CA2016141A1 - 8-substituted 4-(heterocyclylmethylamino) quinolines, the use thereof and drugs prepared therefrom - Google Patents
8-substituted 4-(heterocyclylmethylamino) quinolines, the use thereof and drugs prepared therefromInfo
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- CA2016141A1 CA2016141A1 CA002016141A CA2016141A CA2016141A1 CA 2016141 A1 CA2016141 A1 CA 2016141A1 CA 002016141 A CA002016141 A CA 002016141A CA 2016141 A CA2016141 A CA 2016141A CA 2016141 A1 CA2016141 A1 CA 2016141A1
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- thienyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
O.Z. 0050/40846 Abstract of the disclosure: 8-Substituted 4-(hetero-cyclylmethylamino)quinolines of the formula I
Description
2~3.~
O.Z. 0050/~0846 8-substituted 4-(heterocyclylmethylamino)quinolines, the use thereof and drugs prepared therefrom The present invention relates to novel 8-substituted 4-(heterocyclylmethylamino)quinolines and to the use thereof for controlling diseases.
In a general form, 2-alky1-4-aralkylamino-quinolines ~re mentioned as intermediates in US-P
O.Z. 0050/~0846 8-substituted 4-(heterocyclylmethylamino)quinolines, the use thereof and drugs prepared therefrom The present invention relates to novel 8-substituted 4-(heterocyclylmethylamino)quinolines and to the use thereof for controlling diseases.
In a general form, 2-alky1-4-aralkylamino-quinolines ~re mentioned as intermediates in US-P
3 075 984; no pharmacological actions of these inter-mediates were described. 4-Heteroarylmethylamino-quinolines with fungicidal activity have been describedin US 4 744 823.
The following 4-aminoquinolines may be mentioned from among those with pharmacological activity and a wide variety of substitution patterns on the quinoline moiety:
The following 4-aminoquinolines may be mentioned from among those with pharmacological activity and a wide variety of substitution patterns on the quinoline moiety:
4-Anilino- and 4-benzylamino-3-quinolyl ketones and -3-quinolinecarboxylates which are unsubstituted in the 2 position and inhibit gastric acid secretion (US 4 343 804, US 4 806 549 and US 4 806 550).
4-Amino-2-methyl-3-quinolyl ketones and -3-quinolylalkanols for the treatment of Al~heimer's disease (US 4 789 678 and 4 840 970).
The patent application DE 3 908 767.0 which has not been prior-published describes 2-alky1-4-benzylamino-8-methoxyquinolines which inhibit K+/H+-ATPase.
We have now found that the compounds of the formula I according to the invention R 4~N--CH 2--R 3 R6~RR12 (I), where Rl is hydrogen or Cl-C4-alkyl which can be ~ubstituted by hydroxyl or Cl-C4-alkoxy, R2 is hydrogen or Cl-C6-alkyl, R3 is thienyl, which can be substituted by 1 to 3 ~fi~l4~
- ~ - 890307 o.Z. 0050/40846 Cl-C4-alkyl groups and/or 1 to 2 halogen atoms, furyl which can be substituted by 1 to 3 Cl-C4-alkyl groups, pyrrolyl which can have hydrogen, Cl-C6-alkyl, phenyl-Cl-C3-alkyl or phenyl on the nitrogen and can be substituted on the carbon atoms by 1 to 3 Cl-C4-al~yl groups, it also being possible for the thienyl, furyl or pyrrolyl to be benzo-fused, R4 is hydrogen, Cl-C4-alkyl or -CH2-R3 where R3 has the abovementioned meaning, Rs is C1-C6-alkyl which ca.n be substituted by hydroxyl or Cl-C3-alkoxy, or is hydroxyl, Cl-C6-alkoxy, phenoxy,phenyl-Cl-C3-alkoxy,Cl-C6-alkylthio,phenyl-thio,phenyl-Cl-C3-alkylthio,amino,Cl-C4-alkylamino, di-(Cl-C4-alkyl~amino, phenylamino, N-phenyl-N-(Cl-C4-alkyl)amino, phenyl-Cl-C4-alkylamino, N-phenyl-Cl-C4-alkyl-N-(Cl-C4-alkyl)amino, Cl-C4-alkanoylamino, benzoylamino, phenyl-Cl-C3-alkanoylamino, Cl-C6-alkanoyl, hydroxycarbonyl, Cl-C6-alkoxycarbonyl, aminocarbonyl, Cl-C6-alkylaminocarbonyl, di-(Cl-C6-alkyl)aminocarbonyl, trifluoromethyl or halogen, and R6 is hydrogen, Cl-C4-alkyl, Cl-C4-alkoxy or halogen and the physiologically tolerated salts thereof have valuable pharmacological action Preferred meanings of Rl are hydrogen and C1-C3-alkyl which can be substituted by hydroxyl or Cl-C3-alkoxy. If Rl is Cl-C3-alkyl, it is particularly prefer-ably methyl which can be substituted by hydroxyl or Cl-C3-alkoxy, in particular methoxy.
