US20030130232A1

US20030130232A1 - Amidine derivatives, the preparation and use thereof as medicaments with LTB4 antagonistic effect

Info

Publication number: US20030130232A1
Application number: US10/252,976
Authority: US
Inventors: Ralf Anderskewitz; Kurt Schromm; Ernst-Otto Renth; Frank Himmelsbach; Franz Birke; Armin Fugner
Original assignee: Boehringer Ingelheim GmbH
Current assignee: Boehringer Ingelheim GmbH
Priority date: 1992-02-05
Filing date: 2002-09-23
Publication date: 2003-07-10
Also published as: RU2124002C1; DE59309630D1; YU49038B; AU3349793A; MX9300630A; EP0902013B1; KR0163222B1; CZ287209B6; CA2427890A1; ATE210634T1; IL104589A0; CA2129526A1; ES2132216T3; JP3487851B2; RU94041836A; SI9300066A; SK281016B6; SI9300066B; NO942903L; JP2002322143A

Abstract

Compounds of the formula

which is explained more fully in the specification, may be prepared by conventional methods and used therapeutically in conventional galenic preparations.

Description

The invention relates to new amidine derivatives, the preparation thereof using conventional methods and their use in pharmaceutical compositions.

The new amidine derivatives correspond to the formula

wherein

R ₁and R₂, which may be identical or different, denote CF₃, halogen, R₅, OR₅, COR₆, SR₆, SOR₆, SO₂R₆, SO₂NR₅R₇, C(OH)R₅R₇or together may also denote the double-bonded groups —CR₈═CR₉—CH═CH—, —CH═CR₈—C₉═CH—, —CR₈═CH—CR₉═CH—, —O—CHR₁₀—CH₂—, —O—CH₂—O—, —O—CH₂—CH₂—O—, —(CH₂)_3-4—, —NH—CO—O—, —NH—CO—CH₂—O—, —CO—CH₂—O— or —CO—CH₂CH₂—O—, linked with adjacent carbon atoms of the benzene ring, whilst these groups nay in turn be substituted by C_1-4-alkyl,

R ₃denotes halogen, OH, CF₃, R₅, OR₆, COR₆, CONH₅R₇, CH₂OH, CH₂—O—(C_1-4-alkyl), SR₆, SOR₆, SO₂R₆, SO₂NR₅R₇, NH—CO—(C_1-4-alkyl), NH—SO₂—(C_1-4-alkyl), NR₅R₇or C(OH)R₅R₇(whilst if R₃is the same as R₅, R₅can only denote H if at least one of the substituents R₁and R₂does not denote H), a heterocyclic 5-membered ring having 1 to 3 heteroatoms and of the formula

(wherein D, E and G, which may be identical or different, denote CH, N, C—(C _1-4-alkyl) or C-phenyl and L denotes O or S),

R ₄denotes halogen, NH₂, NH—(C_1-4-alkyl), N(C_1-4-alkyl)₂, OH, C_1-4-alkoxy,

R ₅denotes H, C_1-12-alkyl, phenyl, phenyl optionally substituted by halogen, C_1-4-alkyl, C_1-4-alkoxy or C_2-5-acyl, or phenyl—(C_1-4-alkyl),

R ₆denotes C_1-12-alkyl, phenyl, or phenyl optionally substituted by halogen, C_1-4-alkyl, C_1-4-alkoxy or C₂-C₅-acyl,

R ₇denotes H or C_1-12-alkyl,

R ₈, R₉(which may be identical or different) denote H, OH, C_1-4-alkyl, C_1-4-alkoxy or C_2-5-acyl,

R ₁₀denotes H or C_1-4-alkyl,

R ₁₁, R₁₂, which may be identical or different, denote H, OH, halogen, CF₃, C_1-4-alkyl or C_1-4-alkoxy,

A denotes one of the groups

X₁-A₁-X₂ (II)

X₂-A₂-X₃ (III)

X₄-A₂-X₂ (IV)

(CH₂)_1-2—NH—CO—(CH₂)_1-3—X₂ (V)

—CH═CH-A₂-X₂ (VI)

