WO1994021616A1 - Derives d'amidine contenant des heterocycles, leur preparation et leur utilisation - Google Patents

Derives d'amidine contenant des heterocycles, leur preparation et leur utilisation 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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WIPO (PCT)
Prior art keywords
alkyl
formula
alkoxy
compounds
phenyl
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PCT/EP1994/000856
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German (de)
English (en)
Inventor
Ernst-Otto Renth
Kurt Schromm
Ralf Anderskewitz
Franz Birke
Armin Fügner
Hubert Heuer
Original Assignee
Boehringer Ingelheim Kg
Boehringer Ingelheim International Gmbh
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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 EP94911191A priority patent/EP0690849A1/fr
Priority to JP6520657A priority patent/JPH08508467A/ja
Priority to SK1174-95A priority patent/SK117495A3/sk
Publication of WO1994021616A1 publication Critical patent/WO1994021616A1/fr
Priority to KR1019950704014A priority patent/KR960701026A/ko
Priority to NO953763A priority patent/NO953763L/no
Priority to LVP-95-291A priority patent/LV11465B/lv
Priority to FI954491A priority patent/FI954491A/fi
Priority to BG100069A priority patent/BG100069A/xx

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    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • 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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    • 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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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

On peut préparer par des procédés classiques des composés ayant la formule (I), dont la signification est expliquée plus en détail dans la description, et les utiliser dans des compositions galéniques thérapeutiques.
PCT/EP1994/000856 1993-03-23 1994-03-18 Derives d'amidine contenant des heterocycles, leur preparation et leur utilisation WO1994021616A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
AU63780/94A AU6378094A (en) 1993-03-23 1994-03-18 Heterocycle-containing amidine derivatives, their preparation and use
EP94911191A EP0690849A1 (fr) 1993-03-23 1994-03-18 Derives d'amidine contenant des heterocycles, leur preparation et leur utilisation
JP6520657A JPH08508467A (ja) 1993-03-23 1994-03-18 複素環式基を含むアミジン誘導体、その製造方法及びそれらの使用
SK1174-95A SK117495A3 (en) 1993-03-23 1994-03-18 Heterocycle containing amidine derivatives, their preparation and use
KR1019950704014A KR960701026A (ko) 1993-03-23 1995-09-21 헤테로사이클 함유 아미딘 유도체, 이의 제조방법 및 이의 용도(Heterocycle-containing amidine derivatives, their preparation and use)
NO953763A NO953763L (no) 1993-03-23 1995-09-22 Heterocykel-holdige amidin-derivater, deres fremstilling og anvendelse
LVP-95-291A LV11465B (en) 1993-03-23 1995-09-22 Heterocycle-containing amidine derivatives, their preparation and use
FI954491A FI954491A (fi) 1993-03-23 1995-09-22 Heterosykliä sisältäviä amidiinijohdokset, niiden valmistus ja käyttö
BG100069A BG100069A (en) 1993-03-23 1995-10-17 Amidine derivatives containing heterocylic groups, their preparation and application

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4309285.3 1993-03-23
DE4309285A DE4309285A1 (de) 1993-03-23 1993-03-23 Heterocyclen enthaltende Amidinderivate, ihre Herstellung und Verwendung

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KR (1) KR960701026A (fr)
CN (1) CN1124486A (fr)
AU (1) AU6378094A (fr)
BG (1) BG100069A (fr)
CA (1) CA2158994A1 (fr)
CZ (1) CZ246695A3 (fr)
DE (1) DE4309285A1 (fr)
FI (1) FI954491A (fr)
HU (1) HUT73968A (fr)
IL (1) IL109073A0 (fr)
LV (1) LV11465B (fr)
NO (1) NO953763L (fr)
PL (1) PL310806A1 (fr)
SK (1) SK117495A3 (fr)
WO (1) WO1994021616A1 (fr)
ZA (1) ZA941993B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
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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 (zh) * 2012-12-03 2013-03-27 浙江工业大学 一种脒化合物的制备方法
US9187439B2 (en) 2011-09-21 2015-11-17 Inception Orion, Inc. Tricyclic compounds useful as neurogenic and neuroprotective agents

