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WO1994021616A1 - Heterocycle-containing amidine derivatives, their preparation and use - Google Patents

Heterocycle-containing amidine derivatives, their preparation and use Download PDF

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Publication number
WO1994021616A1
WO1994021616A1 PCT/EP1994/000856 EP9400856W WO9421616A1 WO 1994021616 A1 WO1994021616 A1 WO 1994021616A1 EP 9400856 W EP9400856 W EP 9400856W WO 9421616 A1 WO9421616 A1 WO 9421616A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
formula
alkoxy
compounds
phenyl
Prior art date
Application number
PCT/EP1994/000856
Other languages
German (de)
French (fr)
Inventor
Ernst-Otto Renth
Kurt Schromm
Ralf Anderskewitz
Franz Birke
Armin Fügner
Hubert Heuer
Original Assignee
Boehringer Ingelheim Kg
Boehringer Ingelheim International Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim Kg, Boehringer Ingelheim International Gmbh filed Critical Boehringer Ingelheim Kg
Priority to AU63780/94A priority Critical patent/AU6378094A/en
Priority to JP6520657A priority patent/JPH08508467A/en
Priority to EP94911191A priority patent/EP0690849A1/en
Priority to SK1174-95A priority patent/SK117495A3/en
Publication of WO1994021616A1 publication Critical patent/WO1994021616A1/en
Priority to KR1019950704014A priority patent/KR960701026A/en
Priority to NO953763A priority patent/NO953763L/en
Priority to LVP-95-291A priority patent/LV11465B/en
Priority to FI954491A priority patent/FI954491A0/en
Priority to BG100069A priority patent/BG100069A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/84—Sulfur atoms
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
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    • C07D239/96—Two oxygen atoms
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    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
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    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D277/62—Benzothiazoles
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    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/70—Sulfur atoms
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    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to new, heterocycle-containing amidine derivatives, their preparation by conventional methods and their use as active ingredients in
  • a 1 is a straight-chain or branched double-bonded aliphatic C 2 -C 6 group, which can also contain a double or triple bond, or one of the groups
  • X 1 for O, S, SO, SO 2 , CH 2 , NH or
  • Chiral compounds of the formula I can be in the form of racemates, in enantiomerically pure or enriched form and in each case as a base or as salts with inorganic or organic, in particular physiologically
  • R 1 and R 2 which are the same or different
  • C 1 -C 4 alkyl can be substituted for halogen, OH, CF 3 , R 5 , OR 6 , COR 6 ,
  • R 5 represents a heterocyclic five-membered ring with 1 to 3 heteroatoms and the formula
  • D, E and G which may be the same or different, are CH, N, C- (C 1 -C 4 alkyl) or
  • C is phenyl and L is Ooer S
  • R 4 for H, halogen, NH 2 , NH- (C 1 -C 4 alkyl), C 1 -C 4 alkyl, N (C 1 -C 4 alkyl) 2 , OH, C 1 -C 4 - Alkoxy, phenyl,
  • R 5 is H, C 1 -C 12 alkyl, pydridyl, phenyl, optionally by halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy
  • R 6 for C 1 -C 12 alkyl, phenyl or optionally
  • R 7 is H or C 1 -C 12 alkyl
  • R 8 , R 9 (which may be the same or different)
  • R 10 is H or C 1 -C 4 alkyl
  • R 11 , R 12 which can be the same or different
  • R 13 , R 14 which may be the same or different,
  • radicals from the group fluorine, chlorine, bromine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or pseudohalogens such as CN, CF 3 may be substituted, or for pyridyl.
  • a 1 contains a double or triple bond, this is generally not a hetero atom
  • R 3 generally means hydrogen only if at least one of the radicals R 1 , R 2 is not hydrogen.
  • a 1 ' (CH 2 ) 2-6 , CH 2 -C 6 H 4 -CH 2 ,
  • CH 2 -C C-CH 2 ;
  • X 1 ' O, S;
  • Het ' a group of the above formulas a, b, e, f, g, k, n, where R 1 , R 2 , R 3 , the may be the same or different, mean H, R 5 , OR 5 or COR 5 and
  • R 1 and R 2 together also one
  • condensed ring can mean.
  • Ammonia in an alcohol such as methanol, ethanol, n-propanol, i-propanol, or in an inert solvent, such as dichloromethane,
  • Tetrahydrofuran, dioxane at temperatures between about 0 and 50 ° C, preferably at about 20 ° C. 2. Reduction of an amidoxime of the formula
  • Het, R 4 , A and B have the above meaning
  • a catalyst such as Raney nickel, palladium or platinum.
  • O or S can also be according to the scheme
  • Metal hydroxides, metal hydrides at temperatures between about 0 and 140 ° C or the boiling point of the reaction mixture.
  • the phenols or thiophenols can also be used in the form of salts, for example the alkali salts.
  • Suitable as a nucleofugic leaving group eg halogens, such as Br, Cl or residues of
  • Sulfonic acids such as methanesulfonic acid
  • the starting materials X and XI are preferably from the corresponding nitriles of the formula
  • the further synthetic route consists in the reaction of the corresponding nitriles with HCl via the stage of the imide chlorides or the direct reaction with eg
  • reaction can also be carried out with a trialkyloxonium salt such as
  • nitriles XVI can be reacted with hydroxylamine in alcohols, for example methanol, ethanol, Propanol, isopropanol, the corresponding amidoximes of the formula XI obtained.
  • the starting materials of the formulas XII, XIII, XIV and XV can also be prepared by conventional processes.
  • the compounds according to the invention can be used therapeutically, in particular because of their
  • LTB 4 -antagonistic effect are therefore particularly suitable for use in those diseases in which inflammatory and / or allergic processes play a role, for example IBD (inflammatory bowel diseases), allergic rhinitis; ARDS (adult respiratory distress syndron), asthma, colitis
  • IBD inflammatory bowel diseases
  • ARDS adult respiratory distress syndron
  • asthma chronic respiratory distress syndron
  • ulcerative pain, psoriasis also used to treat gastropathy induced by nonsteroidal anti-inflammatory drugs (NSAID).
  • NSAID nonsteroidal anti-inflammatory drugs
  • the new compounds can also be used in combination with other active ingredients, e.g. B. with antiallergics, secretolytics,
  • Antihistamines and / or PAF antagonists are included in the composition.
  • Administration can be topical, oral, transdermal, nasal, parenteral or inhalative.
  • the therapeutic or prophylactic dose is - apart from the potency of the individual compounds and the body weight of the patient - dependent on the nature and seriousness of the
  • the new compounds can be administered topically, orally,
  • compositions consisting essentially of an inert pharmaceutical carrier and a
  • an effective dose of the active ingredient e.g. Tablets, coated tablets, capsules, wafers, powders, solutions, suspensions, inhalation aerosols, ointments, emulsions, syrups, suppositories, etc.
  • An effective dose of the compounds according to the invention is oral
  • Inhalation should be used in powders or solutions containing 0.5% to 5% active ingredient, with each dose containing approximately 2 to 20 mg active ingredient.
  • the new compounds can be combined, inter alia, with antiallergics, secretolytics, ⁇ 2 -adrenergics, inhalable steroids or antihistamines.
  • Active ingredient according to the invention 20 parts by weight
  • the ingredients are processed in the usual way to tablets of 500 mg weight.
