EP1332128A1

EP1332128A1 - Benzamidine derivatives comprising a sulfate group serving as ltb4 antagonists

Info

Publication number: EP1332128A1
Application number: EP01978439A
Authority: EP
Inventors: Ralf Anderskewitz; Kurt Schromm; Franz Birke; Hans Michael Jennewein
Original assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 2000-10-24
Filing date: 2001-10-19
Publication date: 2003-08-06
Also published as: AU2002210558A1; DE10052333A1; JP3917516B2; MXPA03003465A; CA2425368C; WO2002034715A1; PE20020542A1; JP2004512322A; CA2425368A1

Abstract

The invention relates to novel sulfoxybenzamides of formula (I), wherein: Z0 represents a group selected among formulas -X1-(CH2)r-X2- and -CR?4R5-; A1 and A2¿, independent of one another, represent a 1,4-phenylene group or 1,3-phenylene group optionally substituted by one or more halogen atoms, C¿1?-C8 alkyl groups, C2-C8 alkenyl groups, C1-C8 alkyl halide groups or by C1-C8 alkoxy groups; Z?1 and Z2¿, independent of one another, represent a group of formula -X3-(CH2)8-X4- or a single bond; m and n, independent of one another, represent 0 or 1, and; radicals R?1, R2, R3, R4, R5, X1, X2, X3, X4¿, r and s have the meanings cited in the description. The invention also relates to a method for producing these novel compounds and to their use as medicaments, especially as leukotriene B¿4?(LTB4) antagonists.

Description

BENZAMIDINE DERIVATIVES WITH A SULFATE GROUP AS LTB4 ANTAGONISTS

The present invention relates to new sulfooxybenzamides of the formula I

(i) in which the radicals R ¹ , R ² , R ³ , A ¹ , A ² , Z °, Z ¹ , Z ² , m and n have the meanings given in the claims and in the description, processes for their preparation and their use as medicines, in particular as leukotriene B - (LTB) antagonists.

BACKGROUND OF THE INVENTION Benzamidine derivatives are known from the prior art as active ingredients with valuable pharmaceutical properties. For example, international patent applications WO 97/21670 and WO 98/11062 disclose, inter alia, benzamidines which have free hydroxyl groups. However, there is no reference to benzamidines containing sulfate groups.

The object of the present invention is to provide new ETB ₄ antagonists which, due to their LJB ₄ antagonistic properties, have a wide range of possible uses in the therapeutic field.

Detailed description of the invention Surprisingly, it has been found that sulfate group-containing benzamidine derivatives of the general formula (I)

(I) wherein the radicals R ¹ , R ² , R ³ , A ¹ , A ² , Z °, Z ¹ , Z ² , m and n have the meanings given in the claims and in the description, have an LTB antagonistic effect and can be used according to the invention for the prevention and treatment of diseases in which LTB ₄ antagonists can develop a therapeutic benefit.

The invention thus relates to sulfooxybenza ide of the general formula 1 in which

Z ° for a group selected from the formulas -X ¹ - (CH ₂ ) _r -X ² - and -CR ⁴ R ⁵ -,

A ^J and A ² each independently for one, optionally by one or more

Halogen atoms, Ci-Cg- alkyl groups, C ₂ -Cg alkenyl groups, Cι-C--

Haloalkyl groups or Ci-Cg-alkoxy groups substituted 1,4-phenylene or

1,3-phenylene group, Z ¹ and Z ² each independently represent a group of the formula

-X - (CH ₂ ) _S -X ⁴ - or a single bond, R ^{1 is} hydrogen, hydroxy, -COO-Ci-Cg-alkyl or -COO-C C ₄ -alkyl-phenyl, in which in the above Group of the phenyl ring each

C 1 -C ₄ alkyl or CC alkoxy can be substituted, R ² and R ³ each independently of one another for a hydrogen or halogen atom, or a Ci-Cg-alkyl, C C_-haloalkyl, dC ₈ alkoxy, aryl, aryloxy or

Aralkyl group, R ⁴ and R ⁵ each independently represent hydrogen or CC alkyl, X ¹ and X ² each independently represent -O-, -S-, -NH- or a single bond,

X ^J and X ⁴ each independently represent -O-, -S-, -NH- or a single bond, m and n each independently represent 0 or 1, and r and s each independently represent an integer from 1 to 8,

if appropriate in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable salts.

