the diethylarainoethyl and piperidinoethyl ester. The basic esters can be in the form of a physiological acceptable acid addition salt, e.g. as hydrochloric acid salt.

Notable amides include simple amides derived from ammonia or primary or secondary aliphatic or aromatic amines, such as mono- or di-lower alkylamines (e.g. diethylamine), aniline or a monoalkylaniline, e.g. * methylaniline; and more complex amides derived from amino acids such as glycine, eg amides of the formula

-CONR ¹ -R ¹¹ -COOH

or salts and esters thereof, and derived from mono- or bis- (dialkylarainoalkyl) amines, for example amides of the formula

-CONR ¹ Jl ¹¹ NR ¹¹¹ R ¹¹¹¹

where R stands for hydrogen or an alkyl group (for example a lower alkyl group such as methyl, ethyl, Proßrl or butyl), and R, R ¹¹¹ and R ¹¹¹¹ are as defined above . The amides can be in the form of a physiologically acceptable acid salt thereof, for example a hydrochloride.

009845/1921

Preferred pharmaceutically acceptable derivatives of the compounds of formula Ic are the sodium and ammonium salts, the alkyl, dialkylaminaalkyl and Piperidinoethyl ester in which the alkyl groups have 1-6 carbon atoms contain, e.g. ethyl groups, and amides derived from ammonia, amino acids such as glycine, and dialkylaminoalkylamines, e.g. diethylaminoethylamine. ·

The new compounds of the formula I, their pharmaceutically acceptable derivatives and the new preparations according to the invention are valuable because of their pharmacological properties. In particular, they inhibit the release of toxic products from a combination of certain types of antibodies and specific antigen, for example the combination of reaginic antibody with specific antigen. Both subjective and objective changes from the inhalation of specific antigen by sensitized patients can be markedly inhibited by administration of the new compounds and preparations. The new compounds and preparations are suitable for the treatment of "extrinsic" allergic asthma. The new compounds and preparations can also be used in the treatment of so-called "intrinsic" asthma (in which no sensitivity to external antigen can be detected) and in the treatment of other diseases for which the antigen-antibody reactions are responsible, such as hay fever, Urticaria and auto immune diseases, can be used.

For the sake of simplicity, in the following the pharmaceutical preparations are described only in relation to the compounds of formula Ic, but of course the pharmaceutically acceptable derivatives thereof are also included.

The nature of the preparation and the pharmaceutically acceptable carrier or diluent depends of course on the desired administration refrain from taking it orally, by inhalation, parenterally or by local application can follow.

0 09 8 45/1921 '

The preparation can be formulated in a known manner with the usual ingredients wi'i.i'-n. The preparations can be used, for example, as an aqueous solution or suspension, as Powders or tablets, creams, lotions, or in syrup form.

The preparations according to the invention usually comprise a smaller proportion the compound of formula Ic and a major portion of carrier or diluent. For example, an aqueous solution for administration by means of a conventional nebulizer can contain up to about 10% by weight of the active ingredient in Stadler Contain water; and preparations for use in a pressurized container from a suspension or solution in a liquefied propellant for example, may contain about 0.2-5 wt / 6 active ingredient.

The preparations suitable for administration by inhalation include a compound of formula Ic, preferably in the form of a salt, e.g. the sodium salt, dissolved or suspended in water. Such preparations can be used by means of a conventional nebulizer. Administration of the compounds of formula Ic can, however, also be carried out by means of a conventional aerosol container. Typical propellants for use in the aerosol container include as "FiUiON" known materials of US Pat. No. 2,868,691. The propellant should of course be less toxic, especially where the preparation is ingested by the consumer, e.g. inhaled. Where the connection of Formula Ic is not soluble in the propellant, the addition of a surfactant can be used Means to the preparation will be necessary to the compound of the formula Ic to suspend propellant medium; these can be used for similar purposes surfactants can be used. This use in similar preparations is more fully described in British Patent 1,063,512.

0098 AS / 1921

The preparations according to the invention can also be in the form of powders by means of a Insufflator device such as that disclosed in the British patent 1 122 28 ^ 4- may be used. To improve the powder properties it may be useful to determine the surface properties of the powder particles, e.g. by coating with a pharmaceutically acceptable material, such as sodium stearate. Furthermore, powder of the active ingredient can be used with a fine particle size with a coarser dilution material, such as lactose, which can be mixed in small or larger amounts is present as the active ingredient, e.g., in 50-150% by weight of the compound of formula Ic or other active ingredients. Although the inhalation of the drug above with particular reference to the Oral administration has been described, of course, the nasal Administration be expedient. Therefore, the term "inhalation" should in this context to trachial administration both by oral and also refer to the nasal route.

The preparations according to the invention can also be used as tablets, syrups, etc. or by intradermal or intravenous injection in the usual manner and as creams, lotions or pastes for use in dermatological treatments administered. '

In addition to the compound of formula Ic and the necessary components to share the Compound in the form suitable for the chosen mode of administration bring other active ingredients in the preparations according to the invention to be present. So it can be used in preparations for administration by inhalation the use of a bronchodilator may be appropriate. This can be done within reasonable limiters of any bronchodilator can be used, such as isoprenaline, Adrenaline, urciprenaline, isoetharine and pharmaceutically acceptable derivatives the same, in particular their salts. The use of isoprenaline sulfate is made

009845/1921

preferred. The bronchodilator range used can be over a wide Range vary and depends, inter alia, on the type and activity of the bronchodilator and the compound of formula Ic used. The usage a smaller proportion (i.e. less than 50 Ge * w .- $, based on the However, compound of formula Ic) on bronchodilator is preferred. The use of 0.1-10 wt .- # bronchodilator, based on the weight of the compound of Formula Ic.