  • the active ingredient content can be increased or decreased and the amount of glucose reduced or increased accordingly.
  • Active ingredient according to the invention 100 parts by weight
  • the ingredients are processed in the usual way into suppositories weighing 1.7 g.
  • Micronized active ingredient powder (compound of formula I; particle size approx. 0.5 to 7 ⁇ m) is added in an amount of 5 mg, optionally with the addition of micronized lactose
  • Bottled hard gelatin capsules The powder is inhaled from conventional inhalation devices, for example according to DE-A 3 345 722.
  • the compounds of the invention were examined, inter alia, for their action in the tests below. a) LTB 4 receptor connection test
  • U937 cells differentiated, human monocytic cell line with naturally expressed
  • Concentration of the test substance is dose-dependent inhibited (incubation 2 h at 0 ° C).

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Abstract

Compounds having the formula (I), which is explained in detail in the description, may be prepared by conventional methods and used in standard galenic compositions for therapeutical purposes.

Description

Heterocyclen enthaltende Amidinderivate, ihre Heterocycle-containing amidine derivatives, their
Herstellung und Verwendung Manufacture and use
Die Erfindung betrifft neue, Heterocyclen enthaltende Amidinderivate, ihre Herstellung nach konventionellen Methoden und ihre Verwendung als Wirkstoffe in The invention relates to new, heterocycle-containing amidine derivatives, their preparation by conventional methods and their use as active ingredients in
Arzneimitteln. Medicines.
Die neuen Amidinderivate entsprechen der Formel The new amidine derivatives correspond to the formula
Figure imgf000003_0001
Figure imgf000003_0001
in der in the
A für eine der Gruppen  A for one of the groups
X1-A1-X2 (II) X 1 -A 1 -X 2 (II)
X2-A1-X1 (III) X 2 -A 1 -X 1 (III)
Figure imgf000003_0002
Figure imgf000003_0002
wobei A1 eine geradkettige oder verzweigte zweibindige aliphatische C2-C6-Gruppe bedeutet, die auch eine Doppel- oder Dreifachbindung enthalten kann, oder eine der Gruppen
Figure imgf000004_0001
wherein A 1 is a straight-chain or branched double-bonded aliphatic C 2 -C 6 group, which can also contain a double or triple bond, or one of the groups
Figure imgf000004_0001
bedeutet, means
X1 für O, S, SO, SO2, CH2, NH oderX 1 for O, S, SO, SO 2 , CH 2 , NH or
Figure imgf000004_0002
Figure imgf000004_0002
X2 für O, S, CH2 oderX 2 for O, S, CH 2 or
Figure imgf000004_0003
Figure imgf000004_0003
B für CH=CH, CH=N, S oder
Figure imgf000004_0004
B for CH = CH, CH = N, S or
Figure imgf000004_0004
Het für einen Heterocyclus oder ein heterocyclisches Het for a heterocycle or a heterocyclic
System aus zwei oder drei kondensierten Ringen, das ein bis drei Substituenten enthalten kann. System of two or three condensed rings, which can contain one to three substituents.
Chirale Verbindungen der Formel I können in Form von Racematen, in enantiomerenreiner bzw. angereicherter Form und jeweils als Base oder als Salze mit anorganischen oder organischen, insbesondere physiologisch Chiral compounds of the formula I can be in the form of racemates, in enantiomerically pure or enriched form and in each case as a base or as salts with inorganic or organic, in particular physiologically
unbedenklichen Säuren vorliegen. Als Heterocyclen bzw. als kondensierte Systeme im Sinne der obigen Definition kommen vor allem folgende Gruppen in Betracht: safe acids are present. The following groups are particularly suitable as heterocycles or as condensed systems in the sense of the above definition:
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Dabei stehen  Stand there
R1 und R2, die gleich oder verschieden sein R 1 and R 2 , which are the same or different
können, für CF3, Halogen, R5, OR5, COR6, can, for CF 3 , halogen, R 5 , OR 5 , COR 6 ,
SR6, SOR6, SO2R6, SO2NR5R7, SR 6 , SOR 6 , SO 2 R 6 , SO 2 NR 5 R 7 ,
C(OH)R5R7 oder gemeinsam auch für die mit C (OH) R 5 R 7 or together for those with
benachbarten C-Atomen des Benzolrings verknüpften zweibindigen Gruppen -CR8=CR9-CH=CH-, adjacent C atoms of the benzene ring linked divalent groups -CR 8 = CR 9 -CH = CH-,
-CH=CR8-CR9=CH-, -CR8=CH-CR9=CH-, -CH = CR 8 -CR 9 = CH-, -CR 8 = CH-CR 9 = CH-,
-O-CHR10-CH2-, -O-CH2-O-, -O-CH2 -CH2 -O-, -O-CHR 10 -CH 2 -, -O-CH 2 -O-, -O-CH 2 -CH 2 -O-,
-(CH2)3-4-, -NH-CO-O-, -NH-CO-CH2-O-, - (CH 2 ) 3-4 -, -NH-CO-O-, -NH-CO-CH 2 -O-,
-CO-CH2-O- oder -CO-CH2CH2-O- stehen, wobei -CO-CH 2 -O- or -CO-CH 2 CH 2 -O-, where
diese Gruppen ihrerseits auch durch  these groups for their part
C1-C4-Alkyl substituiert sein können, für Halogen, OH, CF3, R5, OR6, COR6, C 1 -C 4 alkyl can be substituted for halogen, OH, CF 3 , R 5 , OR 6 , COR 6 ,
CONR5R7, CH2OH, CH2-O- (C1-C4-Alkyl), CONR 5 R 7 , CH 2 OH, CH 2 -O- (C 1 -C 4 alkyl),
SR6, SOR6, SO2R6, SO2NR5R7, SR 6 , SOR 6 , SO 2 R 6 , SO 2 NR 5 R 7 ,
NH-CO- (C1-C4-Alkyl), NH-CO- (C 1 -C 4 alkyl),
NH-SO2- (C1-C4-Alkyl), NR5R7 oder NH-SO 2 - (C 1 -C 4 alkyl), NR 5 R 7 or
C(OH)R5R7 steht, für einen heterocyclischen Fünfring mit 1 bis 3 Heteroatomen und der Formel
Figure imgf000010_0001
C (OH) R 5 R 7 represents a heterocyclic five-membered ring with 1 to 3 heteroatoms and the formula
Figure imgf000010_0001
(worin D, E und G, die gleich oder verschieden sein können, CH, N, C-(C1-C4-Alkyl) oder (wherein D, E and G, which may be the same or different, are CH, N, C- (C 1 -C 4 alkyl) or
C- Phenyl bedeuten und L O ooer S ist),  C is phenyl and L is Ooer S),
R4 für H, Halogen, NH2, NH-(C1-C4-Alkyl), C1-C4-Alkyl, N(C1-C4-Alkyl)2, OH, C1-C4-Alkoxy, Phenyl, R 4 for H, halogen, NH 2 , NH- (C 1 -C 4 alkyl), C 1 -C 4 alkyl, N (C 1 -C 4 alkyl) 2 , OH, C 1 -C 4 - Alkoxy, phenyl,
R5 für H, C1-C12-Alkyl, Pydridyl, Phenyl, gegebenenfalls durch Halogen, C1-C4-Alkyl, C1-C4-Alkoxy R 5 is H, C 1 -C 12 alkyl, pydridyl, phenyl, optionally by halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy
