DE19823722A1 - New quinoline derivatives useful as cyclooxygenase and/or lipoxygenase inhibitors, e.g. in treatment of allergies - Google Patents

Abstract

Quinoline derivatives of formula (I), and salts, hydrates and solvates of (I), are new. Quinoline derivatives of formula (I), and salts, hydrates and solvates of (I), are new: R<1> = H, T, or aryl, benzyl or benzoyl (all optionally ring substituted by 1-2 halo, R, RO, OH, CF3 or R'); R<2> = CHR<3>R<4>, CONR<9>R<5>, NHCOR<6> or CONR<9>COR<6>; R<3> = H, 1-8C alkyl or 5-8C cycloalkyl; R<4> = CONR<9>R<5>, CONR<9>-COR<6>, COOH or COOT; R<5> = SO2-T'-SO2-NR<9>-COR<6> or SO2-aryl-SO2-NR<9>-COR<6>; R<6> = a residue of a cyclooxygenase inhibitor with a COX group; the cyclooxygenase inhibitor residue is the portion left after removal of the COX group; R<7>, R<8> = H, R, RO or halo; R<9> = H or R; X = OH or optionally substituted amino; T, R, R' = 1-6C alkyl, 1-4C alkyl and halo(1-4C alkyl respectively.

Description

This invention relates to new quinolinyl methoxyaryl Compounds and pharmaceutical agents containing this compound contain.

It is known that arachidonic acid is metabolized in two different ways:

• - With the cyclooxygenase pathway under the action of the enzyme Cy clooxygenase the arachidonic acid to prostaglandins metaboli siert.
• - In the 5-lipoxygenase route, the arachidonic acid is exposed 5-Lipoxygenase metabolized to the leukotrienes.

The prostaglandins are at the origin of inflammation, fever and pain involved while the leukotrienes are in the process of developing asthma, inflammation and allergies play an important role play. It also plays a role in leukotrienes Development of NSAID-induced gastropathy discussed.

To combat these symptoms, non-steroidal ones are often used Anti-inflammatory drugs used. These derivatives inhibit cyclooxy genase and thus prevent the formation of prostaglandins Arachidonic acid.

However, the use of such derivatives is due to their Ne effects not harmless. The emergence of this ancillary kungen is based on. a. on a reduced synthesis on cytopro selective prostaglandins, on the other hand on an interactive path correlation between cyclooxygenase inhibition and increased leu cotriene formation.

Lipoxygenase inhibitors are known from DE-A-39 00 261 and EP-A-582 916 known.  

Medicinal products, which simultaneously the cycloxygenase and the 5- Inhibit lipoxygenase are known from US-A-5,260,451, in However, no such drugs are commercially available.

Surprisingly, it has now been found that certain substit ated quinolinyl methoxyaryl potent cyclooxygenase and / or 5- Are lipoxygenase inhibitors and therefore for the prevention of diseases conditions where prostaglandins or leukotrienes are useful are involved, for example diseases of the rheumatic Shape range, pain, asthma, allergic diseases, ent inflammatory bowel disease and shock.

The present invention therefore relates to substituted quinolinyl methoxyaryl compounds of the general formula I:

wherein
R ^{1 represents} a hydrogen atom, a C ₁ -C ₆ alkyl, aryl, benzyl or benzoyl group, the aryl group, the phenyl radical of the benzyl group or the benzoyl group optionally being substituted by one or two radicals which are independent of one another selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, trifluoromethyl and Hal-C ₁ -C ₄ alkyl;
R ^{2 represents} -CHR ³ R ⁴ , -CONR ⁹ R ⁵ , -NHCOR ⁶ or CONR ⁹ COR ⁶ ;
R ^{3 represents} a hydrogen atom, a C ₁ -C ₈ alkyl or C ₅ -C ₈ cycloalkyl group;
R ^{4 represents} -CONR ⁹ R ⁵ , -CONR ⁹ -COR ⁶ , COOH or COOC ₁ -C ₆ alkyl, where R ¹ cannot represent a hydrogen atom if R represents COOH or COOC ₁ -C ₆ alkyl ;
R ⁵ for -SO ₂ - (C ₁ -C ₆ ) alkylene-SO ₂ -NR ⁹ -COR ⁶ , in particular -SO ₂ - (C ₃ - C ₆ ) alkylene-SO ₂ -NR ⁹ -COR ⁶ or -SO ₂ -aryl-SO ₂ -NR ⁹ -COR ⁶ ;
R ^{6 stands} for the remainder of a cyclooxygenase inhibitor with a COX group (X = OH or optionally substituted NH ₂ ), which results from removal of the COX group;
R ⁷ , R ⁸ , which may be the same or different, represent H, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or halogen;
R represents H or C ₁ -C ₄ alkyl;
and the physiologically acceptable salts, solvates and hydrates thereof.

The alkyl groups mentioned can be straight-chain or branched be. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl and n-octyl.

Examples of the cycloalkyl group are cyclopentyl, cyclohexyl and cycloheptyl.

Aryl is preferably phenyl or naphthyl.

Halogen stands for F, Cl, Br or J, in particular F, Cl and Br.

If the compounds of the invention have an asymmetry center have, they can be used as a racemate, as enantiomers or, several centers of asymmetry, also as diastereomers.

The radical R ¹ preferably represents a hydrogen atom or a benzoyl group, which can be substituted by one of the radicals mentioned above. Preferred substituents are halogen, in particular F and Cl, and C ₁ -C ₈ alkyl. R ² is preferably -CHR ³ R ⁴ , in which R ^{4 is} CONHCOR ⁶ or CONHR ⁵ , or -NHCOR ⁶ or CONHCOR ⁶ , where R ³ , R ⁵ and R ^{6 have} the meanings given above. The radical R ² is preferably in the para position to the quinolinyl methoxy radical to the phenyl radical.

The radical R ^{6 of} the cyclooxygenase inhibitors is preferably selected from

wherein
R ^{9 has} the meanings given above;
R ^{10 represents} H or C ₁ -C ₄ alkyl;
R ^{11 represents} halogen or trifluoromethyl;
R ^{12 represents} C ₁ -C ₄ alkyl; and
R ^{13 represents} H, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy.

The following residues of cyclooxygenase inhibitors are particularly preferably:

R ¹ then preferably stands for H, R ² for NHCOR ⁶ or CONHCOR ⁶ and R ⁷ and R ⁸ for H.

A preferred embodiment are compounds of the formula I in which
R ^{1 represents} a hydrogen atom;
R ^{2 is} -CHR ³ R ⁴ ;
R ^{3 represents} H, C ₁ -C ₆ alkyl or C ₅ -C ₇ cycloalkyl;
R ^{4 represents} CONHCOR ⁶ or -CONR ⁹ R ⁵ ;
R ^{6 represents} one of the radicals mentioned above;
R ⁷ and R ⁸ , which may be the same or different, are H or C ₁ -C ₄ alkyl; and
R ^{9 represents} H or C ₁ -C ₄ alkyl; and
R ^{5 has} the meanings given above.

A further preferred embodiment are compounds of the formula I in which
R ^{1 represents} a C ₁ -C ₆ alkyl, aryl, benzyl or benzoyl group, the aryl group, the phenyl radical of the benzyl group or the benzoyl group optionally being substituted by one or two radicals which are selected independently of one another from halogen , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, trifluoromethyl and Hal-C ₁ -C ₄ alkyl, preferably halogen, in particular F and Cl, and C ₁ -C ₈ alkyl;
R ^{2 represents} CHR ³ R ⁴ ;
R ^{3 represents} H, C ₁ -C ₆ alkyl or C ₅ -C ₇ cycloalkyl;
R ^{4 represents} COOH or COOC ₁ -C ₆ alkyl; and
R ⁷ and R ⁸ , which may be the same or different, represent H or C ₁ -C ₄ alkyl.

R ¹ is preferably benzyl or benzoyl.

The preparation of the compounds according to the invention is in the following reaction schemes using concrete examples tert. The other compounds of the invention can be found in ana be produced logically.

Reaction scheme 1

Preparation of compounds of formula IA

Alternatively, [4- (quinolin-2-ylmethoxy) phenyl] cycloheptyl acetic acid 4 can be converted into the amide and then reacted with the R ⁶ -COOH activated with 1,1'-carbonyldiimidazole.

Reaction scheme 2

Alternatively, 2 can be converted into the amide and then with the 1,1'-carbonyldiimidazole-activated 4- (quinolin-2-ylmethoxy) - benzoic acid are implemented.

Reaction schemes 1 and 2 Synthesis of the amides

To prepare the primary amides 3 and 8, the corresponding carboxylic acids 2 and 7 are converted to the reactive imidazolides with 1,1'-carbonyldiimidazole in an inert solvent, such as, for example, tetrahydrofuran. When the evolution of CO _{2 has} ended, ammonia, advantageously as a solution in an inert organic solvent, such as methanol or tetrahydrofuran, is added. The mixture is stirred at room temperature until the reaction is complete. The reaction requires longer reaction times when using an ammoniacal tetrahydrofuran solution than when using the methanolic solution. If a methanolic ammonia solution is used, the esterification to the corresponding methyl ester is obtained as a competitive reaction and thus lower yields than if an ammoniacal tetrahydrofuran solution is used. In the case of easily accessible starting materials, it is more time-saving to accept the formation of the ester. The ester can also be easily separated off, saponified after isolation and thus returned to the reaction.

The amide is isolated in a conventional manner, e.g. B. by the or ganic solution largely concentrated and after moving with Neutralizes water. The imidazole contained in the reaction mixture remains in the aqueous phase. Solid residues are removed sucks and extracted oily products with ethyl acetate. Farther one separates that when using the methanolic ammonia solution formed methyl ester by means of flash chromatography, huu fig, however, it is enough to wash the crude product with Diisopro Clean pylether from accompanying substances. The amide stays in pure form back. The ester soluble in diisopropyl ether becomes recovered from the filtrate and again by alkaline saponification converted into the carboxylic acid.

Synthesis of imides

Carboxamides 3 and 8 are used to build up the imide group deprotonated, e.g. B. with sodium hydride in absolute N, N- Dimethylformamide or tetrahydrofuran, and with the imidazolide 5 or 6 of the second acid component.  

Reaction scheme 3

Preparation of the compounds of formula IC

Reaction scheme 3

The reaction of methoxyphenyl isocyanate 10 with 2-methyl-1,1- dioxo-2,3-dihydro-1,2-benzothiazin-4-one 9 is known Way, see DE-A-19 43 265, e.g. B. in absolute N, N-dimethyl formamide and sodium hydride as the base.

The cleavage of the aromatic methyl ether 11 is more common Way performed, e.g. B. with boron tribromide in methylene chloride at -25 to -30 ° C and thin layer chromatography (silica gel; Ethyl acetate: n-hexane = 1: 1) followed. After working up he the product 12 is kept almost quantitative (97%).

The O-alkylation of the phenolic hydroxy function in 12 with 2- Chloromethylquinoline hydrochloride 13 is in the presence of a base in a polar solvent, e.g. B. with potassium carbonate in N, N- Dimethylformamide.

Reaction scheme 4

A.) Preparation of the compounds of the formula ID

B.) Preparation of the compounds of the formula IE

Reaction scheme 4 (A and B)

The production of naphthalene-2,6-disulfonic acid diamide 20 he follows from naphthalene-2,6-disulfonic acid disodium salt 18 via the corresponding disulfonyl dichloride 19.

The naphthalene-2,6-disulfonic acid disodium salt 18 is in übli cher way with phosphorus pentachloride and phosphorus oxytrichloride brought to reaction with heating to 100 to 120 ° C.

After reacting the naphthalene-2,6-disulfonyl dichloride obtained 19 With ammonia solution, the corresponding disulfonic acid is obtained rediamid 20. For this, the naphthalene-2,6-disulfonyl dichloride 19 in an inert solvent, e.g. B. tetrahydrofuran and reacted with ammonia solution at elevated temperature.

To produce ID, propane-1,3-dithiol 14 with chlorine in Carbon tetrachloride and water in propane-1,3-disulfonyl dichloride 15 transferred with ammonia in an inert solution means, e.g. B. dioxane, in the propane-1,3-disulfonic acid diamide 16 is transferred.

The linking of R ⁶ COOH 2 with 16 or 20 to 17 or 21 it follows by activating 2 and reacting the activated product with the salt formed from 1 mol of NaH and 16 or 20 in an inert solvent, for. B. N, N-dimethylformamide or tetrahydrofuran.