To inhibit the effects of antibody-antigen reactions, the compounds or preparations according to the invention in the desired amount administered to the site of the antibody-antigen reaction. Treatment can require repeated doses of the drug at regular intervals. The amount and frequency of administration depend on many factors, and in general, no precise dosage range or prescription can be given will. However, as a general guideline when administering the compounds by inhalation by someone suffering from acute allergic asthma Paitenten achieved good results with dosages of 0.1-50 mg of the compound. In the case of oral administration, the compounds can be used in larger doses are given.

Of course, certain of the above-mentioned meanings of P, Q, R and T can encompass groups which can be adversely affected by the reactants or conditions used in the preparation of the compounds of formula I. In this case, the vulnerable group can be prepared by conventional methods during part or all of the preparation of the compounds of formula I blocked or protected.

0098-45 / 1921

2G06196

Those compounds of formula I in which P, Q, R and T each represents hydrogen, chlorine, bromine or iodine, an alkyl group with 1-6 carbon atoms, a hydroxyl group, an alkoxy group with 1-10, preferably 1-3 carbon atoms, a hydroxyalkoxy group with 1-6 carbons

Alkoxy- ■ -. '"- material atoms, an / alkoxy group with 1-6 carbon atoms, a carboxy group, an amino group, an alkylamino group with 2-3 carbon atoms, a dialkylamino group with 2- ^ carbon atoms, an alkenyl group with 1-6 carbon atoms, for example one Benzyl or phenethyl group, a phenyl group, a nitro group, a carboxy ester group with 1-6 carbon atoms, an alkenyloxy group with 1-6 carbon atoms or an acyl group with 1-10, preferably 1-6, carbon atoms, or P, Q, R and T together with the neighboring carbon atoms in the benzene ring the chains - (CH ₂ ) ^ -, - (CH ₂ X ₃ -, -O-iCH ^ -, -0 (CH ₂ ) -0-, -CH ₂ -CH (CH ₃ ) -0-, -CH = CH-O-, -CH = C (CHj-O-, -0-CO-CH = C (CH -) - or -0-CH ₅ -O-. These chains can bound in every sense to the thiachromone or thionchromone nucleus aeixi,

Particularly preferred are those compounds of formula I in which P, Q, R and T represent hydrogen, chlorine or bromine, a nitro group, an alkyl group, an alkenyl group, / ⁺ hydroxyalkoxy group (e.g. hydroxy per poxy), alkoxyalkoxy (e.g. ethoxyethoxy) or Alkenyloxy group with 1-6 carbon atoms, or an adjacent pair of P, Q, R and T forms a -0-CH ₂ -CH ₂ - or -0-CO-CH = C (CH ₃ ) - chain. P is preferably water .
/ Alkoxy group,

0.8845 / 192 T

- Ik -

Particularly noteworthy compounds are 6-hydroxypropxy-1-thiachromon-2-carboxylic acid and the ö-ethoxyethoxy-l-thiachromon ^ -carboxylic acid.

The following examples, in which all parts are parts by weight, illustrate the present invention without limiting it.

Example _1

6-ethoxy-1-thiachromone-2-carboxylic acid

(a) 4-Ethoxyphenylthiofumaric acid

A solution of 150 parts of 4-ethoxythiophenol in 50 parts of water containing 16.8 parts of potassium hydroxide was prepared. To this solution, a slurry of 20.9 parts Acetyle-ndicarbonsäuremonokaliumsalz was added in 80 parts of water and the mixture, with thorough shaking HO heated minutes on the steam bath. After cooling, it was added with conc. Acid acidified, the precipitated solid filtered off, washed with a little water and recrystallized twice from water; so ^ -Äthoxyphenylthiofumarsäure received mn 10.1 parts having a melting point of 159-L6L ° C. (and decomp.).

Analysis for ^C ₁₂ ^H 12 ^{O |} 5 ^Ö

ber .: C 53.75 H 4 _t * f8 S 12.0 i

Found: C 53.8 H ^, 28 S $ 12.0

(b) o-ethoxy-1-thiachromone-2-carboxylic acid

23 parts conc. Sulfuric acid was slowly added, with stirring, to 6.6 parts of ^ -ethoxyphenylthiofumaric acid. After standing for 1 hour, the solution was poured onto 33 parts of ice and the greenish solid was filtered off, washed acid-free with water and dried. The crude solid was recrystallized twice from ethanol and gave 2.2 parts of o-ethoxy-1-thiachroraon ^ - carboxylic acid with a F. of 210-211 ⁰ C. (and dec.) Analysis for C ₁₂ H ₁₀ O ^ S

bor .: C 57.6 H ^, 03 S 12, a #

found " C 57.8 H 3.99 3 13.1 i

009845/1921

'; ■■ ■; ■■■■ - 15. -. - ^: '

(c) Sodium o-ethoxy-1-thiachromone-Z-carboxylate To 1 part of o-AthiHcy-1-thiachromon ^ -carboxylic acid in water was 0.336 parts Sodium carbcnate was added, the mixture was stirred for a few minutes and the obtained solution filtered and freeze-dried. The sodium ethoxy-1-thiachromone-2-carboxylate was thus obtained.