The compounds of the formula I are preferred

Z ° for a group selected from the formulas -X ^l - (CH ₂ ) rX ² - and -CR ⁴ R ⁵ -,

A ¹ and A ² each independently represent a 1,4-phenylene or 1,3-phenylene group which is optionally substituted by a C ₁ -C ₄ -alkyl group or C ₂ -C ₄ -alkenyl group,

Z ¹ and Z ² each independently represent a group of the formula -X ³ - (CH ₂ ) _S -X ⁴ - or a single bond,

R 'represents hydrogen,

R ² and R ³ each represent a hydrogen atom,

R ⁴ and R ⁵ each independently represent C 1 -C 4 -alkyl,

X ¹ and X ² each independently represent -O- or a single bond, X ^J and X ⁴ each independently represent -O- or a single bond, m and n each independently represent 0 or 1, and r and s each independently represent an integer from 1 to 3.

A further preferred embodiment is the compounds of the formula I in which Z ° represents a group of the formula -CR ⁴ R ⁵ -, A ¹ and A ² each independently represent an optionally substituted by a Cι-C ₄ - alkyl group or C ₂ -C ₄ alkenyl group substituted 1,4-phenylene or 1,3-phenylene group, preferably A is 1,4-phenylene ¹ and A ² 1,3-phenylene, Z ¹ and Z ² each independently represent a group of the formula -X ³ - (CH ₂ ) _S -X ⁴ -, preferably Z ¹ denotes -O-CHz- and Z ² - CH ₂ -O-

R ^{1 represents} hydrogen,

R ² and R ³ each represent a hydrogen atom, R ⁴ and R ⁵ each represent methyl,

X ³ and X ⁴ each independently represent -O- or a single bond, m and n each represent 1, and s represents 1.

Also preferred are those compounds of the formula I in which Z ° is for a group of the formula

-X ^l - (CH ₂ ) _r -X ² -,

A ² for a substituted by a C] -C alkyl group or C ₂ -C alkenyl group

1,4- -phenylene group, preferably a 1,4- -phenylene group substituted by a /. -Propyl or AJlyl group,

Z ^{2 represents} a single bond,

R ^{1 represents} hydrogen,

R ² and R ³ each represent a hydrogen atom,

X ¹ and X ^{2 are} each independently -O-, m is 0, n is 1, and r 2 is.

Unless otherwise specified, the general definitions are used in the following sense: CC "- alkyl and CC - alkyl generally represents a branched or unbranched hydrocarbon radical having 1 to 4 or 8 carbon atoms, which may optionally be substituted by one or more halogen atoms, preferably fluorine, which are identical to one another or can be different. The following hydrocarbon radicals may be mentioned as examples:

Methyl, ethyl, "-propyl, 1-methylethyl (isopropyl)," -butyl, 1-methylpropyl, 2-methylpropyl, 1J-dimethylethyl, w-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1.1 - dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylproypyl, λ? -Hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1J-dimethylbutyl, 1,2-

Dimethylbutyl, 1,3-dimethylbutyl, 2,2, -dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1J, 2-trimethylpropyl, 1,2,2-trimethylpropyl, 1 -Ethyl-l-methylpropyl and l-ethyl-2-methylpropyl. Unless otherwise stated, preference is given to lower alkyl radicals having 1 to 4 carbon atoms, such as methyl; Ethyl, «-propyl, / so-propyl, n-butyl, 1-methylpropyl, 2-methylpropyl or IJ -dimethylethyl.

C ₂ -C ₈ alkenyl and C ₂ -C ₄ alkenyl generally represent a branched or unbranched unsaturated hydrocarbon radical having 2 to 4 or 8 carbon atoms, optionally with one or more halogen atoms, preferably fluorine - Can be substituted, which can be the same or different from each other. The following hydrocarbon radicals may be mentioned as examples:

Vinyl, allyl, prop-1-enyl, butenyl, pentenyi, hexenyl, heptenyl and octenyl. Unless otherwise stated, preference is given to lower alkenyl radicals having 2 to 4 carbon atoms, such as vinyl or allyl.

The group - (CH ₂ ) _r - or - (CH ₂ ) _S - means a branched or unbranched double-bonded hydrocarbon bridge with 1 to 8 carbon atoms, which can optionally be substituted by one or more halogen atoms, preferably fluorine, which can be the same or different from one another. Aryl generally represents an aromatic radical having 6 to 10 carbon atoms, preferably phenyl, the aromatic having one or more lower alkyl group (s), lower alkenyl group (s), trifluoromethyl group (s), cyano group (s), alkoxy group (s), nitro group (n), amino group (s) and / or one or more halogen atom (s) - mutually identical or different - can be substituted; the preferred aryl radical is an optionally substituted phenyl radical, halogen - such as fluorine, chlorine or bromine - and hydroxyl being preferred as substituents.