Preferred meanings of R2 are hydrogen or Cl-C3-alkyl.
In a preferred group of compounds according to the invention, R1 and R2 are each hydrogen.
In another preferred group, R2 is C~-C3-alkyl and Rl is hydrogen or C1-C3-alkyl which can be substituted by hydroxyl or Cl-C3-alkoxy. If R2 is C~-C3-alkyl, R1 is particularly preferably hydrogen or unsubsti~uted _ 3 _ 890307 O.Z. 0050~40846 Cl-C3-alkyl, in particular methyl.
In a particularly preferred group of compounds according to the invention, R2 is hydrogen and R1 is Cl-C3-alkyl which can be substituted by hydroxyl or Cl-C3-alkoxy.
R3 is preferably thienyl or pyrrolyl which can be substituted and/or benzo-fused, in particular thienyl which can be substituted and/or benzo-fused.
The furyl, thienyl or pyrrolyl is preferably substituted one to three times.
A substituent in R3 is preferably in the position ortho to the point of attachment to the quinolinamino methyl group.
If R3 is thienyl which is substituted by 1 to 3 Cl-C4-alkyl groups and~or 1 to 2 halogen atoms, it is preferably substituted by 1 to 3 C1-C3-alkyl groups, in particular methyl groups, and/or 1 to 2 halogen atoms.
Halogens are fluorine, chlorine, bromLne and iodine; chlorine and bromine are preferred.
If R3 is furyl substituted by 1 to 3 Cl-C4-alkyl groups, it is preferably substituted by 1 to 3 C~-C3-alkyl groups, in particular methyl groups.
If R3 is substituted pyrrolyl, the following substituents on the nitrogen are preferred: C1-C4-alkyl, benzyl or phenyl, in particular C1-C4-alkyl. Preferred substituents on the carbon atoms of the ring are 1 to 3 methyl groups.
R4 is preferably hydrogen or methyl, in particu-lar hydrogen.
If R5 is halogen, it can be fluorine, chlorine or bromine. R5 is preferably C1-C3-alkyl which can be substituted by hydroxyl or methoxy, or i hydroxyl or Cl-C3-alkoxy, in particular R5 is C1-C3-alkoxy or Cl-C3-alkyl, with methoxy and methyl being particularly preferred.
R6 is preferably methyl, methoxy, fluorine, chlorine or bromine, in particular hydrogen.
O.Z. 0050/40846 The compounds according to the invention are prepared by reacting a quinoline of the formula II
~N~R I ( I I ), R~
where X is a nucleofugic leaving group such as chlorine or bromine or phenoxy, and Rl, R2, R5 and R6 have the above meanings, and where, if R1 or R5 is a hydroxyl-substituted Cl-C4-alkyl or/and R5 is primary or secondary amino, the hydroxyl and amino can be modified by a suitable conven-tional protective group, with an amine of the formula R3-CH2-NH-R4 where R3 and R4 have the above meanings, in a conventional manner, and eliminating the hydroxyl- or amino-protective group, where present.
The reaction can be carried out in the presence of a solvent such as toluene, xylene, phenol, ethanol, butanol, dimethyl sulfoxide, dimethylethyleneurea, dimethylpropyleneurea, pyrrolidone or N-methyl-pyrrolidone, in mixtures of the~e solvents or in the absence of solvents, in the presence or absence of a cataly~t such as copper or bronze powder or copper(I) chloride, at from 50 to 250C, under atmospheric or superatmospheric pressure. The amines R3CH2NHR4 can be used in equimolar amounts or in excess.
The reaction of the compounds of the formula II
with the amine~ R3CH2NHR4 is preferably carried out in the ratio 1:1 to 1:10 in the presence of phenol at from 60 to 160~C.
The preparation of 4-aminoquinolines by the above process has been described, inter alia, in the following citations:
G. Jones, Quinolines, Part I, John Wiley & Sons, London, New York, 1977, pp. 547-550 and literature cited therein;
J. Indian Chem. Soc. 51 (1974) 880-882; J. Med. Chem. 14 (1971) 1060-1066; Chim. Therap. 1 (1966) 339-346;
4-Amino-2-methyl-3-quinolyl ketones and -3-quinolylalkanols for the treatment of Al~heimer's disease (US 4 789 678 and 4 840 970).