Example 2

5,8-dimetboxy-1-thiachromone-2-carboxylic acid

(a) 2,5-diraethoiyphenylthiofur-marsic acid

To a solution of 1? File potassium hydroxide in ¹ part of water, 20 parts of 2,5-dimethoxythiophenol and then a suspension of 25 parts of acetylenedicarboxylic acid monopotassium salt in 100 parts of water were added. The mixture was heated on a steam bath for MQ minutes, cooled and acidified with conc. Acidified hydrochloric acid; the resulting precipitate was filtered off and recrystallized from water; 17-5 parts of 2,5-dimethoxyphenylthiofumaric acid with a melting point of 183-185 ° C. were obtained in this way

Analysis for C ₁₂ H ₁₂ O ₆ S
Calc .: C 50.7 H ^, $ 26
found: C 51.1 H k, 3 ^%

(b) 5r8-Dijnethoxy-1-thiachromone-2-carboxylic acid

Concentrated to k5 parts. Sulfuric acid was added in small portions to 12.5 parts of .2,5-dimethoxyphenylthiofumaric acid and the mixture was kept at room temperature for JO minutes. Then it was poured onto 80 parts of ice and the

one
tene precipitate was filtered off and recrystallized from / acetone / alcohol mixture {so one obtained 3 _r 5 parts of Se ^ dimethoxy-tl-thiachromon ^ -carboxylic acid with a mp of 210-212 ⁰ C,
Analysis for C ₁₂ H ^ ₀ O ₅ S

Ber .: C 54,14 .H}, ö ί
found r C 53 * 9 H 3.8 ^ 6

009845/1921

(c) Natriiim ^ .ö-diinethoxy-l-thiachranon- ^ - carboxylate The sodium salt of chromonic acid was obtained by treatment with sodium bicarbonate prepared according to Example 1 and freeze-dried.

Example 3.

5,8-diethoxy-1-thiachromone-2-carboxylic acid

(a) 2,5-Diethoxyphenylthiofumaric acid

12.7 parts of 2,5-diethoxythiophenol were dissolved in a solution of 9 parts of potassium hydroxide in 30 parts of water and a suspension of 13 parts of acetylenedicarboxylic acid monopotassium salt in 50 parts of water was added to this solution. The mixture was heated de ^ 10 minutes on a steam bath, cooled and concentrated with conc. Acidified hydrochloric acid. The resulting precipitate was filtered off, washed with water, dried and gave 17 parts of 2,5-diethoxyphenylthiofumaric acid with a F. of 135-1 ¹ K) ⁰ C.

(b) 5,8-diethoxy-1-thiachromone-2-carboxylic acid

8 parts of 2,5-diethoxyphenylthiofurmaric acid were concentrated in small portions with stirring to a solution of ^ 2 parts. Sulfuric acid was added and the resulting solution was left to stand for 30 minutes. The mixture was poured onto 60 parts of Kis and the resulting precipitate was filtered off, washed with water and recrystallized from aqueous ethanol; This gave 4.3 parts of 5,8-ethoxy-1-thiachromone-2-carboxylic acid monohydrate with a b \ of 182 C. Analysis for C ^ H ^ OJSI ^ O

calc .: C 53.84 H 5.16 &'

Found .: C 53.6 H 5.39 i

(c) Sodium 5,8-diethoxy-1-thiachromone-2-carboxylate

The sodium salt of Chromone was made by treatment with sodium bicarbonate and freeze drying according to Example 1 provided.

009845/1921

example k

5,6-BenKo-1-thiachromone-2-carboxylic acid
(a) 2-naphthylthiofurmaric acid

5 parts of 2-naphthiol were added to a solution of 5 parts of potassium hydroxide with stirring given in 90 parts of water, the mixture on a steam bath heated, then a suspension of 6 parts of acetylenedicarboxylic acid monopotassium salt added in 50 parts of water. The mixture was stirred up heated in the steam bath for 50 minutes, filtered and the filtrate cooled and with conc. Acidified hydrochloric acid. The precipitate obtained was filtered off, washed with water and dried to give 6.2 parts of 2-naphthylthiofurmaric acid monohydrate with a m.p. of 188-193 ° C. Analysis for

Calculated: C 57 · 5 H b, 52 $ .

found: C 37 * 7 H ^ Wed

(b) 5 »6-Benzo-1-thiachromone-2-carboxylic acid

4 parts of 2-naphthylthiofurmaric acid were concentrated in small portions with stirring to 1.8 parts. Sulfuric acid is added, the mixture is left to stand for 30 minutes, poured onto '50' parts., Kis and the resulting precipitate is filtered off, washed with water and recrystallized from alcohol; This gave 1.1 parts of 5,6-benzo-1-thiachromone-2-carboxylic acid with a F. of 238-239 ^D. C. Analysis for C ^ H ^ S

Calculated: C 65.63 H 3.15 S $ 12.5
Found: C 65Λ H 3.12 S 12.3 ^

The tyatriume.alt des Chromone was made by treatment with sodium bicarbonate and Freeze drying produced according to Example 1.