B

A ₁denotes C_2-4-alkylene, cis- or trans-CH₂—CH═CH—CH₂, CH₂—C≡C—CH₂or

A ₂denotes C_1-5-alkylene,

X ₁denotes O, NH, S, SO, SO₂, CO, CH₂or

X ₂denotes O, NH, S or —O—

X ₃denotes NH—CO, CO—NH, SO₂—NH or

X ₄denotes NH—CO, CO—NH, NH—SO₂, SO₂—NH or NH—CO—NH, and (if they contain one or more chiral centres), may occur in the form of racemates, in enantiomerically pure or concentrated form, possibly as pairs of diastereomers and (if a double bond is present) in cis- or trans-form and as free bases or as salts, preferably with physiologically acceptable acids.

Within the scope of the above definitions, the preferred compounds are the compounds of formula

wherein

R ₁, R₂, which may be identical or different, denote R₇, OR₇, COR₆, halogen or together denote the double bonded groups —CR₈═R₉—CH═CH—, —CH═CR₈—CR₉═CH—, —O—CHR₁₀—CH₂— or —CO—CH₂—CH₂—O—, linked with adjacent carbon atoms of the benzene ring,

R ₃denotes halogen, CF₃, R₇, OR₇, CO—(C_1-4-alkyl), NH—CO—(C_1-4-alkyl), NHSO₂—(C_1-4-alkyl) or N(R₁₀)₂(whilst R₇can only denote H if at least one of the substituents R₁and R₂does not denote H) or a heterocyclic five-membered ring such as

R ₆and R₇are as hereinbefore defined, and

A denotes the group II.

The following may be particularly mentioned as examples of the group of formula —C ₆H₂R₁R₂R₃:

Of the definitions of A particular mention may be made of:

Special mention should also be made of the compounds of formula

wherein

a denotes 0 or 1,

b denotes 1 or 2,

R denotes C _1-4-alkyl, and if a=0 or 1 and b=1, and if a=1 and b=2, R may also denote hydrogen, and

R preferably denotes CH ₃, C₂H₅or H, and for a=1, b is preferably 1.

In the above definitions, the term halogen denotes F, Cl, Br or I, preferably F, Cl. If the groups listed are alkyl chains or contain alkyl chains, these may be straight-chained or branched. The alkyl chains in R ₅, R₆and R₇preferably contain up to 6 carbon atoms, more particularly 1 to 4 carbon atoms. In particular, as a constituent of COR₆, R₆denoting alkyl may also be mono- or poly-fluorine-substituted. Particular examples of substituents of ring systems are alkyls such as methyl, ethyl and the propyl. A preferred acyl group is COCH₃, a preferred alkoxy group is CH₃O. The bridge A preferably contains 4 to 6 members. The group is arranged between the two ring systems in formula I and in corresponding formulae so as to correspond to the written form of formulae II to VI, whereas the groups which are valid for both R₁and R₂are not listed in the proper orientation. If R₁and R₂together denote a double bonded group, R₃preferably denotes H or C_2-5-acyl, e.g. acetyl. The groups R₁, R₂and R₃should not all simultaneously denote CF₃, COR₆, SR₆, SOR₆, SO₂R₆, SO₂NR₅R₇or C(OH)R₅R₇, but rather these groups as well as OR₅, with the definition phenoxy or substituted phenoxy, preferably occur only once or possibly twice, whilst alkyl, acyl and halogen, in particular, may occur as further substituents. The bonds or CH₂groups in IX/IXa/IXb are generally in the α-position to one another. Typical groups for A are, for example, O—(CH₂)₂—O, O—(CH₂)₄—O, whilst one of the O-atoms may be replaced by S, NH or Co, as well as groups such as CH₂—CH₂—CONH, CH₂—CH₂—NH—CO, CO—NH—CH₂—CH₂or NH—CO—CH₂—CH₂. The amidino group is usually in the para-position relative to the carbon atom to which A is linked.

The new compounds are prepared by conventional methods.