For working up, the reaction solution is poured into water and after acidifying the solution z. B. extracted with ethyl acetate. It the result is a product mix that usually consists of four components consists: In addition to the desired product and sometimes not vice versa set educts, a by-product is obtained. With this side product is the N, N'-bis-acetylated derivative, the by the reaction of two molecules 2 with one molecule 16 or 20 arises. The components can be separated Use of reversed-phase column material (RP 18) as a statio  nary phase. An acetone-water Mixture in the ratio 5: 2. The purification is carried out with MPLC at 10 carried out in cash. To isolate the product and the secondary pro product, either all of the solvent is removed, or but only the acetone is concentrated and the residue is suctioned off and dried.

Connection 21 and 17 is, for. B. in absolute N, N-dimethyl formamide deprotonated with 2 equivalents of sodium hydride. After be Hydrogen evolution ended with the 1,1'- Carbonyldiimidazole activated acid 22, e.g. B. with [4- (quinoline 2yl-methoxy) -phenyl] -cycloheptyl-acetic acid 4 for the reaction brings, where you get ID or IE after usual processing.  

Reaction scheme 5

Production of connections IF

Reaction Scheme 5

Starting from methyl 4-methoxyphenylacetate 23 becomes Compound 24 alkylated in the usual way. As a solvent are z. B. absolute tetrahydrofuran and N, N-dimethylformamide, as base z. B. sodium hydride suitable.

The benzoylation from 24 to 26 according to Friedel-Crafts is also successful Aluminum chloride as a catalyst in a chlorinated solution medium, such as dichloroethane.

The cleavage of the methyl ether 26 and the implementation of the obtained NEN 27 with 13 are carried out according to the description in reaction scheme 3 procedure.

Finally, the methyl ester 28 in the usual manner, for. B. with NaOH, saponified to IF.

The compounds of the invention have proven to be potent Cy clooxygenase and / or lipoxygenase inhibitors proven. You are there forth in the treatment of diseases of the rheumatic For and for the prevention of allergy-induced cranes usable. The compounds according to the invention are so with effective Antiphlogistica, Analgetica, Antipyretica, An tiallergica and broncholytica and are for thrombosis proprophy lax and for the prophylaxis of anaphylactic shock and for Treatment of dermatological diseases such as psoriasis, urtica ria, acute and chronic rash allergic and not allergic genesis usable.

The compounds of the invention can be used either individually therapeutic agents or as mixtures with other thera active substances are administered. You can do it alone administered, but generally they are in the form pharmaceutical agents applied, that is, as mixtures the active ingredients with suitable pharmaceutical carriers or Ver fertilizers. The compounds or agents can be taken orally or  administered parenterally, but preferably they are administered in given oral dosage forms.

The type of pharmaceutical and pharmaceutical Carrier or diluent depends on the desired administration type of delivery. Oral agents can be used, for example, as a tablet Th or capsules are present and can ent usual excipients ent hold such as binders (e.g. syrup acacia, gelatin, sorbitol, Tragacanth or polyvinylpyrrolidone), fillers (e.g. lactose, Sugar, corn starch, calcium phosphate, sorbitol or glycine), lubricant medium (e.g. magnesium stearate, talc, polyethylene glycol or Silicon dioxide), disintegrating agents (e.g. starch or mesh medium, e.g. B. sodium lauryl sulfate). Oral liquid preparations can NEN in the form of aqueous or oily suspensions, solutions, emuls sions, syrups, elixirs or sprays etc. are or can be as dry powder for reconstitution with water or a other suitable carriers. Such liquid preparation te conventional additives, for example suspending agents, Ge contain flavors, diluents or emulsifiers. Solutions or suspensions can be used for parenteral administration use with common pharmaceutical carriers.

The activity of the compounds according to the invention can be started hand the inhibition of 5-lipoxygenase or cyclooxygenase be voices. The investigations were carried out as follows:

Test system for determining the inhibition of 5-lipoxygenase

Human granulocytes serve as the source of the 5-lipoxygenase. By stimulation with calcium ionophore A 23187, LTB ₄ (leukotriene B ₄ ) is formed from endogenous arachidonic acid. The granulocytes are isolated and the enzyme reaction is carried out by known methods (see Arch. Pharm. Pharm. Med. Chem. 330, 307-312 (1997)).

The blood, which is protected against coagulation with heparin, is centrifuged over a discontinuous Percoll® gradient and the granulocyte layer is pipetted off. After lysis of the erythrocytes, the granulocytes are washed several times and then adjusted to a certain number of cells. The enzyme reaction is then started with calcium ionophore A 23187 in the presence or absence of the test substance after addition of Ca ²⁺ . The synthesis of the leukotrienes is stopped after 1.5 minutes. The samples are centrifuged and the supernatant diluted. LTB ₄ is determined quantitatively by means of ELISA.

Test system for determining the inhibition of cyclooxygenase

In this test system, the amount of prostaglandin E ₂ formed by human platelets after the addition of calcium ionophore is determined by means of ELISA. The platelets are obtained after centrifugation using a discontinuous Percoll® gradient. In principle, the enzyme reaction and the determination of the metabolites formed are carried out as in the determination of 5-lipoxygenase inhibition. There are differences in the incubation period. Furthermore, the addition of a thromboxane synthase inhibitor is necessary (see Arch. Pharm. Pharm. Med. Chem. 330, 307-312 (1997)).

Get those when testing the compounds of the invention Results are summarized in the tables below poses.  

Table 1

Table 2

Table 3

Table 4

Table 5

The following examples illustrate the invention without restricting it limit.

All temperature information is uncorrected. The NMR spectra are 200 MHz spectra with tetramethylsilane (TMS) as internal standard dard.

Synthesis of the starting compounds

• - 2- [4- (Quinolin-2-yl-methoxy) phenyl] -2-cycloheptyl acetic acid can be produced according to DE 39 00 261 A1.
• - 5-methoxy-2-methyl-1H-indol-3-yl) acetic acid can, according to J. Am. Chem. Soc. 77, 4319 (1955).
• - 2-Methyl-1,1-dioxo-2,3-dihydro-1,2-benzothiazin-4-one can after J. Org. Chem. 30, 2241-2246 (1965).

example 1 2- [4- (Quinolin-2-yl-methoxy) phenyl] -2-cycloheptyl acetic acid amid Method A

• 1.) Ammonia is sown at -10 ° C in absolute methanol initiated. The solution is stored at -10 ° C.
• 2.) 24 mmol of 2- [4- (quinolin-2-yl-methoxy) phenyl] -2-cycloheptyl-acetic acid are dissolved in 50 ml of tetrahydrofuran, 26.5 mmol of 1,1'-carbonyldiimidazole are added and the mixture is stirred Room temperature until the CO ₂ evolution has ended. Then who added the 20 ml of the methanolic ammonia solution (see under 1.) and stirred for 2 h at room temperature. The solution is concentrated, the residue is taken up in water and acidified with 8% phosphoric acid. After shaking twice with ethyl acetate, the organic phases are dried over sodium sulfate and evaporated. The residue obtained is taken up several times in diisopropyl ether and suction filtered. The filtrate contains the corresponding methyl ester formed as a by-product, which is available again as a starting material after saponification.

Method B

• 1.) Ammonia is at -10 ° C in absolute tetrahydrofuran initiated to saturation. The solution is at -10 ° C preserved.
• 2.) Dissolve 3.6 mmol of 2- [4- (quinolin-2-yl-methoxy) phenyl] -2-cycloheptyl-acetic acid in 70 ml of tetrahydrofuran, add 5.9 mmol of 1,1'-carbonyldiimidazole and stirs at room temperature until the CO ₂ evolution is complete. Then who added the 40 ml ammoniacal tetrahydrofuran solution (see below under 1) and stirred for at least 2 days at room temperature. The solvent is spun off, the residue is taken up in water and neutralized. The product is filtered off, washed with water and dried over phosphorus pentoxide.
  C ₂₅ H ₂₈ N ₂ O ₂ (388.51)
  Yield: 58% (method A), 99% (method B)
  Mp: 178.2 ° C
  IR (KBr): 3414 cm ^-1 (wide, NH ₂ ), 2925 cm ^-1 and 2852 cm ^-1 (CH _aliphatic ), 1653 cm ^-1 (C = O), 1508 cm ^-1 (C = C) , 1248 cm ^-1 (CO- C), 819 cm ^-1 (CH _aromat. ).
  ¹ H-NMR (CDCl ₃ ): δ (ppm) = 0.80-1.95 (m; 12H, -CH ₂ -, cyclohept.), 2.15-2.35 (m; 1H, CH-, cyclohept.), 3.02 (d; ³ J = 10.3 Hz, 1H, CH-CO-), 5.28-5.44 (d; 2H, -NH ₂ ), 5.36 (s; 2H, -CH ₂ -O-), 6.93-7.00 / 7.21-7.28 ([ AB] ₂ ; ³ J = 8.6 Hz, 4H, aromat.), 7.54-8.22 (m; 6H, quinol.).

Example 2

The following compounds were made according to the manufacturing method A and B obtained from Example 1.

1.) 2- (3-trifluoromethyl-anilino) -benzoic acid amide

C ₁₄

H ₁₁

N ₂

OF ₃

(280.25)
Yield: 46% (method A)
Mp: 128.1 ° C
IR (KBr): 3320 cm ^-1

and 3150 cm ^-1

(NH ₂

), 1660 cm ^-1

(C = O), 1327 cm ^-1

.
¹

H-NMR (CDCl ₃

): δ (ppm) = 5.89 (s; broad, 2H, -NH ₂

), 6.75-6.95 (m; 1H, aromat.), 7.15- 7.55 (m; 7H, aromat.), 9.68 (s; 1H, = NH).

2.) 2- (4-isobutylphenyl) propionic acid amide

C ₁₃

H ₁₉

NO (205.30)
Yield: 52% (method A) or 97% (method B)
Mp: 130.3 ° C
IR (KBr): 3358 cm ^-1

and 3177 cm ^-1

(NH ₂

), 2960 cm ^-1

(CH _aliphatic.

), 1659 cm ¹

(C = O).
¹

H-NMR (CDCl ₃

): δ (ppm) = 0.90 (d; ^3rd

J = 6.6 Hz, 6H, -CH- ( CH ₃

) ₂

), 1.52 (d; ³

J = 7.2 Hz, 1H, CH- CH ₃

), 1.70-2.00 (m; 1H, -CH ₂

- CH

(CH ₃

) ₂

), 2.46 (d; ³

J = 7.2 Hz, 2H, -CH ₂

), 3.58 (q; ³

J = 7.2 Hz, 1H, CH

-CH _3rd

), 5.34 / 5.63 (2 s; broad, 2H, -NH ₂

), 7.12 / 7.21 ([AB] ₂

; ^3rd

J = 8.1 Hz,  4H, aromatic.).

3.) 2- (fluoro-4-biphenyl) propionic acid amide

C ₁₅

H ₁₄

NOF (243.28)
Yield: 50% (method A)
Mp: 128.5 ° C
IR (KBr): 3365 cm ^-1

and 3187 cm ^-1

(NH ₂

), 1660 cm ^-1

(C = O), 764 cm ^-1

(CH _aromat.

), 696 cm ^-1

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 1.55 (d; ³

J = 7.1 Hz, 3H, CH- CH ₃

), 3.63 (q; ³

J = 7.1 Hz, 1H, CH

- CH ₃

), 5.53 / 5.98 (2 s; broad, 2H, -NH ₂

), 7.05-7.20 (m; 2H, aromat.), 7.30-7.60 (m; 6H, aromat.).

4.) 2- (3-Benzoyl-phenyl) propionic acid amide

C ₁₆

H ₁₅

NO ₂

(253.30)
Yield: 46% (method A)
Mp: oil
¹

H-NMR (CDCl ₃

): δ (ppm) = 1.55 (d; ³

J = 7.1 Hz, 3H, -CH ₃

), 3.67 (q; ³

J = 7.1 Hz, 1H, CH

- CH ₃

), 5.53 / 5.68 (2 s; broad, 2H, -NH ₂

), 7.40-7.85 (m; 9H, aromatic)

5.) 4- (Quinolin-2-ylmethoxy) benzoic acid amide

C ₁₇

H ₁₄

N ₂

O ₂

(278.31)
Yield: 85%
Mp: 200.3 ° C
IR (KBr): 3376 cm ^-1

and 3167 cm ^-1

(NH ₂

), 1656 cm ^-1

(C = O), 1248 cm ^-1

(COC), 821 cm ^-1

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 5.43 (s; 2H, -CH ₂

-O-), 6.30 / 7.40 (2 s; broad, 2H, -NH ₂

), 7.05 / 7.87 ([AB] ₂

; ^3rd

J = 8.8 Hz, 4H, aromatic), 7.56-7.85 (m; 3H, quinol.), 8.00-8.30 (m; 2H, quinol.).