oder C2-C5-Acyl substituiertes Phenyl oder or C 2 -C 5 acyl substituted phenyl or
Phenyl- (C1-C4-Alkyl), Phenyl- (C 1 -C 4 alkyl),
R6 für C1-C12-Alkyl, Phenyl oder gegebenenfalls R 6 for C 1 -C 12 alkyl, phenyl or optionally
durch Halogen, C1-C4-Alkyl, C1-C4-Alkoxy by halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy
oder C2-C5-Acyl substituiertes Phenyl, or C 2 -C 5 acyl substituted phenyl,
R7 für H oder C1-C12-Alkyl, R 7 is H or C 1 -C 12 alkyl,
R8, R9 (die gleich oder verschieden sein können) R 8 , R 9 (which may be the same or different)
für H, OH, C1-C4-Alkyl, C1-C4-Alkoxy oder for H, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or
C2-C5-Acyl, C 2 -C 5 acyl,
R10 für H oder C1-C4-Alkyl, R 10 is H or C 1 -C 4 alkyl,
R11, R12, die gleich oder verschieden sein können, R 11 , R 12 , which can be the same or different,
für H, OH, Halogen, CF3, C1-C4-Alkyl oder for H, OH, halogen, CF 3 , C 1 -C 4 alkyl or
C1-C4-Alkoxy, C 1 -C 4 alkoxy,
R13, R14, die gleich oder verschieden sein können, R 13 , R 14 , which may be the same or different,
für H, C1-C4-Alkyl, C1-C4-Alkoxy, Phenyl, for H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl,
Naphthyl, wobei diese Ringsysteme ein- oder  Naphthyl, these ring systems one or
mehrfach durch gleiche oder verschiedene Reste aus der Gruppe Fluor, Chlor, Brom, C1-C4-Alkyl, C1-C4-Alkoxy oder Pseudohalogene wie CN, CF3 substituiert sein können, oder für Pyridyl. several times by identical or different radicals from the group fluorine, chlorine, bromine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or pseudohalogens such as CN, CF 3 may be substituted, or for pyridyl.
Soweit A1 eine Doppel- oder Dreifachbindung enthält, ist diese im allgemeinen nicht einem Heteroatom If A 1 contains a double or triple bond, this is generally not a hetero atom
benachbart. Dementsprechend bedeutet A1 in diesem adjacent. Accordingly, A 1 in this means
Fall vorzugsweise Gruppen wie CH2-CH=CH-CH2 (eis If preferred, groups such as CH 2 -CH = CH-CH 2 (ice
oder trans) oder CH2-C=C-CH2. or trans) or CH 2 -C = C-CH 2 .
Wenn A1 für steht, hat X1 dieseIf A 1 stands for, X 1 has it
Figure imgf000011_0001
Figure imgf000011_0001
Bedeutung nicht. Falls A mit einem Stickstoffatom der Gruppe Het verbunden ist (wie z.B. bei den Gruppen j bis o), ist A über ein C-Atom mit diesem Stickstoffatom verknüpft. Im vorliegenden Text ist die Gruppe A  Meaning not. If A is connected to a nitrogen atom of the group Het (as for example in groups j to o), A is linked to this nitrogen atom via a C atom. In the present text, group A is
jeweils so geschrieben, wie sie in die Formel I each written as in Formula I
einzufügen ist.Kommen R1, R2 und R3 nebeneinander vor, so bedeutet R3 in der Regel nur dann Wasserstoff, wenn mindestens einer der Reste R1, R2 nicht Wasserstoff ist. If R 1 , R 2 and R 3 occur next to each other, R 3 generally means hydrogen only if at least one of the radicals R 1 , R 2 is not hydrogen.
Bevorzugte Verbindungen im Rahmen der obigen Preferred compounds in the context of the above
Definitionen umfaßt Formel Ia: Definitions include Formula Ia:
Figure imgf000011_0002
Figure imgf000011_0002
worin A1', X1', X2' und Het' folgendes wherein A 1 ', X 1 ', X 2 'and Het' are the following
bedeuten:  mean:
A1': (CH2)2-6, CH2-C6H4-CH2, A 1 ': (CH 2 ) 2-6 , CH 2 -C 6 H 4 -CH 2 ,
Z oder E CH2-CH=CH-CH2, Z or E CH 2 -CH = CH-CH 2 ,
CH2-C=C-CH2; CH 2 -C = C-CH 2 ;
X1 ' : O, S; X 1 ': O, S;
X2' : O, S; X 2 ': O, S;
Het': eine Gruppe der obigen Formeln a, b, e, f, g, k, n, wobei R1, R2 , R3, die gleich oder verschieden sein können, H, R5, OR5 oder COR5 bedeuten und Het ': a group of the above formulas a, b, e, f, g, k, n, where R 1 , R 2 , R 3 , the may be the same or different, mean H, R 5 , OR 5 or COR 5 and
R1 und R2 gemeinsam auch einen R 1 and R 2 together also one
ankondensierten Ring bedeuten können.  condensed ring can mean.
Die Verbindungen der Formel I werden nach an sich bekannten Verfahren erhalten, insbesondere wie folgt: The compounds of the formula I are obtained by processes known per se, in particular as follows:
1. Umsetzung einer Verbindung der Formel 1. Implementation of a compound of the formula
Figure imgf000012_0001
Figure imgf000012_0001
(worin Het, R4, A und B die obige Bedeutung haben und R bevorzugt für einen (wherein Het, R 4 , A and B have the above meaning and R preferably for one
C1-C4-Alkylrest oder für Benzyl steht) mit C 1 -C 4 alkyl radical or stands for benzyl) with
Ammoniak in einem Alkohol, wie Methanol, Ethanol, n-Propanol, i-Propanol, oder in einem inerten Lösungsmittel, etwa Dichlormethan,  Ammonia in an alcohol, such as methanol, ethanol, n-propanol, i-propanol, or in an inert solvent, such as dichloromethane,
Tetrahydrofuran, Dioxan, bei Temperaturen zwischen etwa 0 und 50°C, vorzugsweise bei etwa 20°C. 2. Reduktion eines Amidoxims der Formel  Tetrahydrofuran, dioxane, at temperatures between about 0 and 50 ° C, preferably at about 20 ° C. 2. Reduction of an amidoxime of the formula
Figure imgf000012_0002
Figure imgf000012_0002
(worin Het, R4, A und B die obige Bedeutung haben) durch Einwirkung von Wasserstoff in Gegenwart eines Katalysators wie Raney-Nickel, Palladium oder Platin. (where Het, R 4 , A and B have the above meaning) by exposure to hydrogen in Presence of a catalyst such as Raney nickel, palladium or platinum.
3. Verbindungen der Formel I, in der X1 bzw. X2 3. Compounds of the formula I in which X 1 or X 2
O oder S bedeuten, können auch gemäß dem Schema  O or S can also be according to the scheme
Figure imgf000013_0001
Figure imgf000013_0001
(wobei A, B, Het, X1, X2 und R4 die obige (where A, B, Het, X 1 , X 2 and R 4 are the above
Bedeutung haben und L eine nucleofuge  Have meaning and L is a nucleofuge
Abgangsgruppe, Z OH oder SH ist) erhalten werden.  Leaving group, Z is OH or SH) can be obtained.
