DE4310051A1 - Treating allergic rhinitis or conjunctivitis - using 3-substd. 6-(substd. phenyl)-pyridazine deriv., also for treating e.g. nasal polyps - Google Patents
Treating allergic rhinitis or conjunctivitis - using 3-substd. 6-(substd. phenyl)-pyridazine deriv., also for treating e.g. nasal polypsInfo
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- DE4310051A1 DE4310051A1 DE19934310051 DE4310051A DE4310051A1 DE 4310051 A1 DE4310051 A1 DE 4310051A1 DE 19934310051 DE19934310051 DE 19934310051 DE 4310051 A DE4310051 A DE 4310051A DE 4310051 A1 DE4310051 A1 DE 4310051A1
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- formula
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- acceptable salts
- pyridazinone
- treatment
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Links
- 206010010744 Conjunctivitis allergic Diseases 0.000 title claims abstract description 8
- 206010039085 Rhinitis allergic Diseases 0.000 title claims abstract description 8
- 208000002205 allergic conjunctivitis Diseases 0.000 title claims abstract description 8
- 201000010105 allergic rhinitis Diseases 0.000 title claims abstract description 8
- 208000024998 atopic conjunctivitis Diseases 0.000 title claims abstract description 8
- 208000000592 Nasal Polyps Diseases 0.000 title claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims abstract description 6
- 230000000172 allergic effect Effects 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims abstract description 4
- 206010039083 rhinitis Diseases 0.000 claims abstract description 4
- 208000010668 atopic eczema Diseases 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 3
- 230000001684 chronic effect Effects 0.000 claims abstract description 3
- 210000002345 respiratory system Anatomy 0.000 claims abstract description 3
- 201000009151 chronic rhinitis Diseases 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 229940126601 medicinal product Drugs 0.000 claims description 4
- HJMQDJPMQIHLPB-UHFFFAOYSA-N zardaverine Chemical compound C1=C(OC(F)F)C(OC)=CC(C2=NNC(=O)C=C2)=C1 HJMQDJPMQIHLPB-UHFFFAOYSA-N 0.000 claims description 3
- ZIBIPBVCDQSCAW-UHFFFAOYSA-N 3-(3-methoxy-4-propoxyphenyl)-1h-pyridazin-6-one Chemical compound C1=C(OC)C(OCCC)=CC=C1C1=NNC(=O)C=C1 ZIBIPBVCDQSCAW-UHFFFAOYSA-N 0.000 claims description 2
- UQBFDCXCVIJNBN-UHFFFAOYSA-N 3-(4-methoxy-3-propoxyphenyl)-1h-pyridazin-6-one Chemical compound C1=C(OC)C(OCCC)=CC(C2=NNC(=O)C=C2)=C1 UQBFDCXCVIJNBN-UHFFFAOYSA-N 0.000 claims description 2
- WWIRWLQXYQJRSZ-UHFFFAOYSA-N 3-[3-methoxy-4-(2-methylpropoxy)phenyl]-1h-pyridazin-6-one Chemical compound C1=C(OCC(C)C)C(OC)=CC(C2=NNC(=O)C=C2)=C1 WWIRWLQXYQJRSZ-UHFFFAOYSA-N 0.000 claims description 2
- BCNGOQWWCARUDA-UHFFFAOYSA-N 3-[4-methoxy-3-(2-methylpropoxy)phenyl]-1h-pyridazin-6-one Chemical compound C1=C(OCC(C)C)C(OC)=CC=C1C1=NNC(=O)C=C1 BCNGOQWWCARUDA-UHFFFAOYSA-N 0.000 claims description 2
- 206010049153 Allergic sinusitis Diseases 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 206010009137 Chronic sinusitis Diseases 0.000 claims 1
- 241000124008 Mammalia Species 0.000 claims 1
- 208000027157 chronic rhinosinusitis Diseases 0.000 claims 1
- 210000001331 nose Anatomy 0.000 claims 1
- 210000003695 paranasal sinus Anatomy 0.000 claims 1
- -1 cyanoamino Chemical group 0.000 abstract description 21
- 125000003545 alkoxy group Chemical group 0.000 abstract description 4
- 125000003302 alkenyloxy group Chemical group 0.000 abstract description 3
- 201000009890 sinusitis Diseases 0.000 abstract description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 abstract 1
- 230000007812 deficiency Effects 0.000 abstract 1
- 239000002585 base Substances 0.000 description 15
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 3
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000005336 allyloxy group Chemical group 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical class CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical class N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 208000030880 Nose disease Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Chemical class NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000572 bronchospasmolytic effect Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 125000003113 cycloheptyloxy group Chemical group C1(CCCCCC1)O* 0.000 description 1
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001477 organic nitrogen group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 201000009482 yaws Diseases 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Die Erfindung betrifft die Verwendung bekannter Pyrid-Herstellung neuer Arzneimittel.The invention relates to the use of known pyride production new drugs.