009845/1921

example

Cyclohexanol ft) -4- thionchromon-2-carboxylic acid (method b)

(a) Ethyl cyclohexano (g) - ^ - thione chromone-2-carboxylate

A mixture of 5-8 parts of ethyl (3-hydroxy-5,6,7,8-tetrahydro-2-naphthoyl) pyruvate, 8.88 parts of phosphorus pentasulphide and 80 parts of benzene was refluxed for 5 hours with stirring now. The benzene was distilled off and the remaining solid dissolved in petroleum ether with warming, chromatographed on a silica column and eluted with petroleum ether (boiling point 60-80 ° C.) and ethyl acetate in a ratio of 3: 1 parts.

The first, colorless, solutions obtained from the column yielded 0.5 part Source material.

The green main band was eluted and the solid was recrystallized after removal of the solvent from petroleum ether (60-80 ° C.) with treatment with animal charcoal; This gave 1.95 part of ethyl cyclohexanol g) - ^ - foionchranon-2-carboxylate with a temperature of 97.5-99.5 ° C.
Analysis for C.Ai.J) rß

Calculated: C 66.65 H 5.59 S $ 11.1
Found: C 66.5 H 5.26 S 11, Jf Jb

(b) Cyc lohexano- (g) - ^ - thionchrcraon ^ -carboxylic acid

To a warm solution of 0.3 * H Äthylcyclohexano- part (g) - ⁱ i 'thionchromon-2-carboxylate in 15 parts of ltethanol 1.22 vol axes of O, 96N sodium hydroxide solution was added from methanol. After refluxing for 1 hour, 30 parts of water were added and the methanol was distilled off. The aqueous solution was cooled, diluted and acidified to give a pale green precipitate which was filtered off, washed with water and dried.

0.31 part of the crude product was recirculated from aqueous ethanol and

gave needles of cyclohexano- (g) - ^ - thionohromon-2-oarboxylic acid with an F. - »ο ,,

from 215-219 G. (u.zers.). Q098AS / '192i

Analysis for ^c ^ i ^ i ^ -ß

Calc .: C 6 ^, 6 H Λ.65 S 12.3% ■

found: G 6M-, 6 H ^ _t 55 S11,8 ί

(c) Sodium cyclohexano-CgJ - ^ - thionchromone-Z-carboxylate Part of the cyclohexano- (g) - ^ - thionchromone-2-carboxylic acid was by mild Warming in water with the equivalent amount of sodium bicarbonate dissolved and the solution freeze-dried; so one got the sodium-oyclohexano-Cg) - ^ - thionchromone-2-carboxylate. .

B is ρ ie 1 6

o-Phenyl-1-thiacheromone-Z-carboxylic acid

(a) ^ -Biphenylylthiofumaric acid

A solution of 7.7 parts of ^ -mercaptobiphenyl in % parts of water, which contained 5 »1 parts of potassium hydroxide, was prepared and to this was added 71 parts of acetylenedicarboxylic acid monopotassium salt and the mixture was heated on a steam bath for 90 minutes with thorough stirring. The mixture was then filtered hot and the solution acidified with dilute hydrochloric acid; the precipitate was filtered off and dried and gave 8.5 parts of a yellow solid which, after recrystallization from aqueous acetic acid, k + 7 parts of ^ -BiphenylyIthιοί umaric acid with a melting point of 213-215 ° C. revealed.

(b) o-Phenyl-1-thiachromone ^ -carboxylic acid

A slurry of 11.0 parts of 4-Biphenylylthiofurmarsäure with! TO manufactured parts polyphosphoric acid and heated for 6 hours IQO Ilo ⁰ G.. The mixture was then stirred with 500 parts of ice water and the precipitated solid was filtered off, washed with water and recrystallized twice from aqueous dioxane; This gave 2.3 parts of 6-phenyl-4-thiachromone-2-carbonic acid with a temperature of 22 ° C.

09845/1921

Analysis for C ₁₆ H ₁₀ Q ₃ S

Calcd .: C 68.1 H 3.6 S 11.3 ^
Found: C 68.2 H 3.5 S $ 11.1

(c) Sodium o-phenyl-1-thiachromone ^ -carboxylate The sodium salt of chromonic acid was made by treatment with sodium bicarbonate and freeze-drying according to Example 1. ■ · ... ·. ·

Example, 7

o-methyl-l-thiachromone - ^ - carboxylic acid,

^, 7 parts of 4-methylphenylthiDfuraaric acid (prepared according to part a) of Example 1) were concentrated in small portions of 20 parts. Sulfuric acid was added with stirring, the solution was left to stand for 30 minutes and then carefully poured onto ice. The resulting precipitate was filtered off, washed with water and / dioxane Üischung umkristallisiertj from an ethanol as o-methyl-l-thiachromon ^ -carboxylic acid to give 2.3 parts having a melting point of 236-237 ⁰ C, Analysis for C ₁₁ HyO ₃ S ... ,, .- "

Calc .: C 60.0 H 3.66 S 1 ^, 53 i
Found: C 60.5 H 3.78 S 1 ^, 2 i

The sodium salt of o ^ lethyl-l-thiachromone-2-carboxylic acid was neutralized with Sodium bicarbonate and freeze-drying the solution prepared,