Die Umsetzung erfolgt in Lösungsmitteln wie The implementation takes place in solvents such as
Dimethylsulfoxid, Dimethylformamid, Acetonitril oder Alkoholen wie Methanol, Ethanol oder Propanol unter Zusatz einer Base (Metallcarbonate,  Dimethyl sulfoxide, dimethylformamide, acetonitrile or alcohols such as methanol, ethanol or propanol with the addition of a base (metal carbonates,
Metallhydroxide, Metallhydride) bei Temperaturen zwischen etwa 0 und 140°C bzw. der Siedetemperatur des Reaktionsgemischs.  Metal hydroxides, metal hydrides) at temperatures between about 0 and 140 ° C or the boiling point of the reaction mixture.
Die Phenole oder Thiophenole können auch in Form von Salzen, etwa der Alkalisalze, eingesetzt werden. Als nucleofuge Abgangsgruppe eignen sich z.B. Halogene, etwa Br, Cl oder Reste von The phenols or thiophenols can also be used in the form of salts, for example the alkali salts. Suitable as a nucleofugic leaving group eg halogens, such as Br, Cl or residues of
Sulfonsäuren wie Methansulfonsäure,  Sulfonic acids such as methanesulfonic acid,
Benzolsulfonsäure.  Benzenesulfonic acid.
Die Ausgangsstoffe X und XI werden vorzugsweise aus den entsprechenden Nitrilen der Formel The starting materials X and XI are preferably from the corresponding nitriles of the formula
Figure imgf000014_0001
Figure imgf000014_0001
(worin A, B, Het und R4 die obige Bedeutung haben) hergestellt, die ihrerseits beispielsweise analog der Umsetzung gemäß Verfahren 3 erhalten werden können. Der weitere Syntheseweg besteht in der Umsetzung der entsprechenden Nitrilen mit HCl über die Stufe der Imidchloride bzw. der direkten Umsetzung mit z.B. (in which A, B, Het and R 4 have the meaning given above), which in turn can be obtained, for example, analogously to the reaction according to process 3. The further synthetic route consists in the reaction of the corresponding nitriles with HCl via the stage of the imide chlorides or the direct reaction with eg
C1-C6-Alkoholen bzw. Benzylalkohol in Gegenwart C 1 -C 6 alcohols or benzyl alcohol in the presence
einer Säure wie HCl. Auch die Umsetzung der Nitrile mit H2S in Lösungsmitteln wie Pyridin oder an acid like HCl. The reaction of the nitriles with H 2 S in solvents such as pyridine or
Dimethylformamid in Gegenwart einer Base wie Dimethylformamide in the presence of a base such as
Triethylamin und anschließende Alkylierung bzw. Triethylamine and subsequent alkylation or
Benzylierung führen zu Verbindungen der Formel X. Benzylation leads to compounds of formula X.
Ausgehend von Carbonsäureamiden, die im übrigen den Verbindungen der Formel X entsprechen, gelangt man auch durch Umsetzung mit einem Trialkyloxoniumsalz wie Starting from carboxamides, which otherwise correspond to the compounds of the formula X, the reaction can also be carried out with a trialkyloxonium salt such as
Triethyloxoniumtetrafluoroborat in einem Lösungsmittel wie Dichlormethan, Tetrahydrofuran oder Dioxan bei Temperaturen zwischen 0 und 50°C, vorzugsweise bei Raumtemperatur zu Verbindungen der Formel X. Triethyloxonium tetrafluoroborate in a solvent such as dichloromethane, tetrahydrofuran or dioxane at temperatures between 0 and 50 ° C., preferably at room temperature, to give compounds of the formula X.
Aus den Nitrilen XVI lassen sich durch Umsetzung mit Hydroxylamin in Alkoholen, z.B. Methanol, Ethanol, Propanol, Isopropanol, die entsprechenden Amidoxime der Formel XI erhalten. The nitriles XVI can be reacted with hydroxylamine in alcohols, for example methanol, ethanol, Propanol, isopropanol, the corresponding amidoximes of the formula XI obtained.
Auch die Ausgangsstoffe der Formeln XII, XIII, XIV und XV sind nach konventionellen Verfahren herstellbar. The starting materials of the formulas XII, XIII, XIV and XV can also be prepared by conventional processes.
Die erfindungsgemäßen Verbindungen sind therapeutisch verwendbar, insbesondere aufgrund ihrer The compounds according to the invention can be used therapeutically, in particular because of their
LTB4-antagonistischen Wirkung. Sie eignen sich daher für die Anwendung vor allem bei solchen Krankheiten, bei denen entzündliche und/oder allergische Vorgänge eine Rolle spielen, beispielsweise IBD (inflammatory bowel diseases), allergische Rhinitis; ARDS (adult respiratory distress syndron), Asthma, Colitis LTB 4 -antagonistic effect. They are therefore particularly suitable for use in those diseases in which inflammatory and / or allergic processes play a role, for example IBD (inflammatory bowel diseases), allergic rhinitis; ARDS (adult respiratory distress syndron), asthma, colitis
ulcerosa, Psoriasis, ferner zur Behandlung einer durch nichtsteroidale Antiphlogistika (NSAID) induzierten Gastropathie. Die neuen Verbindungen können auch in Kombination mit anderen Wirkstoffen angewendet werden, z. B. mit Antiallergika, Sekretolytika, ulcerative pain, psoriasis, also used to treat gastropathy induced by nonsteroidal anti-inflammatory drugs (NSAID). The new compounds can also be used in combination with other active ingredients, e.g. B. with antiallergics, secretolytics,
ß2-Adrenergika, inhalativ anwendbaren Steroiden, ß 2 adrenergics, inhalable steroids,
Antihistaminika und/oder PAF-Antagonisten. Die Antihistamines and / or PAF antagonists. The
Verabreichung kann topisch, oral, transdermal, nasal, parenteral oder inhalativ erfolgen. Administration can be topical, oral, transdermal, nasal, parenteral or inhalative.
Die therapeutische oder prophylaktische Dosis ist - außer von der Wirkungsstärke der einzelnen Verbindungen und dem Körpergewicht des Patienten - abhängig von der Beschaffenheit und Ernsthaftigkeit des The therapeutic or prophylactic dose is - apart from the potency of the individual compounds and the body weight of the patient - dependent on the nature and seriousness of the
Krankheitszustandes. Disease state.