Aus den europäischen Patentanmeldungen bzw. Patenten EP 1 25 636, EP 1 63 965 und EP 3 93 500 sind Verbindungen bekannt, die sich aufgrund ihrer broncho spasmolytischen und cardiotonischen Wirkung zur Behandlung von Atemwegs- und Herzerkrankungen eignen sollen. Von einer der im europäischen Patent 1 63 965 beanspruchten Substanzen (INN: Zardaverin) ist eine antiallergische Wirksamkeit bekannt (R. Beume et al., Europ. Respir. J., 2, Suppl. 5, 399s, 1989; R. Beume et al., Allergologie, 12 (Sondernr.), 138, 1989. Weiterhin ist bekannt, daß sich Allergien z. B. durch Rhinitis und Conjunctivitis äußern können (z. B. selecta 5, 179, 2. Februar 1990).From European patent applications or patents EP 1 25 636, EP 1 63 965 and EP 3 93 500, compounds are known which differ due to their broncho spasmolytic and cardiotonic effects for the treatment of respiratory and heart diseases are said to be suitable. From one of those in the European patent 1 63 965 claimed substances (INN: Zardaverin) is an anti-allergic Efficacy known (R. Beume et al., Europ. Respir. J., 2, Suppl. 5, 399s, 1989; R. Beume et al., Allergologie, 12 (Sondernr.), 138, 1989. Furthermore it is known that allergies z. B. by rhinitis and conjunctivitis can express (e.g. selecta 5, 179, February 2, 1990).
Es wurde nun gefunden, daß die unten näher beschriebenen Verbindungen zur Behandlung von allergischen und/oder chronischen Fehlreaktionen im Bereich der oberen Atemwege (Rachenraum, Nase) und der angrenzenden Regionen (Na sennebenhöhlen, Auge), wie z. B. der allergischen Rhinitis/Sinusitis, chro nischen Rhinitis/Sinusitis, allergischen Conjunctivitis und von Nasenpoly pen in hervorragender Weise geeignet sind.It has now been found that the compounds for Treatment of allergic and / or chronic bad reactions in the area the upper respiratory tract (pharynx, nose) and the adjacent regions (Na sinuses, eye), such as B. allergic rhinitis / sinusitis, chro African rhinitis / sinusitis, allergic conjunctivitis and nasal poly are ideally suited.