Example 8

o-nitro-l-thiachromone ^ -carboxylic acid
(a) ^ -Nitrophenylthiofurmaric acid

8 parts were added to a solution of 6 parts of potassium hydroxide in 100 parts of water ^ -Nitrothiophenol added, the resulting solution filtered and the filtrate » rait a slurry of 8 parts of acetylenedicarboxylic acid monopotassium salt in Share treated water. The mixture was on a steam bath for 30 minutes heated, cooled, treated with animal charcoal and filtered through a filter aid, e.g. "HY1-LO" filtered and finally acidified with 5N hydrochloric acid. The unusual one

009845/1921

-Bl-, · ■

«4

Solid minie filtered off, washed with water and dried and yielded

10.1 parts of ^ -nitrophenyltmafumaric acid with a melting point of 168-17'6 ° C. Analysis for G ^ HJJO ^ S.

calc .: C 4V, 6 H 2.62 N 5.21 ΰ 11.89 $ found : C m, l H2.51 ¹ N 5.22 S 12.59 £ *

(b) o-nitro-i-thiachromoh ^ -carboxylic acid

3.0 parts of ^ -nitrophenylthiofurmaric acid were added in small portions to 22 parts of chlorosulfonic acid, the solution was stirred and then left to stand for 5 minutes. Then it was carefully concentrated with 25 parts. Dilute sulfuric acid and stir until the evolution of gas hardens, then briefly heated to 50 ° C, cooled and poured onto 200 parts of ice. The precipitate was filtered off, washed with water and recrystallized from aqueous ethanol; after drying under vacuum to obtain 2.0 parts of 6-nitro-l-thiachromon-2-carboxylic acid having a melting point of 220 ⁰ C. Analysis for C ₁₀ H JLO ₅ S

Calc .: C Jtf, 8 H 1.99 N 5.57 $
Found: C ^ 8.3 H 2.06 N $ 5.52

(c) Sodium o-nitro-1-thiachromone ^ -carboxyiate

The sodium alkali of the chromonic acid was prepared by treatment with sodium bicarbonate and freeze-drying according to Example 1.

Example 9

l-thiachromone-2,8-dicarboxylic acid

(a) 2-Carbo3 (y-phenylthiofunnaric acid.

To a solution of 2.0 parts of sodium hydroxide and 8.5 parts of sodium bicarbonate

and 7 _{tons of} 7 parts of 2 * mercaptobenzoic acid and 100 parts of water were 7.7 parts

Aoetylenedicarboniauremonokotiumsal * added, the resulting solution on a WMMrdmpfbad **) MinuUn heated, cooled and treated with conc. Acidified hydrochloric acid. The mixture was heated to coagulate the bottom of the kettle and let it down

«A

filtered off, rewashed with water and dried; thus obtained 11.2 2-carboxyphenylthiofurmaric acid with an F. of 1S & -198 C. Analysis for G. JHrDyS

calc .: C ^ 9.3 H 2.99 S 11.94 #
gef ": CW, 7 H 3.01 S 12.22 %

(b) l-thiachromone ^ jS-dicarboxylic acid.

3 parts of 2-carboxyphenylthiofumaric acid were added in small portions to 28 parts of chlorosulfonic acid, the solution was passed and left to stand for 5 minutes. Then it was concentrated with 30 parts. Diluted sulfuric acid, stirred until gas evolution ceased and briefly heated to 50 ° C. The solution was then carefully poured into 250 parts, the precipitate was filtered off, washed with water , recrystallized from aqueous ethanol and dried under vacuum; 1.8 parts of l-thiachroraon ^ .e-dicarboxylic acid hemihydrate with an F. of 3 ^ * 0 ⁰ G. (u.zers.)
Analysis for C ₁₁ H ₆ O ₅ S. 1/2 H ₂ Q

Calculated: C 51.0 H 2.71 S $ 12.36
Found .: C 51.0 H 2.66 S 12.25 i

(c) Dinatriural thiachromone-2,8-dicarboxylate

The disodium salt of chromondicarboxylic acid was obtained by treatment with sodium bicarbonate and freeze-drying according to Example 1 *

Example 10

o-Hydroxy-1-thiachromone ^ -carboxylic acid
( a) 4-Hydroxyphenylthiofurmaric acid

To a solution of 45 parts of potassium hydroxide and 25.2 parts of monothiohydroquinone in 300 parts of water, 31 parts of acetylenedicarboxylic acid monokaliun · salt were added, the mixture was heated in a steam bath for 1 hour, cooled, filtered and treated with con *. Hydrochloric acid acidified. The resulting precipitate was filtered off, washed with water and dried} so obtained 31.7 parts of 4-hydroxyphenylthiofurmar acid with an F. 199.5-201 ⁰ C.

009845/1921

Analysis for C

calc .: C 50.0 H 3.33 'S 13.3 * ^ ^!

Found: C 49.7 H 3Λ7 S 13.6 # "'.

(b) 6-Hydroxy ~ 1-thiachronion-2-carbonic acid.

To a solution of 1 ^ 3 parts of chlorosulfonic acid were added in small portions with stirring within 25 minutes, 30 parts of ^ -hydroxyphenylthiofurmarsäure; added. The solution was gerührt- 10 minutes to cure ζ heated 'at 50 ⁰ C, cooled and cautiously poured onto 1000 parts of ice. The precipitate obtained was filtered off, washed with water and recrystallized from 90% aqueous """*dioxane; this gave 20.2 parts of o-hydroxy-1-thiachromone- "2-carboxylic acid with a F. τοη 251? Ce (and dec.) .. '.