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DE19546452A1 (de) * 1995-12-13 1997-06-19 Boehringer Ingelheim Kg Neue Phenylamidinderivate, Verfahren zu ihrer Herstelung und ihre Verwendung als Arzneimittel
US20080200526A1 (en) * 2004-07-05 2008-08-21 Jin Soo Lee Composition for the Prevention and Treatment of Allergic Inflammatory Disease
US7683060B2 (en) 2006-08-07 2010-03-23 Incyte Corporation Triazolotriazines as kinase inhibitors
PL2099447T3 (pl) 2006-11-22 2013-06-28 Incyte Holdings Corp Imidazotriazyny i imidazopirmidyny jako inhibitory kinaz
HUE034716T2 (hu) 2008-05-21 2018-02-28 Incyte Holdings Corp 2-Fluor-N-metil-4-[7-(kinolin-6-il-metil)-imidazo[1,2-b][1,2,4]triazin-2-il]benzamid sói és eljárások ezek elõállítására
CN102812027B (zh) 2010-02-03 2015-01-07 因西特公司 作为C-MET抑制剂的咪唑并[1,2-b][1,2,4]三嗪
KR101216274B1 (ko) * 2011-06-17 2012-12-28 이화여자대학교 산학협력단 골다공증 완화, 예방 또는 치료효과의 신규한 화합물, 이의 제조방법 및 이를 포함하는 약학조성물
WO2023144450A1 (fr) * 2022-01-28 2023-08-03 Oulun Yliopisto Composés destinés à être utilisés dans le traitement du cancer et d'états inflammatoires
US11919872B1 (en) 2023-10-11 2024-03-05 King Faisal University N′-(2-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthio)acetoxy)benzimidamide as an antimicrobial compound
US11897850B1 (en) 2023-10-11 2024-02-13 King Faisal University N′-(2-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthio)acetoxy)-4-methoxybenzimidamide as an antimicrobial compound
US11912675B1 (en) 2023-10-11 2024-02-27 King Faisal University N'-(2-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthio)acetoxy)-3,4-dimethoxybenzimidamide as an antimicrobial compound
US11976050B1 (en) 2023-10-11 2024-05-07 King Faisal University N′-(2-(5-(4-chlorophenyl)-1,3,4-oxadiazol-2-ylthio)acetoxy)-1-naphthimidamide as an antimicrobial compound
US11891366B1 (en) 2023-10-12 2024-02-06 King Faisal University 4-methoxy-n′-(2-(5-phenyl-1,3,4-oxadiazol-2-ylthio)acetoxy)benzimidamide as an antimicrobial compound
US11932632B1 (en) 2023-10-13 2024-03-19 King Faisal University N'-(2-(5-phenyl-1,3,4-oxadiazol-2-ylthio)acetoxy)benzo[d][1,3]dioxole-5 carboximidamide as an antimicrobial compound
US11905263B1 (en) 2023-10-13 2024-02-20 King Faisal University 4-nitro-N′-(2-(5-phenyl-1,3,4-oxadiazol-2-ylthio)acetoxy)benzimidamide as an antimicrobial compound

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GB868552A (en) * 1957-12-03 1961-05-17 Wellcome Found Improvements in or relating to novel amidines and the preparation thereof
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Cited By (6)

* 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
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
US8030305B2 (en) 2005-12-21 2011-10-04 Janssen Pharmaceutica N.V. Triazolopyridazines as kinase modulators
US8173654B2 (en) 2005-12-21 2012-05-08 Janssen Pharmaceutica N.V. Triazolopyridazine compounds
US9187439B2 (en) 2011-09-21 2015-11-17 Inception Orion, Inc. Tricyclic compounds useful as neurogenic and neuroprotective agents
CN102993109A (zh) * 2012-12-03 2013-03-27 浙江工业大学 一种脒化合物的制备方法

Also Published As

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DE4309285A1 (de) 1994-09-29
EP0690849A1 (fr) 1996-01-10
NO953763L (no) 1995-09-25
IL109073A0 (en) 1994-06-24
JPH08508467A (ja) 1996-09-10
LV11465A (lv) 1996-08-20
AU6378094A (en) 1994-10-11
CA2158994A1 (fr) 1994-09-29
ZA941993B (en) 1994-09-23
HUT73968A (en) 1996-10-28
PL310806A1 (en) 1996-01-08
LV11465B (en) 1996-12-20
NO953763D0 (no) 1995-09-22
CZ246695A3 (en) 1996-02-14
FI954491A0 (fi) 1995-09-22
CN1124486A (zh) 1996-06-12
SK117495A3 (en) 1996-01-10
BG100069A (en) 1996-04-30
FI954491A (fi) 1995-09-22
KR960701026A (ko) 1996-02-24
HU9502778D0 (en) 1995-11-28

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