Gegenstand der Erfindung ist die Verwendung von Verbindungen der Formel I (siehe beigefügtes Formelblatt), worin einer der Substituenten R1 und R2 Wasserstoff, 1-5C-Alkoxy oder Difluormethoxy, und der andere 1-5C-Alkoxy, 4-7C-Cycloalkoxy, 3-7C-Cycloalkylmethoxy, 3-5C-Alkenyloxy oder 1-4C-Poly fluoralkoxy bedeutet, X Hydroxy oder Cyanamino bedeutet, und ihren pharma kologisch verträglichen Salzen mit Basen zur Herstellung von Arzneimitteln für die Behandlung der allergischen Rhinitis und Conjunctivitis sowie von Nasenpolypen.The invention relates to the use of compounds of the formula I. (see attached formula sheet), wherein one of the substituents R1 and R2 Hydrogen, 1-5C-alkoxy or difluoromethoxy, and the other 1-5C-alkoxy, 4-7C-Cycloalkoxy, 3-7C-Cycloalkylmethoxy, 3-5C-Alkenyloxy or 1-4C-Poly fluoroalkoxy means, X means hydroxy or cyanamino, and their pharma ecologically compatible salts with bases for the manufacture of medicinal products for the treatment of allergic rhinitis and conjunctivitis as well as of Nasal polyps.
1-5C-Alkoxy ist geradkettig oder verzweigt. Als beispielhafte 1-5C-Alkoxy reste seien genannt der Methoxy-, Ethoxy-, n-Propoxy-, Isopropoxy-, n-Bu toxy-, Isobutoxy-, sec. -Butoxy-, tert.-Butoxy-, n-Pentyloxy, Isopentyloxy- und der 2,2-Dimethylpropoxyrest.1-5C-Alkoxy is straight or branched. As an example 1-5C-alkoxy residues are called the methoxy, ethoxy, n-propoxy, isopropoxy, n-Bu toxy-, isobutoxy-, sec-butoxy-, tert-butoxy-, n-pentyloxy, isopentyloxy- and the 2,2-dimethylpropoxy radical.
4-7C-Cycloalkoxy steht beispielsweise für Cyclobutyloxy, Cyclopentyloxy, Cyclohexyloxy und Cycloheptyloxy, wovon Cyclopentyloxy bevorzugt ist.4-7C-Cycloalkoxy stands for example for cyclobutyloxy, cyclopentyloxy, Cyclohexyloxy and cycloheptyloxy, of which cyclopentyloxy is preferred.
3-7C-Cycloalkylmethoxy steht beispielsweise für Cyclopropylmethoxy, Cyclo butylmethoxy, Cyclopentylmethoxy, Cyclohexylmethoxy und Cycloheptylmethoxy, wovon Cyclopropylmethoxy und Cyclobutylmethoxy bevorzugt sind.3-7C-Cycloalkylmethoxy stands for example for Cyclopropylmethoxy, Cyclo butyl methoxy, cyclopentyl methoxy, cyclohexyl methoxy and cycloheptyl methoxy, of which cyclopropyl methoxy and cyclobutyl methoxy are preferred.
3-5C-Alkenyloxy ist geradkettig oder verzweigt. Die Doppelbindung von Alk enyloxy geht nicht von dem Kohlenstoffatom aus, das an das Sauerstoffatom bindet. Als beispielhafte 3-5C-Alkenyloxyreste seien genannt der Buten-2- yloxy-, der Allyloxy- und der Methallyloxyrest.3-5C-alkenyloxy is straight or branched. The double bond of alk enyloxy does not start from the carbon atom attached to the oxygen atom binds. Examples of 3-5C-alkenyloxy radicals include butene-2- yloxy, allyloxy and methallyloxy.
1-5C-Alkoxy ist gegenüber 3-5C-Alkenyloxy bevorzugt.1-5C-alkoxy is preferred over 3-5C-alkenyloxy.
Unter 1-4C-Polyfluoralkoxy wird geradkettiges oder verzweigtes 1-4C-Alkoxy verstanden, bei dem mindestens 2 Wasserstoffatome durch Fluor ersetzt sind. Geradkettiges 1-3C-Alkoxy, bei dem mindestens 2 Wasserstoffatome durch Fluor ersetzt sind, ist bevorzugt. Bevorzugte 1-4C-Polyfluoralkoxygruppen sind Trifluormethoxy, 1,1,2,2-Tetrafluorethoxy und insbesondere Difluor methoxy und 2,2,2-Trifluorethoxy.1-4C-Polyfluoroalkoxy is straight-chain or branched 1-4C-Alkoxy understood, in which at least 2 hydrogen atoms are replaced by fluorine. Straight chain 1-3C-alkoxy, in which at least 2 hydrogen atoms pass through Fluorine are preferred. Preferred 1-4C polyfluoroalkoxy groups are trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy and especially difluoro methoxy and 2,2,2-trifluoroethoxy.