6.) [1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indol-3-yl] - acetic acid amide

C ₁₉

H ₁₇

N ₂

O ₃

Cl (356.81)
Yield: 70% (method A)
Mp: 270.3 ° C
IR (KBr): 3405 cm ^-1

(NH ₂

), 1660 cm ^-1

(C = O), 1614 cm ^-1

(C = O), 1367 cm ^-1

, 1225 cm ^-1

(CO-C).
¹

H-NMR (DMSO-d ₆

): δ (ppm) = 2.22 (s; 3H, -CH ₃

), 3.46 (s; 2H, -CH ₂

-), 3.76 (s; 3H, -OCH ₃

), 6.71 (dd; ³

J = 8.9 Hz, ^4th

J = 2.4 Hz, 1H, aro mat.), 6.93 (d; ^3rd

J = 9 Hz, 1H, aro mat.), 7.11 (d; ^4th

J = 2.4 Hz, 1H, aro mat.), 6.90-7.00 / 7.40-7.50 (2 s; broad, 2H, -NH ₂

), 7.63-7.73 ([AB] ₂

; 4H, aromatic.).

Example 3 N - {[4- (quinolin-2-ylmethoxy) phenyl] cycloheptyl acetyl} -2- (3- trifluoromethylphenylamino) benzamide

500 mg (1.28 mmol) of [4- (quinolin-2-ylmethoxy) phenyl] cycloheptyl acetic acid are dissolved in 10 ml of absolute tetrahydrofuran, then 300 mg (1.85 mmol) of 1,1'-carbonyldiimidazole are added and stir at room temperature until the CO ₂ formation has ended. In parallel, 1.30 mmol of the corresponding 2- (3-trifluoromethyl-anilino) -benzoic acid amide are dissolved in 10 ml of tetrahydrofuran and in a suspension consisting of 53 mg (1.30 mmol) of sodium hydride (60% in white oil) and 2 ml of tetrahydrofuran. After the evolution of hydrogen has ended, this solution is added to the above solution and the mixture is stirred at room temperature for 14 h. The reaction solution is poured into water and acidified to pH 5 to 6 with phosphoric acid. Then is extracted 3 times with ethyl acetate, the organic phases are dried over sodium sulfate and concentrated. The residue obtained is purified by column chromatography on silica gel (ethyl acetate: n-hexane = 1: 1; Rf = 0.75).
C ₃₉ H ₃₆ N ₃ O ₃ F (651.73)
Yield: 48%
Mp: 88.8 ° C (amorphous)
IR (KBr): 3400 cm ^-1 -3100 cm ^-1 (NH), 2915 cm ^-1 and 2840 cm ^-1 (CH _aliphatic ), 1709 cm ^-1 (C = O), 1500 cm ^-1 (C = C).
¹ H-NMR (CDCl ₃ ): δ (ppm) = 0.90-1.90 (m; 12H, -CH ₂ -, cyclohept.), 2.25-2.50 (m; 1H, CH-, cyclohept.), 4.37 (d; ³ J = 10.6 Hz, 1H, CH-CO-), 5.35 (s; 2H, -CH ₂ -O-), 6.70- 6.85 (m; 1H, aromatic), 6.90-7.05 / 7.25-7.40 ([AB ] ₂ ; ³ J = 8.7 Hz, 4H, aromat.), 7.25-7.50 (m; 7H, aromat.), 7.50-7.90 (m; 4H, quinol.), 8.00-8.25 (m; 2H, quinol.) , 8.55 (s; 1H, -CO-NH-CO-), 9.35 (s; 1H, NH).

Example 4

The following connections were made according to the procedure of Example 3 obtained.

1.) N - {[4- (Quinolin-2-ylmethoxy) phenyl] cycloheptyl acetyl} -2- (4-isobutylphenyl) propionamide

The product is purified by column chromatography on silica gel (diisopropyl ether; Rf = 0.76). A diastereomeric mixture (A and B) is obtained.
C ₃₈ H ₄₃ N ₂ O ₃ (575.77)
Yield: 22%
Mp: 149.6 ° C
IR (KBr): 3300 cm ^-1 -3100 cm ^-1 (NH), 2923 cm ^-1 and 2853 cm ^-1 (CH _aliphatic ), 1727 cm ^-1 (C = O), 1687 cm ^-1 (C = O), 1508 cm ^-1 (C = C), 1243 cm ^-1 (COC), 819 cm ¹ (CH _aromat. ).
¹ H-NMR (CDCl ₃ ): A: δ (ppm) = 0.85 (d; ³ J = 6.6 Hz, 6H, -CH ( CH ₃ ) ₂ ), 0.90-1.70 (m; 12H, -CH ₂ -, cyclohept.), 1.42 (d; ³ J = 7.0 Hz, 3H, CH- CH ₃ ), 1.70-1.90 (m; 1H, -CH ( CH ₃ ) ₂ ), 2.15-2.35 (m; 1H, CH-, cy clohept.), 2.39 (d; ³ J = 7.1 Hz, 2H, CH- CH ₂ -), 3.90 (d; ³ J = 10.5 Hz, 1H, CH -CH), 3.98 (q; ³ J = 7.0 Hz , 1H, CH - CH ₃ ), 5.35 (s; 2H, -CH ₂ -O-), 6.85-6.95 / 7.05-7.15 ([AB] ₂ ; ³ J = 8.7 Hz, 4H, aromat.), 6.99 ( s; 4H, aromat.), 7.50-7.90 (m; 4H, quinol. and 1H, -CO-NH-CO-), 8.05-8.25 (m; 2H, quinol.).
B: δ (ppm) = 0.89 (d; ³ J = 6.6 Hz, 6H, -CH ( CH ₃ ) ₂ ), 0.90-1.60 (m; 12H, -CH ₂ -, cyclohept.), 1.41 (d; ³ J = 7.1 Hz, 3H, CH- CH ₃ ), 1.70-1.90 (m; 1H, -CH ( CH ₃ ) ₂ ), 2.15-2.35 (m; 1H, CH-, cy clohept.), 2.43 (d; ³ J = 7.2 Hz, 2H, CH- CH ₂ -), 3.60-3.8 (m; 2H, CH -CH and CH -CH ₃ ), 5.36 (s; 2H, -CH ₂ -O-), 6.85-7.25 (m; 8H, aromat.), 7.50-7.90 (m; 4H, quinol. and 1H, -CO-NH-CO-), 8.05-8.25 (m; 2H, quinol.).

2.) N - {[4- (quinolin-2-ylmethoxy) phenyl] cycloheptyl acetyl} -2- (2-fluorobiphenyl-4-yl) propionamide

The product is purified by column chromatography on silica gel (ethyl acetate: n-hexane = 1: 1; Rf = 0.83). The diastereomer mixture is kept approximately in the ratio 1: 1.
C ₄₀ H ₃₉ N ₂ O ₃ F (614.76)
Yield: 27%
Mp: 112 ° C
IR (KBr): 3300 cm ^-1 -3100 cm ^-1 (NH), 2923 cm ^-1 and 2853 cm ^-1 (CH _aliphatic ), 1728 cm ^-1 (C = O), 1688 cm ^-1 (C = O), 1509 cm ^-1 (C = C), 828 cm ^-1 (CH _aromat. ), 764 cm ^-1 (CH _aromat. ), 697 cm ^-1 (CH _aromat. ).
¹ H-NMR (CDCl ₃ ): δ (ppm) = 0.80-1.80 (m; 2 × 12H, -CH ₂ -, cyclohept.), 1.45-1.55 (m; 2 × 3H, CH- CH ₃ ), 2.10 -2.35 (m; 2 × 1H, CH-, cyclohept.), 3.58 (d; ³ J = 10.6 Hz, 1H, CH -CH), 3.70 (d; ³ J = 10.5 Hz, 1H, CH -CH), 4.20-4.40 (m; 2 × 1H, = CH - CH ₃ ), 5.26 (s; 2H, -CH ₂ -O-), 5.35 (s; 2H, -CH ₂ -O-), 6.80-8.20 (m ; 2 × 18H, aromatic and 2 × 1H, -CO-NH-CO-).

3.) 2- (4-Benzoylphenyl) -N - {[4- (Quinolin-2-ylmethoxy) phenyl] - cycloheptyl acetyl} propionamide

The product is purified by column chromatography on silica gel (ethyl acetate: n-hexane = 1: 1; Rf = 0.75). The diastereomer mixture is kept approximately in the ratio 1: 1.
C ₄₁ H ₄₀ N ₂ O ₄ (624.78)
Yield: 14%
Mp: 87.6 ° C
IR (KBr): 3300 cm ^-1 -3100 cm ^-1 (NH), 2926 cm ^-1 and 2852 cm ^-1 (CH _aliphatic ), 1734 cm ^-1 (C = O), 1697 cm ^-1 (C = O), 1660 cm ^-1 (C = O, ketone), 1508 cm ^-1 (C = C), 823 cm ^-1 (CH _aromat. ).
¹ H-NMR (CDCl ₃ ): δ (ppm) = 0.80-1.80 (m; 2 × 12H, -CH ₂ -, cyclohept.), 1.40-1.50 (2 × d; 2 × 3H, CH- CH ₃ ) , 2.10-2.30 (m; 2 × 1H, CH-, cyclohept.), 3.45-3.60 (d; 1H, CH -CH ₃ ), 3.60-3.75 (d; 1H, CH -CH ₃ ), 5.30 (s; 2H, -CH ₂ -O-), 5.36 (s; 2H, -CH ₂ -O-), 6.80-8.25 (m; 2 × 19H, aromatic mat. And 2 × 1H, -CO-NH-CO-) .

4.) N - {(1- (4-chloro-benzoyl) -5-methoxy-2-methyl-1H-indol-3-yl] - acetyl} -2- [4- (quinolin-2-yl-methoxy) phenyl] -2-cycloheptyl acetamide

C ₄₄

H ₄₂

N ₃

O ₅

Cl (728.29)
Yield: 0.5%
¹

H-NMR (CDCl ₃

): δ (ppm) = 0.80-2.00 (m; 12H, -CH ₂

-, cyclohept.), 2.15-2.35 (m; 1H, CH-, cyclohept.), 2.39 (s; 3H, -CH ₃

), 3.59 (d; ³

J = 10.3 Hz, 1H, CH-CO-), 3.75 (s; 3H, -OCH ₃

), 3.97 (s; 2H, -CH ₂

-CO-), 5.34 (s; 2H, -CH ₂

-O-), 6.60-6.90 (m; 3H, aromat.), 6.85-7.00 / 7.10-7.25 ([AB] ₂

; ^{3 _years}

AB = 8.7 Hz, 4H, aromatic), 7.40-7.50 / 7.60-7.70 ([AB] ₂

; ^{3 _years}

FROM = 8.7 Hz, 4H, aromatic), 7.50-7.90 (m; 4H, aromat.), 8.00-8.30 (m; 3H, NH and aromatic.).

Example 5 N - {[4- (quinolin-2-ylmethoxy) phenyl] cycloheptyl acetyl} -2- (5- methoxy-2-methyl-1H-indol-3-yl) acetamide

1.0 g (2.5 mmol) of [4- (quinolin-2-ylmethoxy) phenyl] cycloheptyl acetic acid amide are dissolved in 20 ml of absolute N, N-dimethylformamide. After adding 200 mg (5.0 mmol) of sodium hydride (60% in white oil), the mixture is stirred at room temperature for 1 h. At the same time, 700 mg (3.1 mmol) (5-methoxy-2-methyl-1H-indol-3yl) acetic acid are dissolved in 10 ml absolute N, N-dimethylformamide, 700 mg (4.3 mmol) 1.1 ' -Carbonyldiimidazol added and also stirred for 1 h at room temperature. The solution of the activated carboxylic acid is then added to the deprotonated amide and stirred at room temperature for 20 h. The mixture is poured into 500 ml of water and then neutralized with 8% phosphoric acid (pH 6). After extracting three times with ethyl acetate, the combined organic phases are dried over sodium sulfate and concentrated. The product is purified by column chromatography (silica gel; ethyl acetate: n-hexane = 1: 1).
C ₃₇ H ₃₉ N ₃ O ₄ (589.73)
Yield: 32%
Mp: 97.4 ° C
IR (KBr): 3325 cm ^-1 (NH, indole), 2915 cm ^-1 (CH _aliphatic ), 1742 cm ^-1 (C = O), 823 cm ^-1 (CH _aromat. ).
¹ H-NMR (CDCl ₃ ): δ (ppm) = 0.80-2.10 (m; 13H, cyclohept.), 2.13 (s; 3H, -CH ₃ ), 3.60-3.65 (d; 1H, CH-CO-) , 3.73 (s; 2H, -CH ₂ -CO-), 3.77 (s; 3H, -OCH ₃ ), 5.38 (s; 2H, -CH ₂ -O-), 6.70-7.20 (m; 6H, aromat. ), 7.50-8.30 (m; 7H, aromat.), 8.11 (s; broad, 1H, NH).