1. Reaction of imidoesters of the formula

wherein R ₁to R₄, A and B are as hereinbefore defined and R preferably represents a C_1-6-alkyl group or benzyl (but if desired the man skilled in the art can also use derivatives of other alcohols), and ammonia. The reaction is preferably carried out in an organic solvent at temperatures between about 0° C. and the boiling temperature of the reaction mixture, preferably between ambient temperature and about 100° C. or the boiling temperature, if this is lower. Suitable solvents are polar solvents such as methanol, ethanol and propanol.

If the starting materials are sufficiently acid-resistant the reaction may be carried out via the corresponding acid imide chlorides instead of the imidoesters.

2. In order to prepare compounds of formula I wherein A is linked via O or S to at least one of the ring systems:

reaction

(a) of a phenol or thiophenol of formula

wherein Z denotes OH or SH and R ₁, R₂and R₃are as hereinbefore defined, with a compound of the formula

wherein A ₁, A₂, B, R₄, X₂and X₃are as hereinbefore defined and L represents a nucleofugic leaving group, or

(b) of a phenol or thiophenol of the formula

wherein B, R ₄and Z are as hereinbefore defined, with a compound of the formula

wherein A ₁, A₂, R₁, R₂, R₃and Z are as hereinbefore defined.

The reaction is carried out in aprotic solvents such as dimethylsulphoxide, dimethylformamide, acetonitrile or alcohols such as methanol, ethanol or propanol with the addition of a base (metal carbonates, metal hydroxides, metal hydrides) at temperatures between about 0 and 140° C. or the boiling temperature of the reaction mixture.

The phenols or thiophenols may also be used in the form of salts, e.g. alkali metal salts. Examples of suitable nucleofugic leaving groups include halogens such as Br and Cl.

3. Reduction of an amidoxime of the formula

wherein A, B and R ₁to R₄are as hereinbefore defined.

For the reduction of XIX it is appropriate to use catalytic hydrogenation, particularly with Raney nickel in a lower alcohol such as methanol. Conveniently, the amidoxime of formula XIX is dissolved in methanol, with the addition of the calculated amount of the particular acid the salt of which is the desired end product, and hydrogenated at ambient temperature under gentle pressure, e.g. up to 5 bar, until the uptake of hydrogen has ended.

The starting materials may be obtained from known compounds by conventional methods.

Thus, the starting materials for process 1 may be obtained from the corresponding nitriles by reacting them with HCl via the step of the imide chlorides or directly by reacting them with, for example, C _1-6-alcohols or benzyl alcohol in the presence of an acid such as HCl. The reaction of the nitrites with H₂S in solvents such as pyridine or dimethylformamide in the presence of a base such as triethylamine and subsequent alkylation or benzylation result in compounds of formula X. Starting from carboxylic acid amides, which moreover correspond to the compounds of formula X, compounds of formula X may also be obtained by reaction with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate, in a solvent such as dichloromethane, tetrahydrofuran or dioxane at temperatures between 0 and 50° C., preferably at ambient temperature.

The starting materials XIX may also be obtained by reacting corresponding amidoximes instead of amidine analogously to method 1 or 2; by analogous reaction of corresponding nitrites from which the starting materials XIX are finally obtained by the addition of hydroxylamine.

The compounds according to the invention are therapeutically useful, particularly in the light of their LTB ₄-antagonistic activity. They are therefore suitable for use, particularly, in those diseases in which inflammatory and/or allergic processes are involved, such as asthma, ulcerative colitis, psoriasis and also for treating gastropathy induced by non-steroidal antiphlogistics. The new compounds may also be used in conjunction with other active substances, e.g. antiallergics, secretolytics, β₂-adrenergics, steroids for inhalation, antihistamines and/or PAF-antagonists. They may be administered by topical, oral, transdermal, nasal or parenteral route or by inhalation.

The therapeutic or prophylactic dose is dependent on the nature and gravity of the disease, as well as the potency of the individual compounds and the body weight of the patient. For oral administration the dose is between 10 and 250 mg, preferably between 20 and 200 mg. For inhalation, the patient takes between about 2 and 20 mg of active substance. The new compounds may be administered in conventional preparations such as or coated tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups, aerosols for inhalation, ointments and suppositories.