Die neuen Verbindungen können topisch, oral, The new compounds can be administered topically, orally,
transdermal, parenteral oder durch Inhalation transdermally, parenterally or by inhalation
verabreicht werden. Die Verbindungen liegen hierbei als aktive Bestandteile in üblichen Darreichungsformen vor, z.B. in Zusammensetzungen, die im wesentlichen aus einem inerten pharmazeutischen Träger und einer be administered. The compounds are present as active constituents in customary dosage forms, eg in compositions consisting essentially of an inert pharmaceutical carrier and a
effektiven Dosis des Wirkstoffes bestehen, wie z.B. Tabletten, Dragees, Kapseln, Oblaten, Pulver, Lösungen, Suspensionen, Inhalationsaerosole, Salben, Emulsionen, Sirupe, Suppositorien usw. Eine wirksame Dosis der erfindungsgemäßen Verbindungen liegt bei oraler effective dose of the active ingredient, e.g. Tablets, coated tablets, capsules, wafers, powders, solutions, suspensions, inhalation aerosols, ointments, emulsions, syrups, suppositories, etc. An effective dose of the compounds according to the invention is oral
Anwendung zwischen 20 und 200 mg/Dosis. Für die Use between 20 and 200 mg / dose. For the
Inhalation sollen Pulver oder Lösungen, die 0,5 % bis 5 % Wirkstoff enthalten, eingesetzt werden, wobei die Dosis jeweils ca. 2 bis 20 mg Wirkstoff enthält. Inhalation should be used in powders or solutions containing 0.5% to 5% active ingredient, with each dose containing approximately 2 to 20 mg active ingredient.
Die neuen Verbindungen sind u.a. mit Antiallergika, Sekretolytika, ß2-Adrenergika, inhalativ anwendbaren Steroiden oder Antihistaminika kombinierbar. The new compounds can be combined, inter alia, with antiallergics, secretolytics, β 2 -adrenergics, inhalable steroids or antihistamines.
Die nachstehenden Beispiele zeigen einige Möglichkeiten für die Formulierung der Darreichungsformen. The examples below show some possibilities for the formulation of the dosage forms.
Formulierungsbeispiele Formulation examples
1. Tabletten 1. tablets
Zusammensetzung: Composition:
Wirkstoff gemäß der Erfindung 20 Gew. -Teile Active ingredient according to the invention 20 parts by weight
Stearinsäure 6 Gew. -TeileStearic acid 6 parts by weight
Traubenzucker 474 Gew. -Teile Dextrose 474 parts by weight
Die Bestandteile werden in üblicher Weise zu Tabletten von 500 mg Gewicht verarbeitet. The ingredients are processed in the usual way to tablets of 500 mg weight.
Gewunschtenfalls kann der Wirkstoffgehalt erhöht oder vermindert und die Traubenzuckermenge entsprechend vermindert oder erhöht werden.  If desired, the active ingredient content can be increased or decreased and the amount of glucose reduced or increased accordingly.
2. Suppositorien 2. Suppositories
Zusammensetzung: Composition:
Wirkstoff gemäß der Erfindung 100 Gew. -Teile Active ingredient according to the invention 100 parts by weight
Laktose, gepulvert 45 Gew. -TeileLactose, powdered 45 parts by weight
Kakao-Butter 1555 Gew. -Teile Cocoa butter 1555 parts by weight
Die Bestandteile werden in üblicher Weise zu Suppositorien von 1,7 g Gewicht verarbeitet. The ingredients are processed in the usual way into suppositories weighing 1.7 g.
3. Inhalationspulver 3. Inhalation powder
Mikronisiertes Wirkstoffpulver (Verbindung der Formel I; Teilchengrδße ca. 0,5 bis 7 μm) werden in einer Menge von 5 mg gegebenenfalls unter Zusatz mikronisierter Lactose in Micronized active ingredient powder (compound of formula I; particle size approx. 0.5 to 7 μm) is added in an amount of 5 mg, optionally with the addition of micronized lactose
Hartgelatinekapseln abgefüllt. Das Pulver wird aus üblichen Inhalationsgeräten, z.B. gemäß DE-A 3 345 722, inhaliert. Die erfindungsgemäßen Verbindungen wurden u.a. auf ihre Wirkung in den nachstehenden Testen untersucht. a) LTB4 Rezeptorverbindungstest Bottled hard gelatin capsules. The powder is inhaled from conventional inhalation devices, for example according to DE-A 3 345 722. The compounds of the invention were examined, inter alia, for their action in the tests below. a) LTB 4 receptor connection test
Die Bindung von 3H-LTB4 (3nM) auf vitalen Binding of 3 H-LTB 4 (3nM) to vital
U937-Zellen (differenzierte, humane monozytäre Zellinie mit natürlich exprimierten  U937 cells (differentiated, human monocytic cell line with naturally expressed
LTB4-Rezeptoren) wird durch steigende LTB 4 receptors) is increasing by
Konzentration der Testsubstanz dosisabhängig inhibiert (Inkubation 2h bei 0°C). Nach  Concentration of the test substance is dose-dependent inhibited (incubation 2 h at 0 ° C). To
Abtrennung des ungebundenen 3H-LTB4 durch Separation of the unbound 3 H-LTB 4 by
Membranfiltration wird die Radioaktivität des gebundenen LTB4-Rezeptor/3H-LTB4-Komplexes durch Szintilationsmessung quantifiziert. Membrane filtration, the radioactivity of the bound LTB 4 receptor / 3 H-LTB 4 complex is quantified by scintillation measurement.
Die Bestimmung der Affinität  Determination of affinity
(Inhibitionskonstante Ki) erfolgte durch (Inhibition constant K i ) was carried out by
iterative Anpassung einer Verdrängungskurve an die Meßwerte (Programm: "gekoppelte  iterative adaptation of a displacement curve to the measured values (program: "coupled
Massengleichgewichte" auf Wang- Computer). b) Aggregation von neutrophilen Granulozvten des  Mass equilibria "on Wang computer). B) Aggregation of neutrophilic granulocytes of the
Meerschweinchens  Guinea pig
Induziert durch LTB4 in vitro (Zunahme der Induced by LTB 4 in vitro (increase in
Lichttransmission im Aggregometer, aufgezeichnet in mm; je Experiment Doppelbestimmung): Hemmung 2 min nach Inkubation mit PrüfSubstanz in  Light transmission in the aggregometer, recorded in mm; double determination per experiment): Inhibition 2 min after incubation with test substance in
Polydiol/DMSO. c) Leukotrien-B4-induzierte Neutrophilen- Akkumulation am Mäuseohr Polydiol / DMSO. c) Leukotriene B 4 -induced neutrophil accumulation on the mouse ear
Bewertung des neutrophilen Einstroms durch fotometrische Messung (mOD/min) der Myeloperoxidaseaktivität (Bradley et al.: J. Evaluation of the neutrophil inflow by photometric measurement (mOD / min) of the Myeloperoxidase activity (Bradley et al .: J.
Invest. Dermatol. 78 , 206, 1982) in der Ohrhaut. Zunahme 6h nach topischer Behandlung des linken Ohres mit LTB4 (beidseitig je 250 ng) gegenüber dem rechten Ohr (2 x 5 μl Aceton als Invest. Dermatol. 78, 206, 1982) in the ear skin. Increase 6h after topical treatment of the left ear with LTB 4 (250 ng on both sides) compared to the right ear (2 x 5 μl acetone as
Lösungsmittel).  Solvent).
Substanzgabe per os in 1 %iger Tylose 300, 30 min vor LTB4-Reiz. Substance administration per os in 1% tylose 300, 30 min before LTB 4 stimulus.
Die Ki-Werte aus Test a) liegen für die The K i values from test a) lie for the
erfindungsgemäßen Verbindungen zwischen etwa 1 und compounds according to the invention between about 1 and
20 nmol/l, vorzugsweise unter 10 nmol/1. Hervorzuheben ist die günstige orale Wirkung der neuen Verbindungen. 20 nmol / l, preferably below 10 nmol / 1. The favorable oral effects of the new compounds should be emphasized.