Analysis for

ber> r S lVfc # '«■■. ■■■: .. ~ \ -. ·, ■; -. · .. ■■ · -, -. : ■., ■ ' - *: ■■: .. ■ ■■ ■>' ■■ ■ '■ · - ■■ ·.

gef,: C.14..5 36 "- ■ -..-.

(c) sodium o-hydroxy-1-thiachromone ^ -carboxylate The sodium salt of chrononic acid was obtained by treatment with sodium bicarbonate

and freeze-drying according to Example 1. -. · · ■ ν .- *: ■ · ■

o-Allyloxy-li-thJLachromon - ^ - carboxylic acid ,. -, - · ■ · ' χ.-: ■%:> - ■ - .. (a) Ethyl-o-hydrpay-l-thiachromone ^ -carboxylate,; ..-; t χ.

A solution of 10.6 parts of 6-Hydro3y-1-thiachiOmon-2-carbqnsäi £ re and § J _n ■. Share conc. Sulfuric acid in 750 parts of ethanol was heated to reflux for 20 hours. Most of the ethanol was evaporated · _ and the remaining solution with 500 parts water ye ^ unn ^ ^ mdurch one-NiedersQ-h ^ ag failed. The solid was filtered off washed with .dünnter sodium carbonate solution and with water and. finally recrystallized from ethanol; so, got ₍ ,. one 9, ^ parts ,, Ethy; l ^ -hyd ^ an F-. of,,

00M4M «? 1

Analysis for C ₁₉ H _1n OJS **

Calculated: C 57.6 H 4-, OO S $ 12.8
found: C 57.6 H 4 ·, Ο6 S 12.82 #

(b) ethyl δ-allyloxy-1-thiachromone ^ -carboxylate

A mixture of 12.5 parts of ethyl o-hydroxy-l-thiachromone - ^ - carboxylate, 6.8 parts of allyl bromide and 9.7 parts of anhydrous potassium carbonate in 80 parts of acetone was refluxed for 20 hours, filtered and the solution e- steamed. The remaining material was dissolved in chloroform and the solution washed with water; then the chloroform was evaporated and the remaining material was recrystallized from ethanol; we eihielt 11.8 parts of ethyl - ^ - allyloxy. l thiachromon-2-carboxylate having a melting point of 107.5 to 108 ⁰ C. Analysis for C ₁ Ji ₁₂ O ₂₄ S

Calc .: C 62.1 H ^, 83 S 11.0 ^ 4- $
Found: C 61.9 H 4-, 86 S 11.20 j>

(c) 6-Allylo: xy-1-thiach: romon-2-carboxylic acid

A mixture of 3 parts of ethyl 6-allyloxy-1-thiachromone _i , 2-carbonate, 0.87 part of sodium bicarbonate and k parts of methanol in 25 parts of water was refluxed for a few minutes, then the methanol was distilled off. The aqueous solution was diluted with 25 parts of water, filtered and acidified with conc. Acidified acidic acid; the precipitate obtained was filtered off, washed with water and dried. 2.6 parts of 6-allyloxy-i-thiachromone-2-carboxylic acid with a melting point of 200-200.5 ° C. were obtained in this way.
Analysis for C ₁ -H _1n OrS

Calc .: C 59.5 H $ 3.82
Found: C 59.1 H 3.9 ^ i

(d) Sodium o-aHyloxy-l-thiachromone - ^ - carboxylate

The sodium salt of the chromonic acid was obtained by treatment with sodium bicarbonate and freeze drying prepared as in Example 1.

009845/1921, ...,.,

Example A.

The compounds described in Table 1 below were used for determination tested for their effectiveness in inhibiting antibody-antigen reactions.

In these Tests.wurde the effectiveness of the compounds according to the invention in inhibiting passive cutaneous anaphylaxis in rats. As proven this test form provides reliable qualitative information about the ability the test compounds for inhibiting antibody-antigen reactions in humans.

In this test, (male or female) Sprague-Dawley rats with a body weight of 100-150 g were infected subcutaneously at weekly intervals with N. brasiliensis larvae with doses increasing from about 2000 larvae per animal to 12000 larvae per animal to cause infection of the rats. After 8 weeks, the rats were veined by cardiac puncture and 15-20 ecm of blood was collected from each animal. The blood samples were centrifuged at 35,000 rpm for 30 minutes in order to remove the blood cells from the blood plasma. The blood was collected and used to create a serum containing the N. brasiliensis antibody. There was conducted a basic test sensitivity, to give serum for the determination of the minimum quantity that was necessary in the control animals in the test described below, skin irritation or -rötting cm from / Z diameter. It was found that the optimum sensitivity in rats in the body weight range of 100-130 g was achieved by using a serum which was diluted with 8 parts of physiological saline solution. This diluted solution was called Antibody A.

009845/1921

Afc

The antigen to react with the antibody in Serum A was prepared, by removing the N »brasiliensis worms from the bowels of the infected Rats removed, the homogenate centrifuged and the supernatant liquid collected. This liquid was mixed with water to a protein content diluted by 1 microgram / cem and designated as Serum B.