The Examples which follow illustrate some possible formulations for the preparations.

FORMULATION EXAMPLES

[0061]

1. Tablets

Composition:

Active substance according to 20 parts by weight

the invention

Stearic acid 6 parts by weight

Dextrose 474 parts by weight
The constituents are processed in the usual way to form tablets weighing 500 mg. If desired, the content of active substance may be increased or reduced and the quantity of dextrose reduced or increased accordingly. [0062]

2. Suppositories

Composition:

Active substance according to 100 parts by weight

the invention

Powdered lactose 45 parts by weight

Cocoa butter 1555 parts by weight
The ingredients are processed in the usual way to form suppositories weighing 1.7 g. [0063]
3. Powder for inhalation [0064]
Micronised powdered active substance (compound of formula I; particle size about 0.5 to 7 μm) is packed into hard gelatine capsules in a quantity of 5 mg, optionally with the addition of micronised lactose. The powder is inhaled using conventional inhalation devices, e.g. according to DE-A 3 345 722. [0065]
The compounds according to the invention were tested inter alia for their activity in the tests described below. [0066]
a) U937—Receptor Binding Test/LTB[0067] ₄
The binding of [0068] ³H-LTB₄(3 nM) to vital U937 cells (differentiated human monocytary cell line with naturally expressed LTB₄receptors) is inhibited, in dosage dependent manner, by an increasing concentration of the test substance (incubation 2 hours at 0° C.). After the unbound ³H-LTB₄has been separated off by membrane filtration, the radioactivity of the bound LTB₄receptor/³H-LTB₄g complex is quantified by scintillation measurement. The affinity (inhibition constant K_l) was determined by repeated adaptation of a displacement curve to the measurements (program: “coupled mass equilibria” on Wang computer).
b) Aggregation of Neutrophilic Granulocytes in the Guinea-Pig [0069]
Indicated by LTB[0070] ₄in vitro (increase in light transmission in the aggregometer, recorded in mm; each experiment repeated twice): inhibition 2 minutes after incubation with test substance in polydiol/DMSO.
c) Leukotrien-B[0071] ₄-Indicated Accumulation of Neutrophiles in the Mouse Ear
Evaluation of the neutrophilic influx by photometric measurement (mOD/min) of the myeloperoxidase activity (Bradley et al.: J. Invest. Dermatol. 78, 206, 1982) in the skin of the ear. Increase 6 hours after topical treatment of the left ear with LTB[0072] ₄(250 ng on each side) compared with the right ear (2×5 μl acetone as solvent).
Substance administered by oral route in 1% tylose 300, 30 minutes before the LTB[0073] ₄stimularion.

4. Results

a)* b)** c)***

12.0 1.9 0.8

3.8 6.3 0.06 0.31 1.2 0.9

R = H

R = CH₃

1.7 15.0 0.02 0.32 3.8 2.3

R = H

R = CH₃
The [0074] ³H-LTB₄-receptor binding to guinea-pig spleen cells, in the presence of 10% blood plasma yielded K_l-values of, in some cases, far less than 1 μM, more particularly between 0.2 and 0.02. Inhibition of the LTB₄-induced aggregation of neutrophiles resulted in EC₅₀-values between about 0.5 and 0.05 μM.
Particular mention should be made of the compounds according to Examples 1 and 5 and Nos. 10, 11, 13, 19, 20, 22 and 23 from Table I, No. 1 from Table II, No. 2 from Table III. [0075]
The Examples which follow illustrate the possible methods of preparing the-compounds according to the invention. [0076]
Process 1: [0077]