Unter Cyanamino wird die Gruppe -NHCN verstanden.Cyanamino is understood to mean the group -NHCN.
Als Salze kommen alle pharmakologisch verträglichen Salze der in der Gale nik üblicherweise verwendeten anorganischen und organischen Basen in Be tracht. Als solche eignen sich beispielsweise wasserlösliche und wasserun lösliche Salze, wobei als Kationen für die Salzbildung vor allem die Kati onen der Alkalimetalle oder Erdalkalimetalle verwendet werden; es kommen jedoch auch die entsprechenden Kationen organischer Stickstoffbasen, wie Amine oder Aminoalkanole, Aminozucker etc. zur Anwendung. Beispielsweise seien die Salze von Natrium, Magnesium, Calcium, Dimethylamin, Diethylamin, Ethanolamin, Diethanolamin, Triethanolamin, Glucamin, N-Methylglucamin (Me glumin), Glucosamin und N-Methylglucosamin genannt, wobei bei der Salzher stellung die Basen in äquimolarem oder einem davon abweichenden Mengenver hältnis eingesetzt werden.All pharmacologically acceptable salts in the galle come as salts nik commonly used inorganic and organic bases in Be dress. As such, for example, water-soluble and water-soluble ones are suitable soluble salts, with the Kati as cations for salt formation ones of the alkali metals or alkaline earth metals are used; it will come however also the corresponding cations of organic nitrogen bases, such as Amines or aminoalkanols, amino sugar etc. for use. For example be the salts of sodium, magnesium, calcium, dimethylamine, diethylamine, Ethanolamine, diethanolamine, triethanolamine, glucamine, N-methylglucamine (Me called glumin), glucosamine and N-methylglucosamine, with the Salzher position the bases in equimolar or a different amount ratio.
Die Anwendung der Verbindungen der Formel I erfolgt insbesondere in Form solcher Arzneimittel, die für die Behandlung von Nasen- und Augenerkrankun gen geeignet sind. Für die Herstellung der Arzneimittel werden die Verbin dungen der Formel I und/oder ihre pharmakologisch verträglichen Salze (= Wirkstoffe) vorzugsweise mit geeigneten pharmazeutischen Hilfsstoffen vermischt und zu geeigneten Arzneiformulierungen weiterverarbeitet. Als ge eignete Arzneiformulierungen seien beispielsweise Emulsionen, Suspensionen, Salben, Sprays (z. B. Nasensprays) oder Lösungen (z. B. Augentropfen) ge nannt, in denen der Wirkstoffgehalt vorteilhafterweise zwischen 0,1 und 99% beträgt.The compounds of the formula I are used in particular in the form such medicines used for the treatment of nose and eye diseases are suitable. The Verbin of formula I and / or their pharmacologically acceptable salts (= Active ingredients) preferably with suitable pharmaceutical excipients mixed and processed into suitable pharmaceutical formulations. As ge suitable pharmaceutical formulations are, for example, emulsions, suspensions, Ointments, sprays (e.g. nasal sprays) or solutions (e.g. eye drops) named in which the active ingredient content advantageously between 0.1 and Is 99%.
Welche Hilfsstoffe für die gewünschten Arzneiformulierungen geeignet sind, ist dem Fachmann aufgrund seines Fachwissens geläufig. Neben Lösemitteln und anderen Wirkstoffträgern können beispielsweise Antioxidantien, Disper giermittel, Emulgatoren, Konservierungsmittel, Lösungsvermittler oder Per meationspromotoren verwendet werden.Which excipients are suitable for the desired pharmaceutical formulations is familiar to a person skilled in the art on the basis of his specialist knowledge. In addition to solvents and other active substance carriers can, for example, antioxidants, disper yaws, emulsifiers, preservatives, solubilizers or per meation promoters are used.