Example 6

The following compounds are obtained according to Example 5.

1.) N - {[1- (4-chloro-benzyl) -5-methoxy-2-methyl-1H-indol-3-yl] - acetyl} -2- [4- (quinolin-2-yl-methoxy) phenyl] -2-cycloheptyl acetamide

C ₄₄

H ₄₄

N ₃

O ₄

Cl (714.30)
Yield: 5%
¹

H-NMR (CDCl ₃

): δ (ppm) = 0.80-1.00 (m; 1H, CH-, cy clohept.), 1.00-1.80 (m; 12H, -CH ₂

-, cyclohept.), 2.12 (s; 3H, -CH ₃

), 3.70-3.80 (d; 1H, <CH-CO-), 3.76 (s; 3H, -OCH ₃

), 3.84 (s; 2H, -CH ₂

-CO-), 3.70-3.80 (d; ^3rd

J = not measurable, CH-CO-), 5.19 (s; 2H, -CH ₂

-), 5.34 (s; 2H, -CH ₂

-O-), 6.80-7.30 (m; 11H, aromatic), 7.50-7.90 (m; 4H, quinol.), 8.01 (s; broad, 1H, NH), 8.00-8.30 (m; 2H, quinol.).

2.) 4- (Quinolin-2-ylmethoxy) -N- [(5-methoxy-2-methyl) -1H-indole- 3-yl) acetyl] benzamide

C ₂₉

H ₂₅

N ₃

O ₄

(479.53)
Yield: 26%
Mp: 167-173 ° C
IR (KBr): 3351 cm ^-1

(NH, indole), 1708 cm ^-1

(C = O) 1681 cm ^-1

(C = C), 1244 cm ^-1

(COC), 833 cm ¹

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 2.31 (s; 3H, -CH ₃

), 3.77 (s; 3H, -OCH ₃

), 4.17 (s; 2H, -CH ₂

-CO-), 5.41 (s; 2H, -CH ₂

-O-), 6.78 (dd; ³

J = 8.7 Hz, ⁴

J = 2.3 Hz, 1H, indol.), 6.80-6.95 / 7.50-7.70 ([AB] ₂

; 4H, aro mat.), 6.94 (d; ⁴

J = 2.3 Hz, 1H, in dol.), 7.21 (d; ^3rd

J = 8.7 Hz, 1H, in dol.), 7.50-7.70 (m; 2H, quinol.), 7.70-7.90 (m; 2H, quinol.), 8.10-8.30 (m; 2H, quinol. and 1H, NH), 9.10 (s; 1H, -CO-NH-CO-).

Example 7 (5-Methoxy-2-methyl-1H-indol-3-yl) -acetic acid methyl ester

5.0 g (22.8 mmol) (5-methoxy-2-methyl-1H-indol-3-yl) acetic acid are dissolved in 40 ml absolute tetrahydrofuran, 4.2 g (25.9 mmol) 1, 1'-carbonyldiimidazole was added and the mixture was stirred at room temperature for 20 min. After adding 25 ml of methanol, stirring is continued for 1 h at room temperature. The reaction solution is mixed with 200 ml of water and acidified with 1N hydrochloric acid (pH 1). After extracting three times with ethyl acetate, the organic phases are washed once with water, dried over sodium sulfate and evaporated.
C ₁₃ H ₁₅ NO ₃ (233.27)
Yield: 98%
Mp: 68.2 ° C
IR (KBr): 3398 cm ^-1 (NH, indole), 1732 cm ^-1 (C = O)
¹ H-NMR (CDCl ₃ ): δ (ppm) = 2.37 (s; 3H, -CH ₃ ), 3.66 (s; 2H, -CH ₂ -), 3.67 (s; 3H, -COOCH ₃ ), 3.85 ( s; 3H, -OCH ₃ ), 6.77 (dd; ³ J = 8.7 Hz, ⁴ J = 2.4 Hz, 1H, aromat.), 6.98 (d; ⁴ J = 2.4 Hz, 1H, aromat.), 7.13 (d ; ³ J = 8.7 Hz, 1H, aromatic), 7.80 (s; broad, 1H, NH).

Example 8 [1- (4-chlorobenzyl) -5-methoxy-2-methyl-1H-indol-3-yl] acetic acid methyl ester

560 mg (14 mmol) sodium hydride (60% in white oil) are suspended in 6 ml absolute N, N-dimethylformamide and cooled to -5 ° C to 0 ° C. 2.1 g (9 mmol) (5-methoxy-2-methyl-1H-indol-3-yl) methyl acetate, dissolved in 10 ml of absolute N, N-dimethylformamide, are slowly added dropwise. After the evolution of hydrogen has ended, the 4-chlorobenzyl chloride (9.9 mmol) dissolved in 10 ml of absolute N, N-dimethylformamide is added dropwise. After the temperature has reached 10 ° C, the cooling is removed and stirred at room temperature for 12 h. The mixture is mixed with water and acidified to pH 3 with 1N HCl. After extracting three times with ethyl acetate, the combined organic phases are washed once with water, dried over sodium sulfate and concentrated. The residue obtained is suspended in methanol and suction filtered. A white solid substance is obtained.
C ₂₀ H ₂₀ NO ₃ Cl (357.84)
Yield: 74%
Mp: 109.2 ° C
IR (KBr): 1730 cm ^-1 (C = O)
¹ H-NMR (CDCl ₃ ): δ (ppm) = 2.30 (s; 3H, -CH ₃ ), 3.68 (s; 3H, -COOCH ₃ ), 3.71 (s; 2H, - CH ₂ -COOCH ₃ ), 3.86 (s; 3H, -OCH ₃ ), 5.22 (s; 2H, -CH ₂ -), 6.77 (dd; ³ J = 8.9 Hz, ⁴ J = 2.3 Hz, 1H, in dol.), 6.80-6.90 / 7.15-7.25 ([AB] ₂ ; ^{3 _J} AB = 8.4 Hz, 4H, aromat.), 6.95-7.10 (m; 2H, indol.)

Example 9 [1- (4-chloro-benzyl) -5-methoxy-2-methyl-1H-indol-3-yl] acetic acid acid

To saponify the methyl [1- (4-chlorobenzyl) -5-methoxy-2-methyl-1H-indol-3-yl] acetic acid (25), 2.15 g (6.0 mmol) in 40 ml methanol, 20 ml of ethanol and 15 ml of 1 M sodium hydroxide solution refluxed for 1 h. The solvent is then removed on a rotary evaporator, the batch is mixed with water, acidified with 1N hydrochloric acid and extracted three times with ethyl acetate. After drying the organic phases over sodium sulfate and concentrating, a white solid is obtained.
C ₁₉ H ₁₈ NO ₃ Cl (343.81)
Yield: 94%
Mp: 183.6 ° C
IR (KBr): 3100 cm ^-1 -2700 cm ^-1 (OH), 1698 cm ^-1 (C = O).
¹ H NMR (CDCl ₃ ): δ (ppm) = 2.29 (s; 3H, -CH ₃ ), 3.72 (s; 2H, - CH ₂ -COOH), 3.84 (s; 3H, -OCH ₃ ), 5.22 (s; 2H, -CH ₂ -), 6.77 (dd; ³ J = 8.7 Hz, ⁴ J = 2.5 Hz, 1H, indol.), 6.86 / 7.22 ([AB] ₂ ; ^{3 _J} AB = 8.7 Hz, 4H , aromatic.), 7.00-7.10 (m; 2H, indol.).

Example 10 4- (Quinolin-2-ylmethoxy) -benzoic acid ethyl ester

2.0 g (12 mmol) of ethyl 4-hydroxybenzoate, dissolved in 30 ml of absolute N, N-dimethylformamide, are stirred for 1 h at 60 ° C. with 1.9 g (13 mmol) of potassium carbonate. After adding 2.8 g (13 mmol) of 2-chloromethylquinoline hydrochloride, dissolved in 15 ml of N, N-dimethylformamide, the mixture is stirred at 60 ° C. for 17 h. For working up, the N, N-dimethylformamide is distilled off in a Kugelrohr oven, the residue is mixed with water, acidified to pH 5 and extracted 3 times with ethyl acetate. The combined organic phases are washed twice with water, dried over sodium sulfate and concentrated. A waxy solid substance is obtained.
C ₁₉ H ₁₇ NO ₃ (307.35)
Yield: 97%
Mp: waxy
IR (KBr): 1730 cm ^-1 (C = O)
¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.36 (t; ³ J = 7 Hz, 3H, -CH ₂ - CH ₃ ), 4.34 (q; ³ J = 7 Hz, 2H, - CH ₂ - CH ₃ ), 5.44 (s; 2H, -CH ₂ -O-), 7.00-7.10 / 7.95-8.10 ([AB] ₂ ; ³ J = 8.9 Hz, 4H, aromat.), 7.50-8.30 (m; 6H , quinol.).

Example 11 4- (quinolin-2-ylmethoxy) benzoic acid

3.45 g (11.2 mmol) of ethyl 4-quinolin-2-yl-methoxybenzoate are refluxed for 2 hours in 30 ml of ethanol and 10 ml of 16% sodium hydroxide solution. The ethanol is distilled off, the mixture is poured into water and acidified to pH 6 with 1N HCl. The precipitated product is taken up in ethyl acetate, the organic phase is washed once with water, dried over sodium sulfate and evaporated.
C ₁₇ H ₁₃ NO ₃ (279.29)
Yield: 93%
Mp: 203.3 ° C
IR (KBr): 3000 cm ^-1 -2700 cm ^-1 (OH), 1685 cm ^-1 (C = O) 1603 cm ^-1 (C = C), 1252 cm ^-1 (COC)
¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 5.46 (s; 2H, -CH ₂ -O-), 7.10-7.25 / 7.85-8.00 ([AB] ₂ ; ³ J = 8.8 Hz, 4H , aro mat.), 7.55-8.10 (m; 5H, quinol.) 8.44 (d; ³ J = 8.5 Hz, 1H, quinol.), 12.66 (s; broad, 1H -COOH).

Example 12 4- (quinolin-2-ylmethoxy) -N - ([1- (4-chlorobenzyl) -5-methoxy-2- methyl-1H-indol-3-yl] acetyl) benzamide

650 mg (1.8 mmol) of [1- (4-chlorobenzyl) -5-methoxy-2-methyl-1H-indol-3-yl] acetic acid are dissolved in 10 ml of absolute N, N-dimethylformamide. After adding 340 mg (2.1 mmol) of 1,1'-carbonyldiimidazole, the mixture is stirred at room temperature for 2 h. At the same time, 500 mg (1.8 mmol) of 4- (quinolin-2-ylmethoxy) benzoic acid amide are dissolved in 12 ml of absolute N, N-dimethylformamide, then in a suspension consisting of 100 mg (2.4 mmol) of sodium hydride ( 60% in white oil) and 5 ml of absolute N, N-dimethylformamide, added dropwise and also stirred at room temperature for 2 h. The solution of the activated carboxylic acid is then added to the deprotonated amide and stirred at 40 ° C. for 24 h. The batch is poured into 500 ml of water and then neutralized with 8% phosphoric acid (pH 6). After extracting three times with ethyl acetate, the combined organic phases are dried over sodium sulfate and concentrated. The product is purified by column chromatography (silica gel; ethyl acetate: n-hexane = 2: 1).
C ₃₆ H ₃₀ N ₃ O ₄ Cl (604.10)
Yield: 31%
Mp: 173.5 ° C
IR (KBr): 3383 cm ^-1 (NH, indole), 1694 cm ^-1 (C = O) 1243 cm ^-1 (COC).
¹ H-NMR (CDCl ₃ ): δ (ppm) = 2.31 (s; 3H, -CH ₃ ), 3.81 (s; 3H, -OCH ₃ ), 4.23 (s; 2H, -CH ₂ -CO-), 5.25 (s; 2H, -CH ₂ -), 5.43 (s; 2H, -CH ₂ -O-), 6.70- 7.25 (m; 9H, aromat.), 7.50-7.70 (m; 4H, aromat.), 7.70-7.90 (m; 2H, aromat.), 8.10-8.30 (m; 2H, aromat.), 8.72 (s; broad, 1H, NH).

Example 13 The following connections are made after DE 19 43 265 C3 1.) 4-Hydroxy-2-methyl-N- (2-methoxyphenyl) -2H-1,2-benzothiazine 3-carboxamide-1,1-dioxide

C ₁₇

H ₁₆

N ₂

O ₅

S (360.39)
Yield: 80%
Mp: <165 ° C (dec.)
IR (KBr): 3600 cm ^-1

-3200 cm ^-1

(wide, OH), 3365 cm ^-1

(NH), 1627 cm ^-1

(C = O), 1595 cm ^-1

, 1525 cm ^-1

, 1344 cm ^-1

and 1178 cm ^-1

(SO ₂

), 755 cm ^-1

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 2.97 (s; 3H, NCH ₃

), 3.95 (s; 3H -OCH ₃

), 6.80-7.30 (m; 3H, aro mat.), 7.70-8.50 (m; 5H, aromatic), 8.89 (s; 1H, NH), 13.52 (s; 1H, -OH).