Example 1

[0078]
To a solution of 2.0 g of 7-[4-(4-cyano-phenoxy)-E-but(2 )-enyloxy)]-8-propyl-4H-1-benzopyran-4-one in 50 ml of chloroform and 1.5 ml of ethanol are added 5 ml of a solution of hydrogen chloride in diethylether (17%). The mixture is left to stand for 14 days at ambient temperature and the product is precipitated with diethylether. 1.15 g of 7-[4-(4-imidacarboxyethyl-phenoxy)-E-but (2)-enyloxy]-8-propyl-4H-1-benzopyran-4-one-hydrochloride are obtained. The imidoester is mixed with 50 ml of ethanolic ammonia solution (5 M) and heated for 3 hours to 70° C. The mixture is evaporated down and the residue is chromatographed (chloroform/methanol 7:3, silica gel). After recrystallisation from dichloromethane/diethylether, 0.6 g of 7-[4-(4-amidino-phenoxy)-E-but(2)-enyloxy]-8-propyl-4H-1-benzopyran-4-one-hydrochloride are obtained (m.p. 144-148° C.). [0079]

Example 2

To a solution of 2.5 g of 4-[4-(2-propyl-3-methoxy-phenoxy)-butyloxyl-benzonitrile, prepared from 2-propyl-3-methoxy-phenol and 4-bromobutoxybenzonitrile- in 40 ml of ethanol, hydrogen chloride is introduced at −20° C. with stirring for 1 hour and the mixture is left to stand at ambient temperature for 16 hours. [0080]
The solvent is distilled off in vacuo and the residue is taken up in 50 ml of ethanol. A mixture of 14 ml of ethanolic ammonia solution and 50 ml of ethanol is added dropwise thereto and the mixture is left to stand for 24 hours at ambient temperature. The solvent is evaporated off and the residue is chromatographed (chloroform/methanol 8:2; silica gel 60). 1.8 g of 4-[4-(2-propyl-3-methoxy-phenoxy)-butyloxy]-benzamidine-hydrochloride-hemihydrate are obtained. (M.p. 117-121° C.). [0081]

Example 3

[0082]
Hydrogen chloride is introduced at −20° C. into a solution of 32.0 g of 4-((4-acetyl-2-isopropyl-5-methyl-phenoxy)-butyloxy]-benzonitrile in 350 ml of ethanol and the resulting mixture is stirred for 48 hours. The crystals precipitated are suction filtered and washed with diethylether. 41.0 g of 4-[4-(4-acetyl-2-isopropyl-5-methyl-phenoxy)-butyloxy]-benzimidoethylester-hydrochloride are obtained (m.p. 100-102° C. decomp.). 15.0 g of the imidoester are added at ambient temperature in several batches to 33 ml of ethanolic ammonia solution (5 M) and 100 ml of ethanol. The mixture is stirred for 36 hours at ambient temperature, evaporated down and the residue is stirred with 50 ml of water. The residue is suction filtered, recrystallised from 30 ml of ethanol and washed with diethylether. 11.5 g of 4-[4-(4-acetyl-2-isopropyl-5-methyl-phenoxy)-butyloxy]-benzamidine-hydrochloride are obtained (m.p. 182-183° C. decomp.). [0083]

Example 4

[0084]
Hydrogen chloride is introduced at −20° C. into a solution of 3.0 g of 4-[4-(4-cyano-phenoxy)-butylamino]-acetophenone in 40 ml of ethanol, with stirring, for 4 hours and the mixture is left to stand at ambient temperature for 16 hours. The solvent is distilled off in vacuo and the residue is taken up in 50 ml of ethanol. A mixture of 14 ml of ethanolic ammonia solution and 50 ml of ethanol is added dropwise thereto and the mixture is left to stand for 24 hours at ambient temperature. The solvent is evaporated off and the residue is chromatographed (chloroform/methanol 7:3, silica gel 60). 0.3 g of 4-[4-(4-amidino-phenoxy)butylamino]-acetophenone are obtained (m.p. 200-202° C.). [0085]
Process 2: [0086]