Eine Gruppe (Gruppe 1) von erfindungsgemäß zu verwendenden Verbindungen sind solche der Formel 1, worin einer der Substituenten R1 oder R2 Methoxy und der andere 1-5C-Alkoxy oder 3-5C-Alkenyloxy und X Hydroxy bedeutet, und ihre pharmakologisch verträglichen Salze mit Basen.A group (group 1) of compounds to be used according to the invention are those of formula 1, wherein one of the substituents R1 or R2 methoxy and the other is 1-5C-alkoxy or 3-5C-alkenyloxy and X is hydroxy, and their pharmacologically acceptable salts with bases.
Eine Ausgestaltung der Gruppe 1 (Ausgestaltung 1a) sind Verbindungen der
Formel I, worin
R1 Methoxy,
R2 2-4C-Alkoxy oder 3-4C-Alkenyloxy und
X Hydroxy bedeutet,
und ihre pharmakologisch verträglichen Salze mit Basen.
One embodiment of group 1 (embodiment 1a) are compounds of the formula I in which
R1 methoxy,
R2 2-4C alkoxy or 3-4C alkenyloxy and
X is hydroxy
and their pharmacologically acceptable salts with bases.
Eine weitere Ausgestaltung der Gruppe 1 (Ausgestaltung 1b) sind Verbindun
gen der Formel I, worin
R1 2-4C-Alkoxy oder 3-4C-Alkenyloxy,
R2 Methoxy und
X Hydroxy bedeutet,
und ihre pharmakologisch verträglichen Salze mit Basen.A further embodiment of group 1 (embodiment 1b) are compounds of the formula I in which
R1 2-4C-alkoxy or 3-4C-alkenyloxy,
R2 methoxy and
X is hydroxy
and their pharmacologically acceptable salts with bases.
Bevorzugte Vertreter der Ausgestaltung 1a sind solche der Formel I, worin R2 n-Propoxy, Isopropoxy oder Isobutoxy bedeutet. Besonders bevorzugte Ver treter sind die Verbindungen 6-(3-Methoxy-4-n-propoxyphenyl)-3(2H)pyridazi non und 6-(4-Isobutoxy-3-methoxyphenyl)-3(2H)pyridazinon.Preferred representatives of embodiment 1a are those of the formula I in which R2 means n-propoxy, isopropoxy or isobutoxy. Particularly preferred ver Compounds are 6- (3-methoxy-4-n-propoxyphenyl) -3 (2H) pyridazi non and 6- (4-isobutoxy-3-methoxyphenyl) -3 (2H) pyridazinone.
Bevorzugte Vertreter der Ausgestaltung 1b sind solche der Formel I, worin R1 n-Propoxy, Isopropoxy, Allyloxy oder Isobutoxy bedeutet. Besonders be vorzugte Vertreter sind die Verbindungen 6-(3-Isobutoxy-4-methoxyphenyl)- 3(2H)pyridazinon und 6-(4-Methoxy-3-propoxyphenyl)-3(2H)pyridazinon.Preferred representatives of embodiment 1b are those of the formula I in which R1 means n-propoxy, isopropoxy, allyloxy or isobutoxy. Especially be preferred representatives are the compounds 6- (3-isobutoxy-4-methoxyphenyl) - 3 (2H) pyridazinone and 6- (4-methoxy-3-propoxyphenyl) -3 (2H) pyridazinone.