Alkoxy generally represents a straight-chain or branched hydrocarbon radical with 1 to 8 carbon atoms bound via an oxygen atom. A lower alkoxy radical having 1 to 3 carbon atoms is preferred. - The methoxy group is particularly preferred.

Aryloxy generally represents an aromatic radical having 6 to 10 carbon atoms, preferably phenoxy, which is bonded via an oxygen, the aromatic having one or more lower alkyl group (s), lower alkenyl group (s), trifluoromethyl group (s), cyano group (s), alkoxy group ( n), nitro group (s), amino group (s) and / or one or more halogen atom (s) - mutually identical or different - can be substituted; the preferred aryl radical is an optionally substituted phenyl radical, halogen - such as fluorine, chlorine or bromine - and hydroxyl being preferred as substituents.

Aralkyl generally represents an aromatic radical having 6 to 10 carbon atoms, preferably phenylalkyl, bonded via an alkylene group, the aromatic group having one or more lower alkyl group (s), lower alkenyl group (s), trifluoromethyl group (s), cyano group (s), alkoxy group ( n), nitro group (s), amino group (s) and / or one or more halogen atom (s) - mutually identical or different - can be substituted; the preferred aryl radical is an optionally substituted phenyl radical, halogen - such as fluorine, chlorine or bromine - and hydroxyl being preferred as substituents. The alkylene group is usually a double-bonded hydrocarbon bridge with 1 to 8 carbon atoms, preferably 1 to 3 carbon atoms, optionally with one or more

Halogen atom (s) - preferably fluorine - may be substituted, which may be the same or different from one another. Very particularly preferred compounds are those of the formulas 1A and IB,

(IB)

The compounds IA and IB can arise in vivo as metabolites of a corresponding LTB4-antagonistic compound with a free hydroxy group and have the following Kj values in the receptor binding test:

As has been found, the compounds of the formula I are distinguished by a wide range of possible uses in the therapeutic field. Emphasis should be placed on those applications for which the LTB4 receptor antagonistic properties play a role. The following are particularly worth mentioning: arthritis, asthma, chronic obstructive pulmonary diseases, such as chronic bronchitis, psoriasis, ulcerative colitis, gastro- or enteropathy induced by non-steroidal anti-inflammatory drugs, cystic or pulmonary fibrosis, Alzheimer's disease, shock, reperfusion damage / ischemic heart attack or stroke , Atherosclerosis, multiple sclerosis, autoimmune diseases, malignant neoplasia, alveolitis The new compounds can also be used to treat diseases or conditions in which the passage of cells from the blood via the vascular endothelium into the tissue is important (for example metastasis) or diseases and conditions in which the combination of LTB4 or another active substance (for example 12-HETE) with the LTB4 receptor has an influence on cell proliferation (for example chronic myelocytic leukemia).

The new compounds can also be used in combination with other active ingredients, such as those used for the same indications, or e.g. With

Antiallergics, secretolytics, ß2-adrenergics, inhalable steroids,

Antihistamines, PDE4 inhibitors, peptido-leukotriene antagonists and / or PAF-

Antagonists. Administration can be topical, oral, transdermal, nasal, parenteral or inhalative. Tests such as those in WO 93/16036, pp. 15 to 17, for example, are suitable for the pharmacological and biochemical investigation of the effects on the content

Reference is made - are shown.

The therapeutic or prophylactic dose depends - apart from the potency of the individual compounds and the body weight of the patient - on the

Condition and seriousness of the disease, with oral use the dose is between 10 and 500 mg, preferably between 20 and 250 mg. When used by inhalation, between about 0.5 and 25, preferably between about 2 and 20 mg of active ingredient are administered to the patient.

Inhalation solutions generally contain between about 0.5 and 5% active ingredient. The new compounds can be administered in customary preparations, for example as tablets, dragées, capsules, wafers, powders, granules, solutions, emulsions, syrups, inhalation aerosols, ointments, suppositories

The following examples show some possibilities for the formulation of the dosage forms: formulation Examples

1. tablets composition;

Active ingredient according to the invention 20 parts by weight

Stearic acid 6 parts by weight

Dextrose 474 parts by weight

The ingredients are processed in the usual way to tablets of 500 mg weight.

If desired, the active substance content can be increased or decreased and the amount of glucose reduced or increased accordingly.