Sprague-Uawley rats with a body weight of 100-130 g were sensitized by intradermal injection of 0.1 ecm of serum A into the right flank. The sensitivity was allowed to develop for 2k hours, then the rats were administered intravenously with 1 ecm / 100 g body weight of a mixture of 0.25 ecm Serum B, 0.25 ecm Evans Blue dye solution and 0.5 ecm the solution of the test compound (with different Percentages of active ingredient). Insoluble compounds were administered as a separate intraperitoneal injection 5 minutes prior to intravenous administration of Serum B and Evans Blue dye. For each percentage of the active ingredient in the test solution, 5 rats were injected. In each test, 5 rats were used as control animals. The dosages of test compound were chosen to give a range of inhibition values.

• Thirty minutes after the injection of serum B, the rats were sacrificed and the pelts removed and turned over. The intensity of the anaphylactic reaction was determined by comparing the size of the characteristic blue swelling formed by the spread of Evans Blue dye from the sensitization site with the size of the swelling in the control animals. The size of the swelling was rated from 0 (no detectable swelling, ie 100% inhibition) to ^ - (no difference in swelling size, ie no inhibition); the percent inhibition for each dose was calculated as follows:

009845/1921

./ -r ι · ι "" (values of the control group; values of the tested group) x 100 *> ■ Inhib. = • ⁱ ' ^B - ¹ ^ - ■' -— "-: -; ^l ''

Control group values

The percent inhibition for the various doses was plotted graphically for each compound. From these curves the ^{dose necessary for a 50% Q} inhibition of the anaphylactic reaction (ID ₁₅₀ ) can be determined. The results are shown in Table 1. '

Table 1

.- _-- =. ID ^ ₀ > n mg / kg

"" ^ Link .- "^ of the salt

Sodium o-ethoxy-1-thaichrQtnon-E-carboxylate (Ex . 1) '}; 1

Sodium Siö-dimethoxy-1-thiachromone ^ -carboxylate (Ex. 2). 4.7 Sodium Ste-diethoxy-l-thiachrQraon-Z-carboxylate (Ex. 3) ^ 10 Natritun-Sto-benzo-.li.thiachromon-Z-carboxylate (Ex. 4) 5.5

Sodium cyclohexano- (g) - ^ - thionchromone- _

2-carboxylate (Ex. 5) ^J » ⁵

r>?
Sodium o-phenyl-1-thäichromone E-carboxylate (Ex. 6) 1,4

Natriura-o-nitro-1-thiachromone-Z-carboxylate (Ex. 8) 3.7

09845/1921

Claims (1)