Eine weitere Gruppe (Gruppe 2) von erfindungsgemäß zu verwendenden Verbin dungen sind solche der Formel I, worin einer der Substituenten R1 und R2 Wasserstoff oder 1-5C-Alkoxy und der andere 1-4C-Polyfluoralkoxy und X Hy droxy bedeutet, und ihre pharmakologisch verträglichen Salze mit Basen.Another group (group 2) of verbin to be used according to the invention are those of the formula I in which one of the substituents R1 and R2 Hydrogen or 1-5C-alkoxy and the other 1-4C-polyfluoroalkoxy and X Hy droxy means, and their pharmacologically acceptable salts with bases.
Hervorzuhebende Vertreter der Gruppe 2 sind solche der Formel I, worin einer der Substituenten R1 und R2 Wasserstoff oder geradkettiges 1-3C- Alkoxy und der andere Polyfluor-1-2C-alkoxy und X Hydroxy bedeutet, und ihre pharmakologisch verträglichen Salze mit Basen.Group 2 representatives to be emphasized are those of the formula I in which one of the substituents R1 and R2 is hydrogen or straight-chain 1-3C- Alkoxy and the other polyfluoro-1-2C-alkoxy and X means hydroxy, and their pharmacologically acceptable salts with bases.
Bevorzugte Vertreter der Gruppe 2 sind solche der Formel I, worin einer der Substituenten R1 und R2 Wasserstoff oder Methoxy und der andere Difluor methoxy, Trifluormethoxy, 1,1,2,2-Tetrafluorethoxy oder 2,2,2-Trifluoreth oxy und X Hydroxy bedeutet, und ihre pharmakologisch verträglichen Salze mit Basen.Preferred representatives of group 2 are those of the formula I, in which one of the Substituents R1 and R2 are hydrogen or methoxy and the other difluoro methoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy or 2,2,2-trifluoroeth oxy and X means hydroxy, and their pharmacologically acceptable salts with bases.
Ein besonders bevorzugter Vertreter der Gruppe 2 ist die Verbindung 6-(4- Difluormethoxy-3-methoxyphenyl)-3(2H)pyridazinon und ihre pharmakologisch verträglichen Salze mit Basen. A particularly preferred representative of group 2 is the compound 6- (4- Difluoromethoxy-3-methoxyphenyl) -3 (2H) pyridazinone and its pharmacological compatible salts with bases.
Eine weitere Gruppe (Gruppe 3) von erfindungsgemäß zu verwendenden Verbin dungen sind solche der Formel I, worin einer der Substituenten R1 und R2 Methoxy, Difluormethoxy oder Ethoxy, und der andere 1-5C-Alkoxy, 4-7C-Cy cloalkoxy, 3-7C-Cycloalkylmethoxy, 3-5C-Alkenyloxy oder 1-4C-Polyfluoralk oxy und X Cyanamino bedeutet, und ihre pharmakologisch verträglichen Salze mit Basen.Another group (group 3) of verbin to be used according to the invention are those of the formula I in which one of the substituents R1 and R2 Methoxy, difluoromethoxy or ethoxy, and the other 1-5C-alkoxy, 4-7C-Cy cloalkoxy, 3-7C-cycloalkylmethoxy, 3-5C-alkenyloxy or 1-4C-polyfluoroalk oxy and X means cyanamino, and their pharmacologically acceptable salts with bases.
Eine Ausgestaltung der Gruppe 3 (Ausgestaltung 3a) sind Verbindungen der
Formel I, worin
R1 Methoxy, Difluormethoxy oder Ethoxy,
R2 1-4C-Alkoxy, 4-6C-Cycloalkoxy, 3-6C-Cycloalkylmethoxy, 3-4C-Alkenyloxy
oder 1-2C-Polyfluoralkoxy und
X Cyanamino bedeutet,
und ihre pharmakologisch verträglichen Salze mit Basen.One embodiment of group 3 (embodiment 3a) are compounds of the formula I in which
R1 methoxy, difluoromethoxy or ethoxy,
R2 1-4C-alkoxy, 4-6C-cycloalkoxy, 3-6C-cycloalkylmethoxy, 3-4C-alkenyloxy or 1-2C-polyfluoroalkoxy and
X means cyanamino
and their pharmacologically acceptable salts with bases.