Die nachstehenden Beispiele verdeutlichen die The following examples illustrate the
Herstellmöglichkeiten der erfindungsgemäßen Manufacturing possibilities of the invention
Verbindungen. In den Tabellen bedeutet BS Base, während die in den Salzen enthaltenen Säuren wie folgt abgekürzt sind: Links. In the tables, BS means base, while the acids contained in the salts are abbreviated as follows:
1. AC,  1. AC,
2. MS,  2. MS,
3. FU,  3rd FU,
4. FU1.  4. FU1.
Die in den entsprechenden Salzen vorliegenden Anionen sind  The anions present in the corresponding salts are
1. CH3COO(-), 2. CH3SO3 (-), 1. CH 3 COO (-) , 2. CH 3 SO 3 (-) ,
3. HC-COO(-), 4. HC-COO(-) 3rd HC-COO (-) , 4th HC-COO (-)
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000019_0001
Figure imgf000019_0002
(-)OOC-CH HOOC-CH Verfahren 1 ( -) OOC-CH HOOC-CH Procedure 1
Beispiel 1 example 1
Figure imgf000020_0001
Figure imgf000020_0001
9,6 g 4-[2-(2-Benzthiazolyloxy)-ethoxy]-benzonitril werden in 100 ml absolutem Dichlormethan und 100 ml absolutem Ethanol gelöst. Bei ca. -15°C wird 4 Stunden HCl-Gas eingeleitet. Man läßt über Nacht bei 9.6 g of 4- [2- (2-benzothiazolyloxy) ethoxy] benzonitrile are dissolved in 100 ml of absolute dichloromethane and 100 ml of absolute ethanol. At about -15 ° C, HCl gas is introduced for 4 hours. You let in overnight
Raumtemperatur stehen, fügt ca. 800 ml Aether zu und dekantiert das Lösungsmittel von den angefallenen Stand at room temperature, add about 800 ml of ether and decant the solvent from the accrued
Kristallen ab. Der Rückstand wird in 50 ml Ethanol gelöst und nach Zugabe von 50 ml mit Ammoniak Crystals. The residue is dissolved in 50 ml of ethanol and after the addition of 50 ml with ammonia
gesättigtem Ethanol 1,5 Stunden unter Rückfluß gekocht. Das Lösungsmittel wird im Vakuum abdestilliert und der Rückstand aus Ethanol/Diethylether umkristallisiert. Man erhält 2.5 g 4-[2-(2-Benzthiazolyloxy)-ethoxy]- benzamidin Hydrochlorid mit einem Schmelzpunkt von 205-207°C. saturated ethanol boiled under reflux for 1.5 hours. The solvent is distilled off in vacuo and the residue is recrystallized from ethanol / diethyl ether. 2.5 g of 4- [2- (2-benzothiazolyloxy) ethoxy] benzamidine hydrochloride with a melting point of 205-207 ° C. are obtained.
Verfahren 2 Procedure 2
Beispiel 2 Example 2
Figure imgf000021_0001
Figure imgf000021_0001
3,85 g 4-[5-(5-Methyl-2-benzoxazolyl-mercapto]- pentyloxy-benzamidoxim Methansulfonat werden in 200 ml Methanol gelöst. Nach Zugabe von Raney-Nickel wird bei 50°C unter Normalbedingungen so lange hydriert bis die berechnete Menge Wasserstoff aufgenommen wurde (ca. 5 Stunden). Es wird vom Katalysator abgesaugt, das 3.85 g of 4- [5- (5-methyl-2-benzoxazolyl-mercapto] - pentyloxy-benzamidoxime methanesulfonate are dissolved in 200 ml of methanol. After addition of Raney nickel, the mixture is hydrogenated at 50 ° C. under normal conditions until the calculated amount of hydrogen was absorbed (about 5 hours)
Lösungsmittel abdestilliert und der Rückstand aus Isopropylalkohol umkristallisiert. Das Methansulfonat des 4-[5-(5-Methyl-2-benz.oxyzolyl-mercapto]-pentyloxy- benzamidin schmilzt bei 129-130°C. The solvent was distilled off and the residue was recrystallized from isopropyl alcohol. The methanesulfonate of 4- [5- (5-methyl-2-benz.oxyzolyl-mercapto] -pentyloxy-benzamidine melts at 129-130 ° C.
Verfahren 3 Procedure 3
Beispiel 3 Example 3
Figure imgf000022_0001
Figure imgf000022_0001
1,6 g 2-Mercapto-5-phenyl-1,2,4-oxadiazol werden in 40 ml absolutem Dimethylformamid gelöst. Nach Zugabe von 270 mg Natriumhydrid-Dispersion (80 %ig) wird zunächst eine halbe Stunden bei Raumtemperatur gerührt. Man erwärmt dann auf 50°C und tropft langsam eine 1.6 g of 2-mercapto-5-phenyl-1,2,4-oxadiazole are dissolved in 40 ml of absolute dimethylformamide. After adding 270 mg of sodium hydride dispersion (80%), the mixture is first stirred at room temperature for half an hour. The mixture is then heated to 50 ° C. and one is slowly added dropwise
Lösung 2 g 4-Bromethoxy-benzamidin, gelöst in 40 ml absolutem Dimethylformamid zu. Man läßt noch 2 Stunden bei 50°C nachreagieren, kühlt ab und gießt auf  Solution 2 g of 4-bromoethoxy-benzamidine, dissolved in 40 ml of absolute dimethylformamide. The mixture is left to react for a further 2 hours at 50 ° C., cooled and poured on
Eiswasser. Man saugt ab, suspendiert in Ethanol und gibt etherische Salzsäure bis zur sauren Reaktion zu. Die zwischenzeitlich gelöste Verbindung fällt als  Ice water. It is suctioned off, suspended in ethanol and ethereal hydrochloric acid is added until an acid reaction. The connection that has been released in the meantime falls as
Hydrochlorid aus. Man saugt ab und kristallisiert aus Wasser um. Nach dem Trocknen erhält man 0,6 g  Hydrochloride. It is suctioned off and recrystallized from water. After drying, 0.6 g is obtained
2-[2-(4-amidino-phenoxy)-ethylmercapto]-5-phenyl-1,3,4- oxadiazol als Hydrochlorid (Fp: 237 - 8°C).  2- [2- (4-amidino-phenoxy) -ethylmercapto] -5-phenyl-1,3,4-oxadiazole as hydrochloride (mp: 237-8 ° C).