2. Suppositories

Composition:

Active ingredient according to the invention 100 parts by weight

Lactose, powdered 45 parts by weight

Cocoa butter 1555 parts by weight

The ingredients are processed in the usual way into suppositories weighing 1.7 g.

3. Inhalation powder

Micronized active ingredient powder (compound of the formula I; particle size approx. 0.5 to 7 μm) is filled into hard gelatin capsules in an amount of 5 mg, optionally with the addition of micronized lactose. The powder is extracted from conventional inhalation devices, e.g. according to DE-A 33 45 722, to which reference is hereby made, inhaled.

The compounds according to the invention are prepared by methods which are known per se from the prior art. So the connections of the general Formula I can be prepared in such a way that the hydroxyl-containing benzamides of the formula II known for example from the international patent applications WO 97/21670 and WO 98/1 1062

(π) in which Z °, A ¹ , A ² , ZZ ² , R ¹ , R ² , R ³ , m and n have the meanings given above, with a sulfuric acid derivative of the formula III,

HO ₃ SX (III) in which X is a leaving group which can be substituted by a phenol oxygen, preferably a halogen atom, in particular chlorine, preferably in the presence of a weak base and a metal iodide.

In a preferred embodiment of the process according to the invention, a compound of the formula II or its acid addition salt with a sulfuric acid derivative of the formula III, in particular chlorosulfonic acid in an inert diluent and in the presence of a base, or in a basic solvent such as triethylamine or pyridine and in the presence of catalytic Amounts of a metal iodide, preferably an alkali metal iodide, especially potassium iodide, at a temperature of - 80 to + 120 ° C, preferably from -40 to +100 ° C, in particular from - 10 to + 80 ° C. Under the preferred conditions mentioned, the reaction is usually complete in 2 to 36 hours, preferably 4 to 18 hours.

The compounds according to the invention can be prepared starting from compounds known from the prior art, inter alia, by the processes described in the following examples. Different, different refinements of the methods will become apparent to the person skilled in the art from the present description. However, it is expressly pointed out that these examples and the description associated with them are only intended for the purpose of illustration and are not to be regarded as a limitation of the invention. example 1

Benzenecarboximidamide, 4 - [[3 - [[4- [1 -methyl- 1 - [4- (sulfooxy) phenyl] ethyljphenoxy] methylJphenyl] methoxy] -

7.54 g of benzenecarboximidamide, [[4 - [[3 - [[4- [l- (4-hydroxyphenyl) -l-methylethyl] phenoxy] methyl] phenyl] methoxy] -, monohydrochloride were taken up in 200 ml of pyridine and mixed with 4.0 g of chlorosulfonic acid (slowly added at room temperature) and a trace of potassium iodide. The mixture was stirred at 60 ° C for 6 h. The reaction mixture was then carefully poured into water, the precipitate was filtered off with suction and washed with methanol. Yield: 4.0 g (mp. 284 ° C).

Example 2

[1J'-biphenyl] -4-carboximidamide, 3'-propyl-4 '- [2- [3- (sulfooxy) phenoxy] ethoxy] -

2.43 g of [1J'-biphenyl] -4-carboximidamide, 4 '- [2- (3-hydroxyphenoxy) ethoxy] -3'-propyl ~, monomethanesulfonate, 100 ml of pyridine and 0J g of potassium iodide were combined and 1 , 5 g of chlorosulfonic acid slowly added dropwise. The mixture was stirred at 50-60 ° C for 6 hours. After cooling, the mixture was poured into 1 liter of water, the crystals which had precipitated were filtered off with suction and recrystallized twice from dimethylformamide. 1.25 g of white crystals. Mp> 270 ° C. Examples 3-14

The following compounds are analogous to Examples 1 and 2

made from the corresponding phenols:

Claims

claims

1. New sulfooxybenzamides of the general formula I

(I) in which

Z τ0 for a group selected from the formulas

-X ^ CH- X - and -CR ⁴ R ⁵ -, A ¹ and A ² each independently for one optionally by one or more

Halogen atoms, Cj-C ₈ alkyl groups, C ₂ -C ₈ alkenyl groups, -CC ₈ - haloalkyl groups or -CC ₈ alkoxy groups substituted 1,4-phenylene or

-X ³ - (CH ₂ ) _S -X ⁴ - or a single bond, R ¹ stands for hydrogen, hydroxy, -COO-C, -C ₈ -alkyl or -COO-C C ₄ -alkyl-phenyl, where in each of the above-mentioned group of the phenyl ring