Eine weitere Ausgestaltung der Gruppe 3 (Ausgestaltung 3b) sind Verbindun
gen der Formel I, worin
R1 2-4C-Alkoxy, 4-6C-Cycloalkoxy, 3-6C-Cycloalkylmethoxy, 3-4C-Alkenyloxy
oder 1-2C-Polyfluoralkoxy,
R2 Methoxy, Difluormethoxy oder Ethoxy und
X Cyanamino bedeutet,
und ihre pharmakologisch verträglichen Salze mit Basen.A further embodiment of group 3 (embodiment 3b) are compounds of the formula I in which
R1 2-4C-alkoxy, 4-6C-cycloalkoxy, 3-6C-cycloalkylmethoxy, 3-4C-alkenyloxy or 1-2C-polyfluoroalkoxy,
R2 methoxy, difluoromethoxy or ethoxy and
X means cyanamino
and their pharmacologically acceptable salts with bases.
Bevorzugte Vertreter der Gruppe 3 sind solche der Formel I, worin einer der Substituenten R1 und R2 Methoxy, Difluormethoxy oder Ethoxy, und der andere 1-4C-Alkoxy, 4-6C-Cycloalkoxy, 3-6C-Cycloalkylmethoxy oder 1-2C-Polyfluor alkoxy bedeutet und X Cyanamino bedeutet, und ihre pharmakologisch verträg lichen Salze mit Basen.Preferred representatives of group 3 are those of the formula I, in which one of the Substituents R1 and R2 methoxy, difluoromethoxy or ethoxy, and the other 1-4C-alkoxy, 4-6C-cycloalkoxy, 3-6C-cycloalkylmethoxy or 1-2C-polyfluoro alkoxy means and X means cyanamino, and their pharmacologically acceptable lichen salts with bases.
Bevorzugte Vertreter der Ausgestaltung 3 sind solche, in denen R2 1-4C- Alkoxy, 3-6C-Cycloalkylmethoxy oder 1-2C-Polyfluoralkoxy bedeutet.Preferred representatives of embodiment 3 are those in which R2 1-4C- Alkoxy, 3-6C-cycloalkylmethoxy or 1-2C-polyfluoroalkoxy means.
Bevorzugte Vertreter der Ausgestaltung 3b sind solche, in denen R1 2-4C- Alkoxy, 4-6C-Cycloalkoxy, 3-6C-Cycloalkylmethoxy oder 1-2C-Polyfluoralkoxy bedeutet. Preferred representatives of embodiment 3b are those in which R1 2-4C- Alkoxy, 4-6C-cycloalkoxy, 3-6C-cycloalkylmethoxy or 1-2C-polyfluoroalkoxy means.
Die Ausgestaltung 3b ist gegenüber der Ausgestaltung 3a bevorzugt.The configuration 3b is preferred over the configuration 3a.
Besonders bevorzugte Vertreter der Gruppe 3 sind solche der Formel I, worin R1 2-4C-Alkoxy, Cyclopentyloxy, Cyclopropylmethoxy, Cyclobutylmethoxy, Di fluormethoxy oder 2,2,2-Trifluorethoxy bedeutet, R2 Methoxy, Ethoxy oder Difluormethoxy bedeutet und X Cyanamino bedeutet, und ihre pharmakologisch verträglichen Salze mit Basen.Particularly preferred representatives of group 3 are those of the formula I in which R1 2-4C-alkoxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, Di fluoromethoxy or 2,2,2-trifluoroethoxy means R2 methoxy, ethoxy or Difluoromethoxy means and X means cyanamino, and their pharmacological compatible salts with bases.