2.) 4-Hydroxy-2-methyl-N- (3-methoxyphenyl) -2H-1,2-benzothiazine 3-carboxamide-1,1-dioxide

C ₁₇

H ₁₆

N ₂

O ₅

S (360.39)
Yield: 54%
Mp: 209-213 ° C (decomposition)
IR (KBr): 3600 cm ^-1

-3300 cm ^-1

(wide, OH), 3353 cm ^-1

(NH), 1610 cm ^-1

(C = O), 1551 cm ^-1

, 1342 cm ^-1

(SO ₂

) 1279 cm ^-1

(COC), 1181 cm ^-1

(SO ₂

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 2.94 (s; 3H, NCH ₃

), 3.84 (s; 3H -OCH ₃

), 6.75-6.80 (m; 1H, aro mat.), 7.05-7.40 (m; 3H, aromatic), 7.70-8.20 (m; 4H, aromat.), 8.27 (s; 1H, NH), 13.37 (s; 1H, -OH).

3.) 4-Hydroxy-2-methyl-N- (4-methoxyphenyl) -2H-1,2-benzothiazine 3-carboxamide-1,1-dioxide

C ₁₇

H ₁₆

N ₂

O ₅

S (360.39)
Yield: 56%
Mp: 180 ° C (dec.)
IR (KBr): 3600 cm ^-1

-3300 cm ^-1

(OH), 3325 cm ^-1

(NH), 1618 cm ^-1

(C = O), 1533 cm ^-1

, 1337 cm ^-1

(SO ₂

), 1245 cm ^-1

(COC), 1181 cm ^-1

(SO ₂

), 822 cm ¹

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 2.94 (s; 3H, NCH ₃

), 3.82 (s; 3H, -OCH ₃

), 6.90-6.95 / 7.50-7.55 ([AB] ₂

; ^{3 _years}

AB = 8.9 Hz, 4H, aromat.), 7.70-8.05 (m; 4H, aromat.), 8.21 (s; 1H, NH), 13.43 (s; 1H -OH).
¹³

C-NMR (CDCl ₃

): δ (ppm) = 40.0, 55.5, 111.7, 114.4, 122.4, 124.8, 126.6, 128.6, 129.3, 132.3, 133.1, 134.3, 157.2, 157.6, 166.3.

Example 14 5 4-hydroxy-2-methyl-N- (4-hydroxyphenyl) -2H-1,2-benzothiazine-3- carboxamide-1,1-dioxide

2.2 mmol of methoxy compound are dissolved in 30 ml of absolute methylene chloride and cooled to -30 ° C. Then the boron tribromide (10 mmol) dissolved in 20 ml of absolute methylene chloride is slowly added dropwise. When the dropwise addition has ended, the mixture is stirred at room temperature for 2.5 h. The reaction solution is poured into 150 ml of ice-cooled saturated sodium hydrogen carbonate solution, then the mixture is extracted 3 times with ethyl acetate. The combined organic phases are washed once with saturated sodium chloride solution, dried over sodium sulfate and concentrated.
C ₁₆ H ₁₄ N ₂ O ₅ S (346.36)
Yield: 97%
Mp: <250 ° C (dec.)
IR (KBr): 3500 cm ^-1 -3200 cm ^-1 (OH), 3350 cm ^-1 (NH), 1614 cm ^-1 (C = O), 1535 cm ^-1 , 1506 cm ^-1 , 1336 cm ^-1 and 1181 cm ^-1 (SO ₂ ).
¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 2.85 (s; 3H, NCH ₃ ), 6.70-6.80 / 7.45-7.55 ([AB] ₂ ; ³ J = 8.8 Hz, 4H, aromatic.) , 7.80-8.10 (m; 4H, aro mat.), 9.45 (s; broad, 1H, NH, from exchange.), 10.14 (s; 1H -OH, from exchange.), 14.29 (s; 1H, -OH , from exchange.)
¹³ C-NMR (CDCl ₃ + DMSO-d ₆ = 1: 1): δ (ppm) = 39.5, 110.5, 114.0, 122.4, 122.9, 125.0, 127.3, 127.4, 130.9, 131.7, 133.3, 153.7, 155.9, 165.5 .

Example 15

The following compounds are obtained analogously to Example 14.

1.) 4-Hydroxy-2-methyl-N- (2-hydroxyphenyl) -2H-1,2-benzothiazine 3-carboxamide-1,1-dioxide

C ₁₆

H ₁₄

N ₂

O ₅

S (346.36)
Yield: 100%
Mp: <150 ° C (dec.)
IR (KBr): 3415 cm ^-1

(OH), 3340 cm ^-1

(NH), 1626 cm ^-1

(C = O), 1542 cm ^-1

, 1337 cm ^-1

and 1171 cm ^-1

(SO ₂

), 755 cm ^-1

(CH aro mat.).
¹

H-NMR (DMSO-d ₆

): δ (ppm) = 2.97 (s; 3H, NCH ₃

), 6.80-7.10 (m; 3H, aromat.), 7.70-8.20 (m; 5H, aromat.), 9.08 (s; broad,  1H, NH, exchange.), 9.90 (s; 1H -OH, exchange.), 13.11 (s; 1H, -OH, exchange.)

2.) 4-Hydroxy-2-methyl-N- (3-hydroxyphenyl) -2H-1,2-benzothiazine 3-carboxamide-1,1-dioxide

C ₁₆

H ₁₄

N ₂

O ₅

S (346.36)
Yield: 100%
Mp: <150 ° C (dec.)
IR (KBr): 3470 cm ^-1

(OH), 3355 cm ^-1

(NH), 1627 cm ^-1

(C = O), 1595 cm ^-1

, 1543 cm ^-1

, 1440 cm ^-1

, 1337 cm ^-1

and 1170 cm ^-1

(SO ₂

).
¹

H-NMR (DMSO-d ₆

): δ (ppm) = 2.86 (s; 3H, NCH ₃

), 6.55-6.65 (m; 1H, aromat.), 7.10-7.30 (m; 3H, aromat.), 7.80-8.05 (m; 4H, aromat.), 9.54 (s; 1H, NH), 10.17 (s ; 1H, -OH _aromatic.

), 12.47 (s; 1H, -OH).

Example 16 4-hydroxy-2-methyl-N- [4- (quinolin-2-ylmethoxy) phenyl) -2H-1,2- benzothiazine-3-carboxamide-1,1-dioxide

1.2 mmol of 4-hydroxy-2-methyl-N- (4-hydroxypheny1) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide are dissolved in 7 ml of absolute N, N-dimethylformamide and after adding 3.5 mmol of potassium carbonate, the mixture was stirred at 60 ° C. for 1.5 h. Then 1.2 mmol of 2-chloromethylquinoline hydrochloride, dissolved in 6 ml of absolute N, N-dimethylformamide, are added dropwise and the mixture is stirred at 70 ° C. for 14 h. After cooling, the reaction solution is poured into water and neutralized with 1N hydrochloric acid (pH 6). The precipitate is filtered off and recrystallized in methylene chloride in the presence of activated carbon. The activated carbon is filtered off from the hot solution and the filtrate is concentrated. After the residue has been mixed with diethyl ether, the product precipitates. Alternatively, after neutralization, the reaction solution can be extracted 3 times with ethyl acetate, dried over sodium sulfate and concentrated. The product is purified by column chromatography (silica gel; diisopropyl ether: ethyl acetate 7: 2).
C ₂₆ H ₂₁ N ₃ O ₅ S (487.53)
Yield: 50%
Mp: 190 ° C (dec.)
IR (KBr): 3600 cm ^-1 -3300 cm ^-1 (OH), 3352 cm ^-1 (NH), 1622 cm ^-1 (C = O), 1539 cm ^-1 , 1510 cm ^-1 , 1340 cm ^-1 and 1185 cm ^-1 (SO ₂ ), 840 cm ¹ (CH _aromat. ).
¹ H-NMR (CDCl ₃ ): δ (ppm) = 2.93 (s; 3H, NCH ₃ ), 5.40 (s; 2H, -CH ₂ -O-), 7.05 / 7.52 ([AB] ₂ ; ^{3 _J} AB = 9 Hz, 4H, aromat.), 7.54-8.23 (m; 11H, aromat. And NH), 13.39 (s; 1H, -OH).
¹³ C-NMR (CDCl ₃ ): δ (ppm) = 40.0, 71.6, 111.7, 115.4, 119.1, 122.4, 124.8, 126.6, 127.6, 127.7, 128.6, 129.0, 129.7, 129.8, 132.3, 133.1, 134.3, 137.1, 156.0, 157.6, 157.7, 166.3.

Example 17

The following compounds were obtained analogously to Example 16.

1.) 4-Hydroxy-2-methyl-N- [2- (quinolin-2-ylmethoxy) phenyl) -2H- 1,2-benzothiazine-3-carboxamide-1,1-dioxide

C ₂₆

H ₂₁

N ₃

O ₅

S (487.53)
Yield: 14%
Mp: 195.9 ° C
IR (KBr): 3600 cm ^-1

-3300 cm ^-1

(OH), 3350 (NH), 1632 cm ^-1

(C = O), 1598 cm ^-1

, 1532 cm ^-1

, 1344 cm ^-1

(SO ₂

), 1248 cm ^-1

(COC), 1180 cm ^-1

(SO ₂

), 741 cm ^-1

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 2.88 (s; 3H, NCH ₃

), 5.54 (s; 2H, -CH ₂

-O-), 7.00-8.50 (m; 14H, aromat.), 9.28 (s; 1H, NH), 13.42 (s; 1H, -OH).
¹³

C-NMR (CDCl ₃

): δ (ppm) = 39.8, 71.8, 111.6, 112.2, 118.6, 120.3, 121.8, 124.7, 125.2, 126.5, 126.6, 127.8, 128.0, 128.9, 130.0, 132.2, 133.1, 134.5, 138.0, 147.4, 147.5, 156.6, 157.6, 166.1.

2.) 4-Hydroxy-2-methyl-N- [3- (quinolin-2-ylmethoxy) phenyl) -2H- 1,2-benzothiazine-3-carboxamide-1,1-dioxide

C ₂₆

H ₂₁

N ₃

O ₅

S (487.53)
Yield: 17%
Mp: 183.8 ° C
IR (KBr): 3600 cm ^-1

-3300 cm ^-1

(OH), 3328 cm ^-1

(NH), 1629 cm ^-1

(C = O), 1597 cm ^-1

, 1540 cm ^-1

, 1348 cm ^-1

and 1182 cm ^-1

(SO ₂

), 766 cm ¹

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 2.93 (s; 3H, NCH ₃

), 5.42 (s; 2H; -CH ₂

-O-), 6.80-8.80 (m; 14H, aromat, and NH), 13.34 (s; 1H, -OH).

Example 18 Naphthalene-2,6-disulfonyl dichloride

11.0 g (26.5 mmol) of naphthalene-2,6-disulfonic acid disodium salt (80%) are rubbed with 25.0 g (120.0 mmol) of phosphorus pentachloride and placed in a 100 ml single-necked flask. After adding 20.0 g (130.0 mmol) of phosphorus oxytrichloride, the mixture is stirred at 110 ° C. for 7 h. After cooling, the reaction solution is poured onto ice water and stirred for 30 minutes. The precipitated product is suctioned off and dried.
C ₁₀ H ₆ O ₄ S ₂ Cl ₂ (325.19)
Yield: 96%
Mp: 200-250 ° C (dec.)
IR (KBr): 1380 cm ^-1 and 1164 cm ^-1 (SO ₂ )
¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 7.72 (dd; ³ J = 8.4 Hz, ⁴ J = 1.4 Hz, 2H, aromatic), 7.93 (d; ³ J = 8.4 Hz, 2H, aromat.), 8.14 (d; ⁴ J = 1.4 Hz, 2H, aromat.).

Example 19 Naphthalene-2,6-disulfonic acid diamide

50 ml of concentrated aqueous ammonia solution are heated to 60 ° C. 8.8 g (27 mmol) of naphthalene-2,6-disulfonyl dichloride are suspended in 30 ml of tetrahydrofuran and added dropwise. At closing, the mixture is refluxed for 30 h. After the reaction solution has cooled, the tetrahydrofuran is largely removed, the precipitated white product is filtered off with suction, washed several times with water and dried at 40 ° C. in a drying gun.
C ₁₀ H ₁₀ N ₂ O ₄ S ₂ (286.33)
Yield: 84%
Mp: <300 ° C
IR (KBr): 3320 cm ^-1 and 3240 cm ^-1 (NH), 1322 cm ^-1 and 1152 cm ^-1 (SO ₂ ).
¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 7.57 (s; broad, 4H, -NH ₂ ), 7.99 (dd; ³ J = 8.6 Hz, ⁴ J = 1.4 Hz, 2H, aromatic.) , 8.36 (d; ³ J = 8.6 Hz, 2H, aromatic), 8.52 (d; ⁴ J = 1.4 Hz, 2H, aromatic).
¹³ C NMR (DMSO-d ₆ ): δ (ppm) = 123.4, 125.4, 130.3, 132.7, 143.1.