Analog diesen Beispielen können folgende Verbindungen hergestellt werden:
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
The following compounds can be prepared analogously to these examples:
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000045_0001
Figure imgf000046_0001

Claims

Patentansprüche Claims
Amidinderivate der Formel Amidine derivatives of the formula
Figure imgf000047_0001
Figure imgf000047_0001
in der für eine der Gruppen in for one of the groups
X1-A1-X2 (II) X 1 -A 1 -X 2 (II)
X2-A1-x1 (III) X 2 -A 1 -x 1 (III)
Figure imgf000047_0002
wobei eine geradkettige oder verzweigte zweibindige aliphatische C2-C6-Gruppe bedeutet, die auch eine Doppel- oder Dreifachbindung enthalten kann, oder eine der Gruppen
Figure imgf000048_0001
Figure imgf000047_0002
wherein a straight-chain or branched double-bonded aliphatic C 2 -C 6 group, which can also contain a double or triple bond, or one of the groups
Figure imgf000048_0001
bedeutet, X1 für O, S, SO, SO2, CH2, NH oder X
Figure imgf000048_0002
means X 1 for O, S, SO, SO 2 , CH 2 , NH or X
Figure imgf000048_0002
X2 für O, S, CH2 oder OX 2 for O, S, CH 2 or O
Figure imgf000048_0003
Figure imgf000048_0003
B für CH=CH, CH=N, S oder
Figure imgf000048_0004
B for CH = CH, CH = N, S or
Figure imgf000048_0004
Het für einen Heterocyclus oder ein heterocyclischesHet for a heterocycle or a heterocyclic
System aus zwei oder drei kondensierten Ringen, das ein bis drei Substituenten enthalten kann, System of two or three condensed rings, which can contain one to three substituents,
R4 für H, F, Cl, Br, J, NH2, NH- (C1-C4-Alkyl), R 4 for H, F, Cl, Br, J, NH 2 , NH- (C 1 -C 4 alkyl),
N(C1-C4-Alkyl)2, OH, C1-C4-Alkoxy, N (C 1 -C 4 alkyl) 2 , OH, C 1 -C 4 alkoxy,
C1-C4-Alkyl, Phenyl, R11, R12, die gleich oder verschieden sein C 1 -C 4 alkyl, phenyl, R 11 , R 12 , which may be the same or different
können,  can,
für H, OH, F, Cl, Br, J, CF3, C1-C4-Alkyl oderfor H, OH, F, Cl, Br, J, CF 3 , C 1 -C 4 alkyl or
-Alkoxy, stehen, -Alkoxy, stand,
(wobei chirale Verbindungen in Form von Racematen, enantiomerenreiner bzw. angereicherter Form vorliegen können), jeweils als Base oder als Salze mit anorganischen oder organischen Säuren.  (where chiral compounds can be in the form of racemates, enantiomerically pure or enriched form), in each case as a base or as salts with inorganic or organic acids.
Verbindungen nach Anspruch 1, worin Het für die Gruppen (a) bis (z): Compounds according to claim 1, wherein Het for groups (a) to (z):
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
und
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
and
R1 und R2, die gleich oder verschieden sein R 1 and R 2 , which are the same or different
können, für CF3, Halogen, R5, OR5, COR6, can, for CF 3 , halogen, R 5 , OR 5 , COR 6 ,
SR6, SOR6, SO2Rg, SO2NR5R7, SR 6 , SOR 6 , SO 2 Rg, SO 2 NR 5 R 7 ,
C(OH)R5R7 oder gemeinsam auch für die mit C (OH) R5R 7 or together for those with
benachbarten C-Atomen des Benzolrings verknüpften zweibindigen Gruppen -CR8=CR9-CH=CH-, adjacent C atoms of the benzene ring linked divalent groups -CR 8 = CR 9 -CH = CH-,
-CH=CR8-CR9=CH- , -CR8=CH-CR9=CH-, -CH = CR 8 -CR 9 = CH-, -CR 8 = CH-CR 9 = CH-,
-O-CHR10-CH2-, .-O-CH2-O-, -O-CH2-CH2-O-, -O-CHR 10 -CH 2 -,.-O-CH 2 -O-, -O-CH 2 -CH 2 -O-,
-(CH2)3-4-, -NH-CO-O-, -NH-CO-CH2-O-, - (CH 2 ) 3-4 -, -NH-CO-O-, -NH-CO-CH 2 -O-,
-CO-CH2-O- oder -CO-CH2CH2-O- stehen, wobei -CO-CH 2 -O- or -CO-CH 2 CH 2 -O-, where
diese Gruppen ihrerseits auch durch  these groups for their part
C1-C4-Alkyl substituiert sein können, C 1 -C 4 alkyl can be substituted,
R3 für Halogen, OH, CF3, R5, OR6, COR6, R 3 for halogen, OH, CF 3 , R 5 , OR 6 , COR 6 ,
CONR5R7, CH2OH, CH2-O- (C1-C4-Alkyl), CONR 5 R 7 , CH 2 OH, CH 2 -O- (C 1 -C 4 alkyl),
SR6, SOR6, SO2R6, SO2NR5R7, SR 6 , SOR 6 , SO 2 R 6 , SO 2 NR 5 R 7 ,
NH-CO-(C1-C4-7llkyl), NH-CO- (C 1 -C 4 -7 alkyl),
NH-SO2-(C1-C4-Alkyl), NR5R7 oder NH-SO 2 - (C 1 -C 4 alkyl), NR 5 R 7 or
C(OH)R5R7 steht, für einen heterocyclischen Fünfring mit 1 bis 3 Heteroatomen und der Formel C (OH) R 5 R 7 represents a heterocyclic five-membered ring with 1 to 3 heteroatoms and the formula
Figure imgf000054_0002
Figure imgf000054_0002
(worin D, E und G, die gleich oder verschieden  (where D, E and G are the same or different
sein können, CH, N, C-(C1-C4-Alkyl) oder can be, CH, N, C- (C 1 -C 4 alkyl) or
C-Phenyl bedeuten und L O oder S ist), R4 für H, Halogen, C1-C4-Alkyl, NH2, NH-(C1-C4-Alkyl), N(C1-C4-Alkyl)2, OH, C1-C4-Alkoxy oder Phenyl, Is C-phenyl and is LO or S), R 4 for H, halogen, C 1 -C 4 alkyl, NH 2 , NH- (C 1 -C 4 alkyl), N (C 1 -C 4 alkyl) 2 , OH, C 1 -C 4 - Alkoxy or phenyl,
R5 für H, C1-C12-Alkyl, Pyridyl, Phenyl, gegebenenfalls durch Halogen, C1-C4-Alkyl, C1-C4-Alkoxy R 5 is H, C 1 -C 12 alkyl, pyridyl, phenyl, optionally by halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy
oder C2-C5-Acyl substituiertes Phenyl oder or C 2 -C 5 acyl substituted phenyl or
Phenyl- (C1-C4-Alkyl), Phenyl- (C 1 -C 4 alkyl),
R6 für C1-C12-Alkyl, Phenyl oder gegebenenfalls R 6 for C 1 -C 12 alkyl, phenyl or optionally
durch Halogen, C1-C4-Alkyl, C1-C4-Alkoxy by halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy
oder C2-C5-Acyl substituiertes Phenyl, or C 2 -C 5 acyl substituted phenyl,
R7 für H oder C1-C12-Alkyl, R 7 is H or C 1 -C 12 alkyl,
R8, R9 (die gleich oder verschieden sein können) R 8 , R 9 (which may be the same or different)
für H, OH, C1-C4-Alkyl, C1-C4-Alkoxy oder for H, OH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or
C2-C5-Acyl, C 2 -C 5 acyl,
R10 für H oder C1-C4-Alkyl, R 10 is H or C 1 -C 4 alkyl,
R11, R12, die gleich oder verschieden sein können, R 11 , R 12 , which can be the same or different,
für H, OH, Halogen, CF3, C1-C4-Alkyl oder for H, OH, halogen, CF 3 , C 1 -C 4 alkyl or
C1-C4-Alkoxy, C 1 -C 4 alkoxy,
R13, R14, die gleich oder verschieden sein können, R 13 , R 14 , which may be the same or different,
für H, C1-C4-Alkyl, C1-C4-Alkoxy, Phenyl, for H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, phenyl,
Naphthyl, wobei diese Ringsysteme ein- oder  Naphthyl, these ring systems one or
mehrfach durch gleiche oder verschiedene Reste aus der Gruppe Fluor, Chlor, Brom, C1-C4-Alkyl, several times by identical or different radicals from the group fluorine, chlorine, bromine, C 1 -C 4 alkyl,
C1-C4-Alkoxy oder Pseudohalogene wie CN, CF3 substituiert sein können, oder für Pyridyl. C 1 -C 4 alkoxy or pseudohalogens such as CN, CF 3 may be substituted, or for pyridyl.