C 1 -C 4 alkyl or C 1 -C 4 alkoxy can be substituted, R ² and R ³ each independently of one another for a hydrogen or halogen atom, or a C 1 -C 6 -alkyl, -C 6 -haloalkyl, d-C 6 -alkoxy, aryl, Aryloxy or

Aralkyl group, R ⁴ and R ⁵ each independently represent hydrogen or -CC ₄ alkyl,

X ¹ and X ² each independently represent -O-, -S-, -NH- or a single bond, X ³ and X ⁴ each independently represent -O-, -S-, -NH- or a single bond, m and n each independently represent 0 or 1, and r and s each independently represent an integer from 1 to 8. optionally in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, and, if appropriate, their pharmacologically acceptable salts.

2. Compounds of formula I according to claim 1, wherein

Z τ for a group selected from the formulas

-X ^l - (CE ₂ ) rX ² - and -CR ⁴ R ⁵ -, A ¹ and A ² each independently of one another for a _{1 which is} optionally substituted by a C ₁ -C ₄ alkyl group or C ₂ -C ₄ alkenyl group, 4-phenylene or 1,3-phenylene group,

Z and Z ² each independently represent a group of the formula -X ³ - (CH.) _S -X ⁴ - or a single bond,

R 'represents hydrogen,

R ² and R ³ each represent a hydrogen atom, RR ⁴⁴ and RR ^ ⁵ each independently represent CC alkyl,

X ^{1 and} X ² each independently represent -O- or a single bond,

X ^{3 and} X ⁴ each independently represent -O- or a single bond, m and n each independently represent 0 or 1, and r and s each independently represent an integer from 1 to 3,

3. Compounds of formula I according to claim 1 or 2, wherein Z ° for a group of the formula

-X ¹ - (CH ₂ ) _r -X ² -, A ^{2 represents} a 1, 4- phenylene group substituted by a C ₁ -C ₄ -alkyl group or C ₂ -C ₄ alkenyl group,

Z ^{2 represents} a single bond,

R ^{l represents} hydrogen,

R ² and R ³ each represent a hydrogen atom, X ^! and X ^{2 are} each independently -O-, m is 0, n is 1, and r 2 is

4. Compound of formula IA

(IA)

5. Compounds of formula I according to claim 1 or 2, wherein for a group of formula

-CR ⁴ R ⁵ - stands,

A ¹ and A ² each independently represent a 1,4-phenylene or 1,3-phenylene group optionally substituted by a Cχ-C - alkyl group, Z 'and Z' each independently represent a group of the formula -X ³ - ( CH ₂ ), - X ⁴ - stand,

R ^{1 represents} hydrogen,

6. Compound of formula IB

(IB)

7. Compounds of formulas I, IA or B according to any one of claims 1 to 6 for use as a medicament.

8. A process for the preparation of compounds of the formulas I, IA or IB according to one of claims 1 to 6, characterized in that a hydroxybenzamidine of the formula II

(H) in which Z °, A ¹ , A ² , Z ¹ , Z ² , R ¹ , R ² , R ³ , m and n have the meanings given in claims 1 to 6, are reacted with a sulfuric acid derivative of the formula Iü . wherein X represents a leaving group which can be substituted by a phenolate oxygen.

9, Method according to claim 7, characterized in that the implementation in

Presence of a weak base and a metal iodide is carried out.

10. A pharmaceutical preparation containing a compound according to any one of claims 1 to 6 and pharmaceutically acceptable carriers and excipients.

11. Use of compounds according to one of claims 1 to 6 for the manufacture of a medicament.

12. Use of compounds according to claim 10 for the manufacture of a medicament with LTB4 antagonistic activity

13. Use of compounds of general formula I according to one of claims 1 to 6, their stereoisomers and their acid addition salts for the preparation of a Medicinal product for the therapeutic treatment of arthiritis, asthma, chronic obstructive pulmonary disease, psoriasis, ulcerative colitis, gastro- or enteropathy induced by non-steroidal anti-inflammatory drugs, cystic or pulmonary fibrosis, Alzheimer's disease, shock, reperfusion damage / ischemia, malignant atherosclerosis, atherosclerosis, atherosclerosis Neoplasia, alveolitis.

14. Method for the treatment and / or prevention of diseases in which LTB ₄ antagonists develop a therapeutic benefit by administering a therapeutically effective amount of one or more compounds of the general formula I according to one of claims 1 to 6, their stereoisomers or their acid addition salts.