Example 20 N- [2- (2-Fluoro-biphenyl-4-yl) propionyl] naphthalene-2,6-disulfone acid diamide

844 mg (3.46 mmol) of flurbiprofen is dissolved in 10 ml of absolute tetrahydrofuran, 840 mg (5.18 mmol) of 1,1'-carbonyldiimidazole are added and the mixture is stirred at room temperature for 90 min. At the same time, 140 mg (3.50 mmol) of sodium hydride (60% in white oil) are suspended in 12 ml of absolute tetrahydrofuran and, after addition of 1 g (3.50 mmol) of naphthalene-2,6-disulfonic acid diamide, stirred for 1 h at room temperature. The carboxylic acid activated with 1,1'-carbonyldiimidazole is then added to the sodium hydride solution and stirred for 2 days at room temperature. The contents of the flask are mixed with water and acidified with 8% phosphoric acid. After extracting three times with ethyl acetate, the combined organic phases are washed with water, dried over magnesium sulfate and concentrated. The product is treated after column chromatographic purification (MPLC, RP 18; acetone: water = 5: 2).
C ₂₅ H ₂₁ N ₂ O ₅ S ₂ F (512.58)
Yield: 25%
Mp: 241.5 ° C
IR (KBr): 3362 cm ^-1 and 3290 cm ^-1 and 3263 cm ^-1 (NH), 1728 cm ^-1 (C = O), 1332 cm ^-1 and 1159 cm ^-1 (SO ₂ ).
¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 1.27 (d; ³ J = 7.0 Hz, 3H, CH- CH ₃ ), 3.81 (q; ³ J = 7.0 Hz, 1H, CH - CH ₃ ), 7.00-7.10 (m; 2H, aromat.), 7.30-7.55 (m; 6H, aromat.), 7.62 (s; 2H, -NH ₂ ), 7.91 (dd; ³ J = 8.7 Hz, ⁴ J = 1.8 Hz, 1H, naphth.), 8.02 (d; ³ J = 8.6 Hz, ⁴ J = 1.6 Hz, 1H, naphth.), 8.36 (d; ³ J = 12.3 Hz, 1H, naphth.), 8.40 (d ; ³ J = 12.1 Hz, 1H, naphth.), 8.55 (d; ⁴ J = not resolved, 1H, naphth.), 8.64 (d; ⁴ J = not resolved, 1H, naphth.), 12.56 (s; broad , 1H, -SO ₂ - NH -CO-).

Example 21 N - {[4- (Quinolin-2-ylmethoxy) phenyl] cycloheptyl acetyl} -N '- [2- (2-fluoro-biphenyl-4-yl) propionyl] naphthalene-2,6- disulfonic acid diamide

In a sodium hydride suspension of 90 mg (2.25 mmol) sodium hydride (60% in white oil) and 5 ml absolute N, N-dimethylformamide, 550 mg (1.07 mmol) N- [2- (2-fluorine -biphenyl-4-yl) - propionyl] -naphthalene-2,6-disulfonic acid diamide, dissolved in 10 ml of absolute N, N-dimethylformamide, added dropwise and stirred at room temperature for 180 min. 500 mg (1.28 mmol) [4- (quinolin-2-ylmethoxy) phenyl] cycloheptyl acetic acid are dissolved in 6 ml absolute N, N-dimethylformamide, 300 mg (1.85 mmol) 1.1 ' Carbonyldiimidazole added and stirred for 2 h at room temperature. This solution is then added to the sodium hydride suspension and the mixture is stirred at 50 ° C. for 2 days. The solvent is distilled off in a Kugelrohr oven, water is added to the residue and the mixture is acidified to pH 4-5 with 8% phosphoric acid. A white precipitate precipitates, which is filtered off, washed with water and dried over phosphorus pentoxide. The product is isolated by column chromatography (silica gel; n-hexane: dioxane = 1: 1). You get an oil. After adding water, the white product precipitates, which is suctioned off, washed with water and dried.
C ₅₀ H ₄₆ N ₃ O ₇ S ₂ F (884.06)
Yield: 74%
Melting point: sinters from 116 ° C
IR (KBr): 3246 cm ^-1 (NH), 2927 cm ^-1 and 2854 cm ^-1 (CH _aliphatic ), 1720 cm ^-1 (C = O), 1509 cm ^-1 (C = C), 1346 cm ^-1 and 1134 cm ^-1 (SO ₂ ).
¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 0.75-1.70 (m; 12H, -CH ₂ -, cy clohept.), 1.20-1.30 (d; superimposed, 3H, CH- CH ₃ ), 1.85-2.15 (m; 1H, <CH-, cyclo hept.), 3.25-3.35 (d; overlaid by LM signal, 1H, CH -CH), 3.82 (q; ³ J = 7.0 Hz, 1H, CH - CH ₃ ), 5.33 (s; 2H, -CH ₂ -O-), 6.90-7.20 (m; 6H, aromat.), 7.30-7.55 (m; 6H, aromat.), 7.55-8.15 (m; 7H, aromat.), 8.30-8.45 (m; 3H, aromat.), 8.60-8.75 (m; 2H, aromat.), 12.52 (s; broad, 2H, -SO ₂ - NH -CO-).

Example 22 Propane-1,3-disulfonyl dichloride

15.0 g (138.9 mmol) of propane-1,3-dithiol are mixed in a 250 ml three-necked flask with KPG stirrer, thermometer, reflux condenser and inlet tube with 30 ml of water and 30 ml of carbon tetrachloride. Chlorine gas is introduced into the reaction solution while cooling with ice. The temperature in the reaction mixture should not exceed 40 ° C. The reaction is complete when the yellowish substance fails (after approx. 15 min). The contents of the flask are carefully poured onto water, then extracted 3 times with methylene chloride. After drying over sodium sulfate, the organic phase is concentrated. A white, waxy solid substance is obtained.
C ₃ H ₆ S ₂ O ₄ Cl ₂ (241.11)
Yield: 84%
Mp: 51.4 ° C
IR (KBr): 3004 cm ¹ and 2923 cm ^-1 (CH ₂ aliphatic), 1367 cm ^-1 and 1163 cm ^-1 (SO ₂ ).
¹ H-NMR (CDCl ₃ ): δ (ppm) = 2.79 (m; ³ J = 7.0 Hz, 2H, -CH ₂ - CH ₂ -CH ₂ -), 3.95 (t; ³ J = 7.0 Hz, 4H, - CH ₂ -CH ₂ - CH ₂ -).

Example 23 Propane-1,3-disulfonic acid diamide

90 ml of dioxane are saturated with ammonia gas (ice cooling). Then 2 g (8.3 mmol) of propane-1,3-disulfonyl dichloride are dissolved in 10 ml of dioxane and added dropwise so that the temperature in the flask does not exceed 50 ° C. After the dropwise addition is complete, stirring is continued for 5 min while introducing ammonia gas. The dioxane is distilled off, the residue is filtered off with suction and washed thoroughly with diethyl ether. The ammonium chloride contained in the product is separated by sublimation (110 ° C, 3 × 10 ^-3 mbar).
C ₃ H ₁₀ N ₂ O ₄ S ₂ (202.25)
Yield: 90%
Mp: 158.6 ° C
IR (KBr): 3352 cm ^-1 and 3241 cm ^-1 (NH ₂ ), 1335 cm ^-1 and 1142 cm ^-1 (SO ₂ ).
¹ H-NMR (DMSO-d ₆ ): δ (ppm) = 2.13 (m; ³ J = 7.5 Hz, 2H, -CH ₂ - CH ₂ -CH ₂ -), 3.13 (t; ³ J = 7.5 Hz, 4H, - CH ₂ -CH ₂ - CH ₂ -), 6.89 (s; broad, 4H, -NH ₂ ).

Example 24 N- [2- (2-fluorobiphenyl-4-yl) propionyl] propane-1,3- disulfonic acid diamide

• A) 574.5 mg (2.35 mmol) flurbiprofen in 4 ml absolute N, N-dimethylformamide dissolved, 564.5 mg (3.48 mmol) 1,1'- Carbonyldiimidazole added and 100 min at room temperature touched.
• B) In parallel, 139.6 mg (3.48 mmol) of sodium hydride (60% in white oil) are suspended in 7 ml of absolute N, N-dimethylformamide, 705.2 mg (3.49 mmol) of propane-1,3 Disulfonic acid diamide (39) was added and the mixture was stirred at room temperature for 90 min. After adding solution A to solution B, the mixture is stirred at 60 ° C. for 24 h. The solvent is distilled off in a Kugelrohr oven, the residue is taken up in water and acidified with 8% phosphoric acid (pH 5). The precipitate is filtered off, washed with water and dried over phosphorus pentoxide. The product is purified by column chromatography (MPLC: RP-18; acetone: water = 5: 2).
  C ₁₈ H ₂₁ N ₂ O ₅ S ₂ F (428.50)
  Yield: 48%
  Mp: 161.8 ° C
  IR (KBr): 3383 cm ^-1 and 3278 cm ^-1 (NH ₂ ), 1681 cm ^-1 (C = O), 1336 cm ^-1 and 1137 cm ^-1 (SO ₂ ).
  ¹ H NMR (DMSO-d ₆ ): δ (ppm) = 1.41 (d; ³ J = 6.9 Hz, 3H, CH- CH ₃ ), 1.90-2.25 (m; 2H, -CH ₂ - CH ₂ -CH ₂ -), 3.00-3.25 (m; 2H, - CH ₂ -SO ₂ -NH ₂ ), 3.40-3.70 (m; 2H, - CH ₂ -SO ₂ -NH-), 3.84 (q; ³ J = 6.9 Hz, 1H, CH -CH ₃ ), 6.92 (s; broad, 2H, -NH ₂ ), 7.10-7.35 (m; 2H, aromat.), 7.35-7.65 (m; 6H, aromat.), 11.89 (s ; broad, 1H, -SO ₂ -NH-CO-).

Example 25

The following compound was obtained analogously to Example 24.

N - {[4- (Quinolin-2-ylmethoxy) phenyl] cycloheptyl acetyl} -N '- [2- (2-fluoro-biphenyl-4-yl) propionyl] propane-1,3- disulfonic acid diamide

C ₄₃

H ₄₆

N ₃

O ₇

FS ₂

(799, 99)
Yield: 30%
IR (KBr): 3252 cm ^-1

(NH) 1699 cm ^-1

(C = O) 1347 cm ^-1

and 1138 cm ^-1

(SO ₂

).
¹

H-NMR (DMSO-d ₆

): δ (ppm) = 0.75-2.5 (m; 18H), 3.16 (d; ³

J = 10.4 Hz, 1H), 3.2-3.55 (m; 4H), 3.55-3.8 (m; 1H), 5.32 (s; 2H), 6.75-8.25 (m; 18H), 11.9-12.4 (s; 2H).

Example 26 Methyl 2- (4-methoxyphenyl) propionate

2.2 g (55.5 mmol) sodium hydride (60% in white oil) are suspended in 30 ml absolute tetrahydrofuran and cooled to -10 to -15 ° C (ice / NaCl cooling). 10 g (55.5 mmol) of methyl 4-methoxyphenylacetate, dissolved in 40 ml of absolute tetrahydrofuran, are added over the course of 15 minutes, followed by stirring for 30 minutes. 3.8 ml (60 mmol) of methyl iodide are dissolved in 40 ml of absolute tetrahydrofuran and slowly added dropwise. When the dropwise addition is complete, stirring is continued for 30 minutes, then the cooling is removed and the mixture is stirred at room temperature for 14 hours. The reaction solution is largely concentrated and 400 ml of water are added. After acidifying the mixture with 1N hydrochloric acid, it is extracted 3 times with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate and evaporated. The result is an oily liquid.
C ₁₁ H ₁₄ O ₃ (194.23)
Yield: 80%
Mp: oil
IR (NaCl): 2950 cm ^-1 (CH _aliphatic ), 1733 cm ^-1 (C = O), 1507 cm ^-1 , 1246 cm ^-1 (COC), 829 cm ^-1 (CH _aromat. ).
¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.47 (d; ³ J = 7.2 Hz, 3H, CH- CH ₃ ), 3.64 (s; 3H, -COOCH ₃ ), 3.60-3.70 (m; 1H CH -CH ₃ ), 3.78 (s; 3H -OCH ₃ ), 6.80-6.90 / 7.15-7.30 ([AB] ₂ ; ^{3 _J} AB = 8.7 Hz, 4H, aromatic.).