Example 6

[0087]
8.2 g of 4-acetyl-3-methoxy-2-propyl-phenol are dissolved in 80 ml of dimethylformamide and 1.1 g of sodium hydride is added in batches to the solution (as an 80% dispersion in white oil). The mixture is heated to 80° C. for 30 minutes and combined with a solution of 5.75 g oft 4-(4-bronopropylthio)-benzamidine (prepared from dibromobutane and 4-cyanobenzothiol by means of 4-(4-bromobutyl-thio)-benzonitrile) in 40 ml of dimethylformamide. After 5 hours at 80° C. the mixture is allowed to cool, acidified with ethereal hydrochloric acid and the solvents are distilled off in vacuo. The residue is taken up in ethanol and filtered. The filtrate is concentrated by evaporation. The process is repeated with chloroform and acetonitrile. The residue is stirred with diethylether. After decanting, 5.65 g of a brownish-yellow oil are left. The product is chromatographed (chloroform/methanol 7:3, silica gel). 2.4 g of an oil are obtained which is crystallised from toluene. The product is dissolved in acetonitrile, acidified with ethereal hydrochloric acid. The crystals are suction filtered, washed with cold acetonitrile, dissolved in water and crystallised once more after the addition of 2 N hydrochloric acid. 0.8 g of 4-[4-4-acetyl-3-methoxy-2-propylphenoxy)-butylthio]-benzamidine-hydrochloride are obtained (m.p. 120-122° C.). [0088]
Process 3: [0089]

Example 7

a) 4-[4-(4-Acetylphenoxy-butoxy]-benzamidoxime [0090]
45.6 g (0.3 mol) of 4-hydroxybenzamidoxime and 81.3 g (0.3 mol). of 4-bromo-butoxy-acetophenone are dissolved in 300 ml of dimethylformamide. After the addition of 55.2 g (0.4 mol) of anhydrous potassium carbonate the mixture is heated to 80° C. for 2 hours. The inorganic salts are suction filtered, evaporated down in vacuo and recrystallised from acetonitrile. [0091]
Yield: 47.8 g [0092]
M.p.: 164.5-165.5° C. [0093]
b) 3-[4-(4-Acetylphenoxy)butoxy]-benzamidine-methanesulphonate [0094]
47.8 g of the compound synthesised according to a) are dissolved in 10 times the quantity of methanol with the addition of the calculated amount of methanesulphonic acid. After the addition of Raney nickel, the mixture is hydrogenated at 5 bar until the uptake of hydrogen has ended. The mixture is suction filtered, the solvent is distilled off in vacuo and the residue is recrystallised from ethanol. [0095]
Yield: 45.2 g [0096]
M.p.: 204-204.5° C. [0097]

The-other-compounds of formula I can be obtained according to the processes described above. “Ac” hereinafter denotes CH ₃CO—.

TABLE I


Compounds of formula

			M.p.[° C.]
			(Hydro-
No.	R_a	b	chloride)


1		2	240

2		2	209-10

3		4

4		4	143

5		4	124

6		4	190

7		4	199-4

8		4	189

9		4	125-31

10		4	148-50

11		4	132-40

12		4	160-3

13		4	160-5

14		4	228-31

15		4	140-6

16		4

17		4	170-2

18		4	149-50

19		4	167 (decomp.)

20		4	179

21		4	168-70

	CH₃

22		4	187 (decomp.)

23		4	166-8

24		4

25		4

26		4

27		4

28		4

29		4	174-5

30		4	155-60

31		4	194-60

32		4	214-23

33		4

34		4

35		4	145-8

36		4	128-31

37		4

38		4

39		4

40		4	194

41		6	132

42		4

43		4

44		4

TABLE II


Compounds of formula

					M.p.[° C.]
No.	B	R₁	X₁	X₂	(Hydrochloride)

1	CH═CH	Ac	O	S
2	CH═CH	Ac	O	SO
3	CH═CH	Ac	O	SO₂	160-2 (Base)
4	CH═CH	Ac	S	S
5	N═CH	Ac	O	S	152-60
6	CH═CH	Ac	O	NH	200-2
7	CH═CH	Ac	S	O	196-
8	CH═CH	Ac	SO	O
9	CH═CH	Ac	SO₂	O	208

[0100]

TABLE III

Compounds of formula

M.p.[° C.]