Die Verbindungen der Formel I können als tautomere Formen vorliegen. Das Proton der Hydroxygruppe bzw. der Cyanaminogruppe in 3-Stellung des Pyri dinringes vermag zwischen diesen Gruppen und dem Stickstoff in 2-Stellung des Pyridazinrings zu wandern. Erfindungsgemäß ist bei Angabe oder Darstel lung nur eines Tautomeren jeweils auch das andere Tautomere zu verstehen.The compounds of formula I can exist as tautomeric forms. The Proton of the hydroxy group or the cyanamino group in the 3-position of the pyri dinringes is capable of 2-position between these groups and nitrogen of the pyridazine ring. According to the invention is given or presented only one tautomer to understand the other tautomer.
Die Verbindungen der Formel I sind bekannt aus den europäischen Patentan meldungen bzw. Patenten EP 1 25 636, EP 1 63 965 und EP 3 93 500 bzw. sie kön nen auf analoge Weise wie dort beschrieben hergestellt werden.The compounds of formula I are known from the European patent applications or patents EP 1 25 636, EP 1 63 965 and EP 3 93 500 or you can NEN are produced in an analogous manner as described there.
Claims (7)
6-(4-Isobutoxy-3-methoxyphenyl)-3(2H)pyridazinon,
6-(3-Isobutoxy-4-methoxyphenyl)-3(2H)pyridazinon,
6-(4-Methoxy-3-propoxyphenyl)-3(2H)pyridazinon und
6-(4-Difluormethoxy-3-methoxyphenyl)-3(2H)pyridazinon
und ihren pharmakologisch verträglichen Salzen mit Basen.2. Use according to claim 1 of compounds of the formula I selected from the group consisting of 6- (3-methoxy-4-n-propoxyphenyl) -3 (2H) pyridazinone,
6- (4-isobutoxy-3-methoxyphenyl) -3 (2H) pyridazinone,
6- (3-isobutoxy-4-methoxyphenyl) -3 (2H) pyridazinone,
6- (4-methoxy-3-propoxyphenyl) -3 (2H) pyridazinone and
6- (4-difluoromethoxy-3-methoxyphenyl) -3 (2H) pyridazinone
and their pharmacologically acceptable salts with bases.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19934310051 DE4310051A1 (en) | 1992-04-11 | 1993-03-27 | Treating allergic rhinitis or conjunctivitis - using 3-substd. 6-(substd. phenyl)-pyridazine deriv., also for treating e.g. nasal polyps |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4212247 | 1992-04-11 | ||
| DE19934310051 DE4310051A1 (en) | 1992-04-11 | 1993-03-27 | Treating allergic rhinitis or conjunctivitis - using 3-substd. 6-(substd. phenyl)-pyridazine deriv., also for treating e.g. nasal polyps |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE4310051A1 true DE4310051A1 (en) | 1993-10-14 |
Family
ID=25913882
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19934310051 Withdrawn DE4310051A1 (en) | 1992-04-11 | 1993-03-27 | Treating allergic rhinitis or conjunctivitis - using 3-substd. 6-(substd. phenyl)-pyridazine deriv., also for treating e.g. nasal polyps |
Country Status (1)
| Country | Link |
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| DE (1) | DE4310051A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7531500B2 (en) | 1998-08-18 | 2009-05-12 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
| US8048844B1 (en) | 1998-08-18 | 2011-11-01 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
| EP1303301B1 (en) * | 2000-07-14 | 2014-02-12 | The Regents of The University of California | Preventing airway mucus production by administration of egf-r antagonists |
-
1993
- 1993-03-27 DE DE19934310051 patent/DE4310051A1/en not_active Withdrawn
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7531500B2 (en) | 1998-08-18 | 2009-05-12 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
| US7700547B2 (en) | 1998-08-18 | 2010-04-20 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
| US8048844B1 (en) | 1998-08-18 | 2011-11-01 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
| US8071074B2 (en) | 1998-08-18 | 2011-12-06 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
| EP1303301B1 (en) * | 2000-07-14 | 2014-02-12 | The Regents of The University of California | Preventing airway mucus production by administration of egf-r antagonists |
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