Example 27 Cycloheptyl- (4-methoxyphenyl) -acetic acid methyl ester

In a suspension consisting of 5.3 g (0.13 mol) of sodium hydride (60% in white oil) and 20 ml of absolute N, N-dimethylformamide who at 0 ° C 20 g (0.11 mol) of 4-methoxyphenylacetic acid methyl ester, dissolved in 30 ml of absolute N, N-dimethylformamide, slowly added dropwise. After the evolution of hydrogen has ended, 21.6 g (0.12 mol) of cycloheptyl bromide, dissolved in 20 ml of N, N-dimethylformamide, are added dropwise. The cooling is removed and the mixture is stirred at room temperature for 16 h. The mixture is poured into 1.2 l of water, neutralized with 8% phosphoric acid and extracted 3 times with ethyl acetate. The combined organic phases who dried over sodium sulfate and concentrated. After column chromatographic purification (silica gel; ethyl acetate: n-hexane = 1: 4), a yellowish white solid is obtained.
C ₂₄ H ₂₇ O ₄ Cl (276.37)
Yield: 53%
Mp: 45.4 ° C
IR (KBr): 2928 cm ^-1 (CH _aliphatic ), 2850 cm ^-1 (CH _aliphatic ), 1730 cm ^-1 (C = O, ester), 1506 cm ^-1 , 1245 cm ^-1 (COC), 826 cm ^-1 (CH _aromat. ).
¹ H-NMR (CDCl ₃ ): δ (ppm) = 0.85-1.10 (m; 1H, cyclohept.), 1.18-1.85 (m; 11H, cyclohept.), 2.10-2.30 (m; 1H, cyclohept.), 3.25 (d; ³ J = 10.8 Hz, 1H, CH-CO-), 3.61 (s; 3H, -COOCH ₃ ), 3.76 (s; 3H -OCH ₃ ), 6.80-6.90 / 7.20-7.30 ([AB] ₂ ; ^{3 _J} AB = 8.6 Hz, 4H, aromatic.).

Example 28 Methyl 2- (3-benzoyl-4-methoxyphenyl) propionate

2.4 g (18 mmol) AlCl ₃ are suspended in 6 ml 1,2-dichloroethane and cooled to 0 ° C. With a syringe, 18 mmol of the acid chloride are added dropwise through a serum cap so that the temperature in the flask does not exceed 5 ° C. After the dropwise addition, stirring is continued for 30 minutes. 15 mmol of methyl 2- (4-methoxyphenyl) propionate or methyl 2-cycloheptyl-2- (4-methoxyphenyl) acetic acid are then slowly added dropwise. The temperature should be kept between 0 ° C and 5 ° C. After the addition has ended, the cooling is removed and the mixture is then stirred for 12 h. The mixture is poured onto 300 ml of ice and stirred until the ice has liquefied. It is then acidified with 1N hydrochloric acid and extracted 3 times with chloroform. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. The product is isolated by column chromatography (silica gel; diisopropyl ether: n-hexane = 1: 2).
C ₁₈ H ₁₈ O ₄ (298.34)
Yield: 18%
Mp: semi-solid
IR (NaCl): 2945 cm ¹ (CH _aliphatic ), 1731 cm ^-1 (C = O, ester), 1662 cm ^-1 (C = O, ketone), 1246 cm ^-1 (COC).
¹ H-NMR (CDCl ₃ ): 6 (ppm) = 1.50 (d; ³ J = 7.2 Hz, 3H, CH- CH ₃ ), 3.66 (s; 3H, -COOCH ₃ ), 3.70 (s; 3H-OCH ₃ ), 3.60-3.80 (m; 1H CH -CH ₃ ), 6.95 (d; ³ J = 8.6 Hz, 1H, aromat.), 7.26-7.50 (m; 5H, aromat.), 7.70-7.80 (m; 2H, aro mat.).

Example 29

The following compounds were prepared analogously to Example 28 poses.

1.) 2- [3- (4-chlorobenzoyl) -4-methoxyphenyl] propionic acid methyl ester

C ₁₈

H ₁₇

O ₄

Cl (332.5)
Yield: 20%
Mp: oil
IR (NaCl): 2975 cm ^-1

(CH _aliphatic.

), 1730 cm ¹

(C = O, ester), 1663 cm ^-1

(C = O, ketone), 1491 cm ^-1

, 1256 cm ^-1

(COC), 844 cm ^-1

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 1.50 (d; ³

J = 7.3 Hz, 3H, CH- CH ₃

), 3.67 (s; 3H, -COOCH ₃

), 3.71 (s; 3H -OCH ₃

), 3.60-3.80 (m; 1H CH

- CH ₃

), 6.95 (d; ³

J = 8.6 Hz, 1H, aro mat.), 7.20-7.50 (m; 2H, aromat.), 7.35-7.45 / 7.70-7.80 ([AB] ₂

; ^3rd

J = 8.6 Hz, 4H, aromatic.).

2.) (3-Benzoyl-4-methoxyphenyl) cycloheptyl acetic acid methyl ester

C ₂₄

H ₂₈

O ₄

(380.48)
Yield: 19%
Mp: 101.6 ° C
IR (KBr): 2920 cm ^-1

(CH _aliphatic.

), 2845 cm ^-1

(CH _aliphatic.

), 1726 cm ^-1

(C = O, ester), 1648 cm ^-1

(C = O, ketone), 1250 cm ^-1

(C-OC), 746 cm ^-1

(CH _aromat.

), 701 cm ^-1

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 0.90-1.20 (m; 1H, cyclo hept.), 1.20-1.85 (m; 11H, cyclo hept.), 2.10-2.35 (m; 1H, cyclo hept.), 3.29 (d; ^3rd

J = 10.8 Hz, 1H, CH-CO-), 3.64 (s; 3H, -COOCH ₃

), 3.71 (s; 3H -OCH ₃

), 6.90-7.90 (m; 9H, aromat.).

3.) [3- (4-chlorobenzoyl) -4-methoxyphenyl] cycloheptyl methyl acetate

C ₂₄

H ₂₇

O ₄

Cl (414.93)
Yield: 19%
Mp: oil
IR (NaCl): 2920 cm ^-1

(CH _aliphatic.

), 1730 cm ^-1

(C = O, ester), 1664 cm ^-1

(C = O, ketone), 1490 cm ^-1

, 1257 cm ^-1

(COC), 843 cm ^-1

(CH _aromat.

), 767 cm ¹

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 0.90-1.10 (m; 1H, cyclo hept.), 1.20-1.80 (m; 11H, cyclo hept.), 2.10-2.30 (m; 1H, cyclo hept.), 3.29 (d; ^3rd

J = 10.8 Hz, 1H, CH-CO-), 3.64 (s; 3H, -COOCH ₃

), 3.71 (s; 3H -OCH ₃

), 6.94 (d; ³

J = 8.6 Hz, 1H, aromat.), 7.31 (d; ⁴

J = 2.3 Hz, 1H, aromatic., 7.40 / 7.73 ([AB] ₂

; ^{3 _years}

AB = 8.4 Hz, 4H, aromatic), 7.48 (dd; ^3rd

J = 8.6 Hz, ^4th

J = 2.3 Hz, 1H, aromatic.).

Example 30 Methyl 2- (3-benzoyl-4-hydroxyphenyl) propionate

2.75 mmol of methyl 2- (3-benzoyl-4-methoxyphenyl) propionate are dissolved in 20 ml of absolute methylene chloride and cooled to 5-30 ° C. 12 mmol of boron tribromide, dissolved in 10 ml of methylene chloride, are then slowly added dropwise. After the dropping, stirring is continued for 1.5 hours. The completeness of the reaction is monitored by thin layer chromatography (silica gel; diisopropyl ether). For working up, the reaction solution is poured into 250 ml of cold saturated sodium bicarbonate solution and extracted 3 times with ethyl acetate. The combined organic phases are washed once with saturated sodium chloride solution, dried over sodium sulfate and evaporated.
C ₁₇ H ₁₆ O ₄ (284.31)
Yield: 93%
Mp: oil
IR (NaCl): 3400 cm ^-1 -3200 cm ^-1 (OH), 2950 cm ^-1 (CH _aliphatic ), 1732 cm ^-1 (C = O, ester), 1627 cm ^-1 (C = O, ketone ).
¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.44 (d; ³ J = 7.2 Hz, 3H, CH- CH ₃ ), 3.65 (s; 3H, -COOCH ₃ ), 3.60-3.80 (m; 1H CH -CH ₃ ), 6.76 (d; ³ J = 8.5 Hz, 1H, aromat.), 7.40-7.70 (m; 7H, aromat.), 11.94 (s; 1H, -OH, exchange.).

Example 31

The following compounds were obtained analogously to Example 30.

1.) 2- [3- (4-chlorobenzoyl) -4-hydroxyphenyl] propionic acid methyl ester

C ₁₇

H ₁₅

O ₄

C1 (318.75)
Yield: 97%
Mp: oil
IR (NaCl): 3600 cm ^-1

-3200 cm ^-1

(OH), 2975 cm ^-1

(CH _aliphatic.

), 1731 cm ^-1

(C = O, ester), 1628 cm ^-1

(C = O, ketone), 1479 cm ^-1

, 1214 cm ^-1

, 840 cm ^-1

(CH _aromat.

), 782 cm ^-1

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 1.45 (d; ³

J = 7.1 Hz, 3H, CH- CH ₃

), 3.66 (s; 3H, -COOCH ₃

), 3.50-3.70 (m; 1H, CH

-CH _3rd

), 7.05 (d; ³

J = 9.2 Hz, 1H, aromat.), 7.40-7.60 (m; 2H, aromat.), 7.40-7.55 / 7.60-7.70 ([AB] ₂

; ^3rd

J = 8.5 Hz, 4H, aro mat.), 11.79 (s; 1H, -OH).

2.) (3-Benzoyl-4-hydroxyphenyl) cycloheptyl acetic acid methyl ester

C ₂₃

H ₂₆

O ₄

(366.45)
Yield: 98%
Mp: 84.8 ° C
IR (KBr): 3455 cm ¹

, wide, (OH), 2926 cm ^-1

(CH _aliphatic.

), 2851 cm ^-1

(CH _aliphatic.

), 1730 cm ^-1

(C = O, ester), 1633 cm ^-1

(C = O, ketone), 760 cm ^-1

(CH _aromat.

), 707 cm ¹

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 0.85-1.10 (m; 1H, cyclo hept.), 1.20-1.80 (m; 11H, cyclo hept.), 2.05-2.25 (m; 1H, cyclo hept.), 3.22 (d; ^3rd

J = 10.8 Hz, 1H, CH-CO-), 3.63 (s; 3H, -COOCH ₃

), 7.03 (d; ³

J = 8.3 Hz, 1H, aromatic.), 7.30-7.80 (m; 7H, aromat.), 11.90 (s; 1H, -OH).

3.) [3- (4-Chlorobenzoyl) -4-hydroxyphenyl] cycloheptyl vinegar acid methyl ester

C ₂₃

H ₂₅

O ₄

Cl (400.90)
Yield: 99%
Mp: 76.2 ° C
IR (KBr / NaCl): 3200 cm ^-1

-3000 cm ^-1

(OH), 2920 cm ^-1

(CH _aliphatic.

), 2852 cm ^-1

(CH _aliphatic.

), 1730 cm ^-1

(C = O, ester), 1627 cm ^-1

(C = O, ketone), 841 cm ^-1

(CH _aromat.

), 782 cm ¹

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 0.90-1.10 (m; 1H, cyclo hept.), 1.20-1.80 (m; 11H, cyclo hept.), 2.00-2.20 (m; 1H, cyclo hept.), 3.22 (d; ^3rd

J = 10.8 Hz, 1H, CH-CO-), 3.64 (s; 3H, -COOCH ₃

), 7.03 (d; ³

J = 9.2 Hz, 1H, aromatic.), 7.40-7.70 (m; 6H, aromat.), 11.75 (s; 1H, -OH).