No. A′ X′₁ X′₂ (Hydrochloride)

1 CH₂—CH═CH—CH₂ O O 215-8

2
O O 196-202

3
O O 205-9

4
O O 183

TABLE IV


Compounds of formula

					M.p.[° C.]
No.	R_b	R₁	R₂	R₄	(Hydrochloride)


1		H	H	H

2		H	H	H	174-6

3		n-C₃H₇	OCH₃	2-OCH₃	124-7

No.	R	a	b	M.p.[° C.]

1	H	0	1	178-80 (Hydrochloride)
2	H	1	1	248-51 (Hydrochloride)
3	H	1	2
4	CH₃	0	1	176-8 (Hydrochloride)
5	CH₃	1	1	236-40 (Methanesulphonate)
6	C₂H₅	0	1
7	C₂H₅	0	2
8	n-C₃H₇	0	2
9	n-C₃H₇
10	i-C₃H₇	1	1
11	n-C₄H₉	0	1	144-7 (Hydrochloride)
12	n-C₄H₉	0	2

Claims

1. Compounds of the formula

wherein

R₁and R₂, which may be identical or different, denote CF₃, halogen, R₅, OR₅, COR₆, SR₆, SOR₆, SO₂R₆, SO₂NR₅R₇, C(OH)R₅R₇or together may also denote the double-bonded groups —CR₈═CR₉—CH═CH—, —CH═CR₈—CR₉═CH—, —O—CHR₁₀—CH₂—, —O—CH₂—O—, —O—CH₂—CH₂—O—, —(CH₂)_3-4—, —NH—CO—O—, —NH—CO—CH₂—O—, —CO—CH₂—O— or —CO—CH₂CH₂—O—, linked with adjacent carbon atoms of the benzene ring, whilst these groups may in turn be substituted by C_1-4-alkyl,

R₃denotes halogen, OH, CF₃, R₅, OR₆, COR₆, CONH₅R₇, CH₂OH, CH₂—O—(C_1-4-alkyl), SR₆, SOR₆, SO₂R₆, SO₂NR₅R₇, NH—CO—(C_1-4-alkyl), NH—SO₂—(C_1-4-alkyl), NR₅R₇or C(OH)R₅R₇(whilst if R₃is the same as R₅, R₅can only denote H if at least one of the substituents R₁and R₂does not denote H), a heterocyclic 5-membered ring having 1 to 3 heteroatoms and of the formula

(wherein D, E and G, which may be identical or different, denote CH, N, C—(C_1-4-alkyl) or C-phenyl and L denotes O or S),

R₄denotes halogen, NH₂, NH—(C_1-4-alkyl), N(C_1-4-alkyl)₂, OH, C_1-4-alkoxy,

R₅denotes H, C_1-12-alkyl, phenyl, phenyl optionally substituted by halogen, C_1-4-alkyl, C_1-4-alkoxy or C_2-5-acyl, or phenyl-(C_1-4-alkyl),

R₆denotes C_1-12-alkyl, phenyl, or phenyl optionally substituted by halogen, C_1-4-alkyl, C_1-4-alkoxy or C₂-C₅-acyl,

R₇denotes H or C_1-12-alkyl,

R₈, R₉(which may be identical or different) denote H, OH, C_1-4-alkyl, C_1-4-alkoxy or C_2-5-acyl,

R₁₀denotes H or C_1-4-alkyl,

R₁₁, R₁₂, which may be identical or different, denote H, OH, halogen, CF₃, C_1-4-alkyl or C_1-4-alkoxy,

A denotes one of the groups

X₁-A₁-X₂ (II) X₂-A₂-X₃ (III) X₄-A₂-X₂ (IV) (CH₂)_1-2—NH—CO—(CH₂)_1-3—X₂ (V) —CH═CH-A₂-X₂ (VI)

B denotes CH═CH, CH═N, S or

A₁denotes C_2-4-alkylene, cis- or trans-CH₂—CH═CH—CH₂, CH₂—C≡C—CH₂or

A₂denotes C_1-5-alkylene,

X₁denotes O, NH, S, SO, SO₂, CO, CH₂or

X₂denotes O, NH, S or

X₃denotes NH—CO, CO—NH, SO₂—NH or

X₄denotes NH—CO, CO—NH, NH—SO₂, SO₂—NH or NH—CO—NH,

as racemates, in enantiomerically pure or concentrated form, possibly as pairs of diastereomers and in cis- or trans-form and as free bases or as salts, preferably with physiologically acceptable acids.