Fat ent to sayings * ^ 1.- Process for the preparation of compounds of the formula I: R- in which P ₁ Q, R and T, which may be the same or different, each represent hydrogen, halogen, an alkyl group having 1-10 carbon atoms, a ^, Hydroxy, alkoxy, hydroxyalkoxy, alkoxyalkoxy, acetoxy, carboxy, amino, Alkylamino, dialkylamino, alkenyl or aralkyl group with 1-10 carbon atoms, a phenyl, nitro, carboxyester, alkenyloxy or acyl group or an adjacent pair of the substituents P, Q, R and T with the neighboring carbon atoms in the benzene ring one condensed 5- or 6-membered carbocyclic or heterocyclic ring can form, and V and W, which are different, are each oxygen or sulfur provided that 1) not all substituents P, Q, R and T are hydrogen ii) when P, R and T all represent hydrogen atoms, Q is not a chlorine atom is, iii) when T is a methoxy group, Q and R are hydrogen, V is an oxygen atom and W is sulfur and P is not a methyl group stands and pharmaceutically acceptable derivatives thereof, characterized in that that he 09845/1921 a) a compound of the formula la: in which P, Q, R T UNT have the above meaning, and said advance-s etzungen apply, is prepared by cyclization of a compound of formula II: ? COOM R-LJ [ _S JJ-COOM in which P, Q, R and f have the above meaning and the requirements mentioned apply and M stands for hydrogen or an alkali metal catone; or b) a compound of the formula Ib:. " in which P, Q, R and T have the above meaning and the conditions mentioned apply, by treating a corresponding compound of the formula III: R- or a compound of the formula IV: P IV Q-fi ^ S -CX) CH ₉ COCOOm -OM 0 09845/1921 in which P, Q, K, T and M have the above meaning and the conditions mentioned apply and M ^{1 stands} for hydrogen, an alkali metal cation or an alkyl group, with Phosphorpentaailfid produces and optionally the compound formed of Formula I into a pharmaceutically acceptable derivative. 2. Process according to part a) of claim 1, characterized in that the cyclization is carried out in the presence of a dehydrating agent. 3. - Process according to part a) of claim 1, characterized in that the cyclization by conversion of the -COOM groups in the compound of formula II takes place to acyl chloride groups, whereupon the acyl chloride obtained subjected to an internal Friedel-Crafts reaction. 4.- The method according to part b) of claim 1, characterized in that the Reaction is carried out at an elevated temperature in a solvent which is inert under the reaction conditions. 5.-Process for the preparation of a pharmaceutically acceptable salt of a Compound of formula I according to claim 1, characterized in that the compound of formula I, a different salt, an ester or »Converts an amide of the same into the desired salt. 6.- Process for the preparation of a compound of formula II: ^? COOM II ^Q ^ " in which P, Q, R and T have the above meaning and the requirements mentioned in claim 1 apply and M stands for hydrogen or an alkali metal cation, characterized in that a compound of the formula V: 009845/1921 Q- in which P, Q, R, T and M have the above meaning and the specified Conditions apply. ' with acetylenedicarboxylic acid or an ester or salt thereof or ei Monohalofumaric acid or a precursor thereof among alkaline ones Implements conditions and «■ ' the product obtained is optionally hydrolyzed to form a compound of formula II. 7 - Compounds of the formula I according to claim 1. 8.- Compounds of the formula Ia: ¹ I-CO ₂ H in which P, Q, R and T have the meaning given in claim 1 and the conditions there apply. ■ 9.- Compounds of the formula Ib: in which P, Q, H. and T have the meaning given in claim 1 and the conditions there apply. 0 9845 '/ 1921 lü, - compounds Ha ( ¹ Ii claims 7 to 9, characterized in that 1-, Q, K and T, which can be the same or different, each for hydrogen, chlorine, 13rom or iodine, an alkyl group with 1-6 Carbon atoms, a hydroxyl group, an alkoxy group with 1-lü carbon atoms, a hydroxyalkoxy group with 1-6 carbon atoms, an alkoxyalkoxy group with 1-6 carbon atoms, a carboxy group, an amino group, an alkyl imino group with 2-3 carbon atoms, a dialkylamino group with 2-4 carbon atoms, an alkenyl group with 1-6 carbon atoms, an aralky] group with 1-6 carbon atoms, a phenyl group, a Nitro groups, a carboxy ester group with 1-6 carbon atoms, a ADkenyloxy group with 1-6 carbon atoms or an acyl group with 1-10 Carbon atoms stand or P, Q ₁ , R and T together with the adjacent carbon atoms in the benzene ring form the chains - (CH.,) .-. - (GH K-, -0- (CH ₉ ), -, -0 (CHJ-O-, -CH ₉ -CH (CHJ-O-, JiH = CH-O-, -CH = C (CH ^) -O-, -0-CO-CH = C (CH) - or -0-CH ₂ -O- can form. 11.- Compounds according to claim 7 to 9 $ characterized in that P, Q, K and T, which can be the same or different, each represent hydrogen, chlorine or bromine, a nitro group or an alkyl, alkenyl, alkoxy, * Hydroxyalkoxy, alkoxyalkoxy or alenyloxy groups with 1-6 carbon atoms or an adjacent pair of the substituents P, Q, U and T can form a chain -0-GH ^ CH ₂ - or -0-CO-OH = C (CH) - can form. 12.- Compounds according to claim 7 to 11, characterized in that P is hydrogen. 13.- o-Hydroxypropoxy-1-thiachromone ^ -oarboxylic acid. Ik, - o-Äthoxyäthoxy-l-thiachromon ^ -earboxylic acid. 15.- 6-Athojty-1-thiachromone-2-carboxylic acid. 16.- 5,8-uimethoxy-1-t hi aohromon-2 ~ carboxylic acid, Ü 09845/1 92 1 _ ^ · ^{: I;} BAD ORIGINAL 17. ~ S.e-diethoxy-l-thiachromone-S-carbonfjic acid. 18, - 5} ö-BHnzo-l-thiachromon-2-carboxylic acid »19» - Cyclohexanolg) ~ 4 ~ thionchrtmon ~ 2 ~ carbons * aur8a 20, - o-phenyl-l-bhiachromon ^ -carboxylic acid * 21.- 6 -44ethyl ^ l ~ thiachromon-2 ~ carbOTisäure, 22.- 6-M itro-1-bhiachrcmon-2-carboxylic acid , 23, - l-Thiachrcstton ^ jB-dicarboxylic acid ,, 2k, - 6 ~ Hydroxy-1- thIachromon-2-carboxylic acid _! . 25 »- 6-Allyloxy-l" -bhiachromon-2-carboxylic acid _<) 26, - Compounds according to claims 6 to 25 in the form of a pharmasseutiach aTmciha « b ~ aren derivatives of the same * " 27, - Compounds according to claim 6 to 25 in the form of the iJabrixaisalaea derselban, '2Ö-. => ■ Compounds of the formula II in claim 1 * 2y, - remedies containing a compound of the formula Ioj in different P, Q, R and T, which can be the same or different, each for hydrogen, halogen, an alkyl group with 1 to 1 carbon atoms »a hydroxy, aiko.)? / -, hydroxyalkoxy, alkoxyalkoxy, can be acetoxy, carboxy, amino, alkylamino, ~ _s Uialkylam'ino-, alkenyl or aralkyl group having l · ~ 10 Kohlenstoffatonen., eäns Phönyl-, nitro, Garboxyestar-, alkenyloxy or Aoylgruppa or sin adjacent pair represents Substituents P, Cl ₉ R and T can be condensed together with the neighboring carbon atoms in the benzene ring. or o-membered eax'booyclisobBxi or hatsrooyolisqhen ring can form » V and W, dio vsrsöhioden atod ₈ jeoieils for oxygen or stand s 009845/1 921 ^% ': -; -: -; - , A ^ BAD ORißiNAL 200G 196 odor; · ιιι tli.-in ^ nitJiil · u; ;; ι υ ui-hüit ^ irr ^ ·: ί) "υϊΐ it; · r: syllables aLr; a kt, Lvtm: kv. t, indte LL in Kombiirth ion ΐαϋ. η in ·.;:; iur-ii ι! 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