Example 32 2- [3-Benzoyl-4- (quinolin-2-ylmethoxy) phenyl] propionic acid methyl ester

0.54 g (3.9 mmol) of potassium carbonate are added to the solution of 2.5 mmol of methyl 2- (3-benzoyl-4-hydroxyphenyl) propionate in 10 ml of absolute N, N-dimethylformamide and 2.5 hours at 60 ° C to 70 ° C stirred. After adding 0.56 g (2.6 mmol) of 2-chloromethylquinoline hydrochloride (suspended in 10 ml of absolute N, N-dimethylformamide), stirring is continued for 17 h. The reaction solution is poured into 250 ml of water and acidified with 1N hydrochloric acid (pH 4). The mixture is then extracted three times with ethyl acetate, the combined organic phases are then washed with water, dried over sodium sulfate and evaporated. The product is purified by column chromatography (silica gel; ethyl acetate: n-hexane = 1: 2).
C ₂₇ H ₂₃ NO ₄ (425.48)
Yield: 53%
Mp: 115 ° C
IR (KBr): 1733 cm ^-1 (C = O, ester), 1649 cm ^-1 (C = O, ketone), 1489 cm ^-1 , 1250 cm ^-1 (COC), 826 cm ^-1 (CH _aromat. ), 740 cm ^-1 (CH _aromat. ), 698 cm ¹ (CH _aromat. ).
¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.50 (d; ³ J = 7.2 Hz, 3H, CH- CH ₃ ), 3.66 (s; 3H, -COOCH ₃ ), 3.73 (q; ³ J = 7.2 Hz, 1H CH -CH ₃ ), 5.27 (s; 2H, -CH ₂ -O-), 6.92 (d; ³ J = 8.5 Hz, 1H, aromatic), 7.05 (d; ³ J = 9.2 Hz, 1H, aromat.), 7.40-8.10 (m; 12H, aromat.).

Example 33

The following compounds were obtained analogously to Example 32.

1.) 2- [3- (4-chlorobenzoyl) -4- (quinolin-2-ylmethoxy) phenyl] methyl propionate

C ₂₇

H ₂₂

NO ₄

Cl (459.93)
Yield: 59%
Mp: 81 ° C
IR (NaCl): 2975 cm ¹

(CH _aliphatic.

), 1730 cm ¹

(C = O, ester), 1659 cm ^-1

(C = O, ketone), 1488 cm ^-1

; 1245 cm ^-1

(COC), 842 cm ^-1

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 1.50 (d; ³

J = 7.2 Hz, 3H, CH- CH ₃

), 3.67 (s; 3H, -COOCH ₃

), 3.73 (q; ³

J = 7.2 Hz, 1H CH

-CH _3rd

), 5.28 (s; 2H, -CH ₂

-O-), 6.90-7.10 (m; 2H, aro mat.), 7.35-7.50 (m; 4H, aromatic), 7.50-7.60 (m; 1H, aromatic), 7.65-7.75 (m; 1H, aromat.), 7.75-7.85 (m; 3H, aromatic), 7.95-8.05 (m; 2H, aro mat.).

2.) [3-Benzoyl-4- (quinolin-2-ylmethoxy) phenyl] cycloheptyl methyl acetate

C ₃₃

H ₃₃

NO ₄

(507.63)
Yield: 59%
Mp: 120.7 ° C
IR (KBr): 2927 cm ¹

(CH _aliphatic.

), 2850 cm ^-1

(CH _aliphatic.

), 1724 cm ^-1

(C = O, ester), 1656 cm ^-1

(C = O, ketone), 1250 cm ^-1

(C-OC), 821 cm ^-1

(CH _aromat.

), 705 cm ^-1

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 0.80-1.80 (m; 12H, -CH ₂

-, cyclohept.), 2.10-2.35 (m; 1H, CH-, cyclohept.), 3.32 (d; ³

J = 10.8 Hz, 1H, CH-CO-), 3.64 (s; 3H, -COOCH ₃

), 5.29 (s; 2H, -CH ₂

-O-), 6.90-7.10 (m; 2H, aromatic), 7.25-8.10 (m; 12H, aromat.).

3.) [3- (4-chlorobenzoyl) -4- (quinolin-2-ylmethoxy) phenyl] cycloheptyl acetic acid methyl ester

C ₃₃

H ₃₂

NO ₄

Cl (542.07)
Yield: 60%
Mp: oil; amorphous after foaming
IR (KBr): 2920 cm ^-1

(CH _aliphatic.

), 2850 (CH _aliphatic.

), 1728 cm ^-1

(C = O, ester), 1660 cm ^-1

(C = O, ketone), 1487 cm ^-1

, 821 cm ^-1

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 0.90-1.80 (m; 12H, -CH ₂

-, cyclohept.), 2.10-2.30 (m; 1H, CH-, cyclohept.), 3.31 (d; ³

J = 10.8 Hz, 1H, CH-CO-), 3.65 (s; 3H, -COOCH ₃

), 5.29 (s; 2H, -CH ₂

-O-), 6.95-7.10 (m; 2H, aromatic), 7.35-8.10 (m; 11H, aromat.).

Example 34 2- [3-Benzoyl-4- (quinolin-2-ylmethoxy) phenyl] propionic acid

300 mg (0.7 mmol) of methyl 2- [3-benzoyl-4- (2-quinolinylmethoxy) phenyl] propionate are heated at 60 ° C. for 2.5 h in 30 ml of methanol and 1.5 ml of 1 M sodium hydroxide solution. Most of the solvent is removed and water is added to the residue. After acidification to pH 5.5 with 1N hydrochloric acid, the precipitate is filtered off, washed with water and dried. A white residual substance is obtained.
C ₂₆ H ₂₁ NO ₄ (411.45)
Yield: 79%
Mp: 142.4 ° C
IR (KBr): 3500 cm ^-1 -2300 cm ^-1 (OH), 1713 cm ^-1 (C = O), 1651 cm ^-1 (C = O, ketone), 1488 cm ^-1 , 1250 cm ^-1 ( COC), 827 cm ^-1 (CH _aromat. ), 742 cm ^-1 (CH _aromat. ), 698 cm ^-1 (CH _aromat. ).
¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.56 (d; ³ J = 7.1 Hz, 3H, CH- CH ₃ ), 3.81 (q; ³ J = 7.1 Hz, 1H CH -CH ₃ ), 5.27 (AB; 2H, -CH ₂ -O-), 6.87 (d; ³ J = 8.6 Hz, 1H, quinol.), 7.05 (d; ³ J = 8.6 Hz, 1H, aromat.), 7.30-8.20 (m ; 12H, aro mat.).

Example 35

The following compounds were obtained analogously to Example 34.  

1.) [3-Benzoyl-4- (quinolin-2-ylmethoxy) phenyl] cycloheptyl acetic acid

C ₃₂

H ₃₁

NO ₄

(493.60)
Yield: 17%
Mp: 113.4 ° C
IR (NaCl): 3400 cm ^-1

-2700 cm ^-1

(OH), 2925 cm ^-1

(CH _aliphatic.

), 2854 cm ^-1

(CH _aliphatic.

), 1705 cm ^-1

(C = O, ester), 1664 cm ^-1

(C = O, ketone), 1250 cm ^-1

(COC), 829 cm ^-1

(CH aromat.), 733 cm ^-1

(CH _aromat.

).
¹

H-NMR (CDCl ₃

): δ (ppm) = 0.80-2.00 (m; 12H, -CH ₂

-, cyclohept.), 2.10-2.40 (m; 1H, CH-, cyclohept.), 3.37 (d; ³

J = 10.8 Hz, 1H, CH-CO-), 5.27 / 5.38 (AB; ^J

AB = 13.9 Hz, 2H, -CH ₂

-O-), 6.90-7.15 (m; 2H, aromat.), 7.20-8.20 (m; 13H, aromat., -COOH).

2. 2- [3- (4-chlorobenzoyl) -4- (quinolin-2-ylmethoxy) phenyl] - propionic acid

C ₂₆

H ₂₀

NO ₄

Cl (445.90)
Yield: 69%
Mp: 134.8 ° C
IR (KBr): 3500 cm ^-1

-2800 cm ^-1

(OH), 1704 cm ^-1

(C = O), 1659 cm ^-1

(C = O).
¹

H-NMR (CDCl ₃

): δ (ppm) = 1.53 (d; ³

J = 7.1 Hz, 3H, CH- CH ₃

), 3.84 (q; ³

J = 7.1 Hz, 1H CH

-CH _3rd

), 5.77 (AB: ^J

AB = 13.8 Hz, 2H, -CH ₂

-O-), 6.80-8.20 (m; 13H, aro mat.).

Claims (11)

1. Compounds of the general formula I:
wherein
R ^{1 represents} a hydrogen atom, a C ₁ -C ₆ alkyl, aryl, benzyl or benzoyl group, the aryl group, the phenyl radical of the benzyl group or the benzoyl group optionally being substituted by one or two radicals which are independent of one another selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, trifluoromethyl and Hal-C ₁ -C ₄ alkyl;
R ^{2 represents} -CHR ³ R ⁴ , -CONR ⁹ R ⁵ , -NHCOR ⁶ or CONR ⁹ COR ⁶ ;
R ^{3 represents} a hydrogen atom, a C ₁ -C ₈ alkyl or C ₅ -C ₈ cycloalkyl group;
R ^{4 is} -CONR ⁹ R ⁵ , -CONR ⁹ -COR ⁶ , COOH or COOC ₁ -C ₆ alkyl, where R ¹ cannot represent a hydrogen atom if R ^{4 is} COOH or COOC ₁ -C ₆ alkyl stands;
R ^{5 represents} -SO ₂ - (C ₁ -C ₆ ) alkylene-SO ₂ -NR ⁹ -COR ⁶ or -SO ₂ -aryl-SO ₂ -NR ⁹ -COR ⁶ ;
R ^{6 stands} for the remainder of a cyclooxygenase inhibitor with a COX group (X = OH or optionally substituted NH ₂ ), which results from removal of the COX group,
R ^7, R ^8, which may be the same or different, are H, C ₁ - C -C ₄ alkyl, C _{1 -C 4} alkoxy or halogen;
R ^{9 represents} H or C ₁ -C ₄ alkyl and the physiologically tolerable salts, solvates and hydrates thereof. 2. Compounds according to claim 1 of formula I, wherein R ^{1 represents} a hydrogen atom or a benzoyl group, which may be by halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, trifluoromethyl or Hal-C ₁ -C ₄ alkyl is substituted. 3. Compounds according to claim 1 or 2 of formula I, wherein R ^{2 is} CHR ³ R ⁴ , R ^{4 is} CONHR ⁵ , NHCOR ⁶ or CONHCOR ⁶ and R ³ and R ^{6 have} the meaning given in claim 1. 4. Compounds according to any one of the preceding claims of formula I, wherein R ^{6 represents} a radical of the following formulas:
wherein
R ^{9 has} the meanings given in claim 1;
R ^{10 represents} H or C ₁ -C ₄ alkyl;
R ^{11 represents} halogen or trifluoromethyl;
R ^{12 represents} C ₁ -C ₄ alkyl; and
R ^{13 represents} H, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy. 5. Compounds according to claim 4, wherein R ^{6 represents} a radical of the following formulas:
6. Compounds according to claim 4 or 5, wherein
R ^{1 represents} a hydrogen atom,
R ^{2 represents} CHR ³ R ⁴ ,
R ^{3 represents} H, C ₁ -C ₆ alkyl or C ₅ -C ₇ cycloalkyl,
R ^{4 stands} for CONH-COR ⁶ or CONHR ⁵
R ^{5 has} the meanings given in claim 1 and
R ⁷ and R ^{8 represent} a hydrogen atom. 7. A compound according to claim 4 or 5, wherein
R ^{1 represents} a hydrogen atom,
R ^{2 stands} for NHCOR ⁶ or CONHCOR ⁶ and
R ⁷ and R ^{8 represent} a hydrogen atom. 8. Compounds according to claim 1, wherein
R ^{1 represents} a C ₁ -C ₆ alkyl, aryl, benzyl or benzoyl group, the aryl group, the phenyl radical of the benzyl group or the benzoyl group optionally being substituted by one or two radicals which are selected independently of one another from halogen , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, trifluoromethyl and Hal-C ₁ -C ₄ alkyl;
R ^{2 is} CHR ³ R ⁴ ;
R ^{3 represents} H, C ₁ -C ₆ alkyl or C ₅ -C ₇ cycloalkyl;
R ^{4 represents} COOH or COOC ₁ -C ₆ alkyl; and
R ⁷ and R ⁸ , which may be the same or different, represent H or C ₁ -C ₄ alkyl. 9. Compounds according to claim 8, wherein R ^{1 represents} a benzyl or benzoyl group, the phenyl radical of the benzyl group or the benzoyl group optionally being substituted by one or two halogens. 10. Pharmaceutical composition containing at least one verb dung of formula I according to one of claims 1 to 9, given if necessary together with usual auxiliary substances. 11. Use of at least one connection according to one of the An claims 1 to 9 for the manufacture of a pharmaceutical co for thrombosis prophylaxis and prophylaxis of the anaphy lactic shocks or to treat dermatological er diseases, diseases of the rheumatic type, Pain, asthma, allergic reactions and inflammatory Intestinal diseases.