2. Compounds of the formula

wherein

R₁, R₂, which may be identical or different, denote R₇, OR₇, COR₆, halogen or together denote the double bonded groups —CR₈═R₉—CH═CH—, —CH═CR₈—CR₉═CH—, —O—CHR₁₀—CH₂— or —CO—CH₂—CH₂—O—, linked with adjacent carbon atoms of the benzene ring,

R₃denotes halogen, CF₃, R₇, OR₇, CO—(C_1-4-alkyl), NH—CO—(C_1-4-alkyl), NHSO₂—(C_1-4-alkyl) or N(R₁₀)₂(whilst R₇can only denote H if at least one of the substituents R₁and R₂does not denote H) or a heterocyclic five-membered ring such as

R₆and R₇are at hereinbefore defined, and

A denotes the group II.

3. Compounds according to claim 1 or 2, wherein

R₁/R₂/R₃have the meanings C_2-5-acyl/H/H;

C₆H₅CO/H/H; C_1-4-alkyl/OH/H;

C_2-5-acyl/C_1-4-alkyl/H;

C_2-5-acyl/OH/C_1-4-alkyl;

OH/C_2-5-acyl/C_1-4-alkyl.

4. Compounds according to claim 1 or 2 characterised in that A denotes

O—(CH₂)₂—O, O—(CH₂)₄—O or

5. compounds according to claim 1 or 2 characterised in that the group II is acetylphenyl.

6. Compounds according to claim 1 or 2 characterised in that the group

7. Compounds of the formula

wherein

a denotes 0 or 1,

b denotes 1 or 2,

R denotes C_1-4-alkyl, and if a=0 or 1 and b=1 and

if a=1 and b=2 it may also denote hydrogen,

in the form of free bases or acid addition salts.

8. Compounds according to claim 7, wherein a=0 or 1 and b=1 or a=0 and b=2 as free bases or as acid addition salts.

9. Compounds according to claim 8, wherein R denotes H, CH₃, or C₂H₅, a denotes 0 or 1 and b denotes 1, as free bases or as acid addition salts.

10. Compounds according to claim 8, wherein a denotes 0, b denotes 2 and R denotes CH₃, as free bases or as acid addition salts.

11. Pharmaceutical compositions, characterised in that they contain a compound according to claims 1, 2 or 7.

12. Use of compounds according to claims 1, 2 or 7 in the preparation of pharmaceutical compositions for the treatment of diseases in which inflammatory and/or allergic processes are involved, especially asthma, ulcerative colitis, psoriasis and for treating gastropathy induced by non-steroidal antiphlogistics.

13. Use of an effective dose of a compound according to claims 1, 2 or 7 for treating diseases in which LTB₄-antagonistic compounds can be used.

14. Use of an effective dose of a compound according to claims 1, 2 or 7 for the treatment of diseases in which inflammatory and/or allergic processes are involved, particularly asthma, ulcerative colitis, psoriasis, and for treating gastropathy induced by non-steroidal antiphlogistics.

15. Process for preparing compounds according to claims 1, 2 or 7 characterised in that

a) an imidoester of the formula

wherein R₁to R₄, A and B are as hereinbefore defined and R preferably represents a C_1-6-alkyl group or benzyl, is reacted with ammonia, or

b1) a phenol or thiophenol of the formula

wherein Z denotes OH or SH and R₁, R₂and R₃are as hereinbefore defined, is reacted with a compound of formula

wherein A₁, A₂, B, R₄, X₂and X₃are as hereinbefore defined and L denotes a nucleofugic leaving group, or

b2) a phenol or thiophenol of formula

wherein B, R₄and Z are as hereinbefore defined, is reacted with a compound of formula

wherein A₁, A₂, R₁, R₂, R₃and Z are as hereinbefore defined; or

c) an amidoxime of the formula

wherein A, B and R₁to R₄are as hereinbefore defined, is reduced to form the corresponding amidine.