3. Verbindungen nach Anspruch 1 oder 2 mit der Formel 3. Compounds according to claim 1 or 2 with the formula
Het' -X1' -A1' -X2'— (Ia),Het '-X 1 ' -A 1 '-X 2 ' - (Ia),
Figure imgf000056_0001
Figure imgf000056_0001
worin A1 ', X1' , X2 'und Het' folgendes wherein A 1 ', X 1 ', X 2 'and Het' are the following
bedeuten:  mean:
A1 ' : (CH2)2-6, CH2-C6H4-CH2, A 1 ': (CH 2 ) 2-6 , CH 2 -C 6 H 4 -CH 2 ,
Z oder E CH2-CH=CH-CH2, Z or E CH 2 -CH = CH-CH 2 ,
CH2-C=C-CH2; CH 2 -C = C-CH 2 ;
X1 ' : O, S; X 1 ': O, S;
X2 ': O, S; X 2 ': O, S;
Het' : eine Gruppe der obigen Formeln a, b, e, f, g, k, n, wobei R1, R2, R3, die gleich oder verschieden sein können, H,Het ': a group of the above formulas a, b, e, f, g, k, n, where R 1 , R 2 , R 3 , which may be the same or different, H,
R5, OR5 oder COR5 bedeuten und R 5 , OR 5 or COR 5 mean and
R1 und R2 gemeinsam auch einen R 1 and R 2 together also one
ankondensierten Ring bedeuten können.  condensed ring can mean.
4. Die Verbindungen der Formel 4. The compounds of the formula
Figure imgf000056_0002
Figure imgf000057_0001
Figure imgf000056_0002
Figure imgf000057_0001
bedeutet, und ihre Säureadditionssalze. 5. Arzneimittel, gekennzeichnet durch einen Gehalt an einer Verbindung nach Anspruch 1 bis 4. 6. Verwendung von Verbindungen nach Anspruch 1 bis 4 bei der Herstellung von Arzneimitteln für die Behandlung von Krankheiten, bei denen entzündliche und/oder allergische Vorgänge eine Rolle spielen, insbesondere Asthma, Colitis ulcerosa, Psoriasis und zur Behandlung einer durch nichtsteroidale Antiphlogistika induzierten Gastropathie. means, and their acid addition salts. 5. Medicaments, characterized in that they contain a compound according to Claims 1 to 4. 6. Use of compounds according to Claims 1 to 4 in the manufacture of medicaments for the treatment of diseases in which inflammatory and / or allergic processes play a role. especially asthma, ulcerative colitis, psoriasis and for the treatment of gastropathy induced by non-steroidal anti-inflammatory drugs.
7. Verwendung einer wirksamen Dosis einer Verbindung nach Anspruch 1 - 4 zur Behandlung von 7. Use of an effective dose of a compound according to claims 1-4 for the treatment of
Krankheiten, bei denen LTB4-antagonistische Diseases where LTB 4 is antagonistic
Verbindungen eingesetzt werden können. 8. Verwendung einer wirksamen Dosis einer Verbindung nach Anspruch 1 bis 4 für die Behandlung von  Connections can be used. 8. Use of an effective dose of a compound according to claims 1 to 4 for the treatment of
Krankheiten, bei denen entzündliche und/oder allergische Vorgänge eine Rolle spielen,  Diseases in which inflammatory and / or allergic processes play a role,
insbesondere Asthma, Colitis ulcerosa, Psoriasis, sowie zur Behandlung einer durch nichtsteroidale Antiphlogistika induzierten Gastropathie. 9. Verfahren zur Herstellung der Verbindungen nach  in particular asthma, ulcerative colitis, psoriasis, and for the treatment of gastropathy induced by non-steroidal anti-inflammatory drugs. 9. Process for the preparation of the compounds according to
Anspruch 1 bis 4 in an sich bekannter Weise, dadurch gekennzeichnet, daß man a) eine Verbindung der Formel  Claims 1 to 4 in a manner known per se, characterized in that a) a compound of the formula
Figure imgf000058_0001
Figure imgf000058_0001
(worin Het, R4, A und B die obige Bedeutung haben und R bevorzugt für einen (wherein Het, R 4 , A and B have the above meaning and R preferably for one
C1-C4-Alkylrest oder für Benzyl steht) mit Ammoniak in einem inerten Lösungsmittel umsetzt oder daß man b) ein Amidoxim der Formel
Figure imgf000059_0001
C 1 -C 4 alkyl radical or stands for benzyl) with ammonia in an inert solvent or that b) an amidoxime of the formula
Figure imgf000059_0001
(worin Het, R4, A und B die obige Bedeutung haben) mit Wasserstoff in Gegenwart eines Katalysators reduziert oder daß man c) Verbindungen der Formel XII mit Verbindungen der Formel XIII bzw. Verbindungen der Formel XIV mit Verbindungen der Formel XV umsetzt. (in which Het, R 4 , A and B have the above meaning) reduced with hydrogen in the presence of a catalyst or that c) reacting compounds of the formula XII with compounds of the formula XIII or compounds of the formula XIV with compounds of the formula XV.
PCT/EP1994/000856 1993-03-23 1994-03-18 Heterocycle-containing amidine derivatives, their preparation and use WO1994021616A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6380259B2 (en) 1997-12-12 2002-04-30 Novartis Ag Use of substituted amidino compounds in the treatment of chronic obstructive pulmonary disease
US8030305B2 (en) 2005-12-21 2011-10-04 Janssen Pharmaceutica N.V. Triazolopyridazines as kinase modulators
US8178688B2 (en) 2004-08-04 2012-05-15 Dong Wha Pharmaceutical Co., Ltd. Benzamidine derivatives, process for the preparation thereof and pharmaceutical composition comprising the same
CN102993109A (en) * 2012-12-03 2013-03-27 浙江工业大学 Preparation method of amidine compound
US9187439B2 (en) 2011-09-21 2015-11-17 Inception Orion, Inc. Tricyclic compounds useful as neurogenic and neuroprotective agents

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US9187439B2 (en) 2011-09-21 2015-11-17 Inception Orion, Inc. Tricyclic compounds useful as neurogenic and neuroprotective agents
CN102993109A (en) * 2012-12-03 2013-03-27 浙江工业大学 Preparation method of amidine compound

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