The patent application DE 3 908 767.0 which has not been prior-published describes 2-alky1-4-benzylamino-8-methoxyquinolines which inhibit K+/H+-ATPase.
We have now found that the compounds of the formula I according to the invention R 4~N--CH 2--R 3 R6~RR12 (I), where Rl is hydrogen or Cl-C4-alkyl which can be ~ubstituted by hydroxyl or Cl-C4-alkoxy, R2 is hydrogen or Cl-C6-alkyl, R3 is thienyl, which can be substituted by 1 to 3 ~fi~l4~
- ~ - 890307 o.Z. 0050/40846 Cl-C4-alkyl groups and/or 1 to 2 halogen atoms, furyl which can be substituted by 1 to 3 Cl-C4-alkyl groups, pyrrolyl which can have hydrogen, Cl-C6-alkyl, phenyl-Cl-C3-alkyl or phenyl on the nitrogen and can be substituted on the carbon atoms by 1 to 3 Cl-C4-al~yl groups, it also being possible for the thienyl, furyl or pyrrolyl to be benzo-fused, R4 is hydrogen, Cl-C4-alkyl or -CH2-R3 where R3 has the abovementioned meaning, Rs is C1-C6-alkyl which ca.n be substituted by hydroxyl or Cl-C3-alkoxy, or is hydroxyl, Cl-C6-alkoxy, phenoxy,phenyl-Cl-C3-alkoxy,Cl-C6-alkylthio,phenyl-thio,phenyl-Cl-C3-alkylthio,amino,Cl-C4-alkylamino, di-(Cl-C4-alkyl~amino, phenylamino, N-phenyl-N-(Cl-C4-alkyl)amino, phenyl-Cl-C4-alkylamino, N-phenyl-Cl-C4-alkyl-N-(Cl-C4-alkyl)amino, Cl-C4-alkanoylamino, benzoylamino, phenyl-Cl-C3-alkanoylamino, Cl-C6-alkanoyl, hydroxycarbonyl, Cl-C6-alkoxycarbonyl, aminocarbonyl, Cl-C6-alkylaminocarbonyl, di-(Cl-C6-alkyl)aminocarbonyl, trifluoromethyl or halogen, and R6 is hydrogen, Cl-C4-alkyl, Cl-C4-alkoxy or halogen and the physiologically tolerated salts thereof have valuable pharmacological action Preferred meanings of Rl are hydrogen and C1-C3-alkyl which can be substituted by hydroxyl or Cl-C3-alkoxy. If Rl is Cl-C3-alkyl, it is particularly prefer-ably methyl which can be substituted by hydroxyl or Cl-C3-alkoxy, in particular methoxy.
Preferred meanings of R2 are hydrogen or Cl-C3-alkyl.
In a preferred group of compounds according to the invention, R1 and R2 are each hydrogen.
In another preferred group, R2 is C~-C3-alkyl and Rl is hydrogen or C1-C3-alkyl which can be substituted by hydroxyl or Cl-C3-alkoxy. If R2 is C~-C3-alkyl, R1 is particularly preferably hydrogen or unsubsti~uted _ 3 _ 890307 O.Z. 0050~40846 Cl-C3-alkyl, in particular methyl.
In a particularly preferred group of compounds according to the invention, R2 is hydrogen and R1 is Cl-C3-alkyl which can be substituted by hydroxyl or Cl-C3-alkoxy.
R3 is preferably thienyl or pyrrolyl which can be substituted and/or benzo-fused, in particular thienyl which can be substituted and/or benzo-fused.
The furyl, thienyl or pyrrolyl is preferably substituted one to three times.
A substituent in R3 is preferably in the position ortho to the point of attachment to the quinolinamino methyl group.
If R3 is thienyl which is substituted by 1 to 3 Cl-C4-alkyl groups and~or 1 to 2 halogen atoms, it is preferably substituted by 1 to 3 C1-C3-alkyl groups, in particular methyl groups, and/or 1 to 2 halogen atoms.
Halogens are fluorine, chlorine, bromLne and iodine; chlorine and bromine are preferred.
If R3 is furyl substituted by 1 to 3 Cl-C4-alkyl groups, it is preferably substituted by 1 to 3 C~-C3-alkyl groups, in particular methyl groups.
If R3 is substituted pyrrolyl, the following substituents on the nitrogen are preferred: C1-C4-alkyl, benzyl or phenyl, in particular C1-C4-alkyl. Preferred substituents on the carbon atoms of the ring are 1 to 3 methyl groups.
R4 is preferably hydrogen or methyl, in particu-lar hydrogen.
If R5 is halogen, it can be fluorine, chlorine or bromine. R5 is preferably C1-C3-alkyl which can be substituted by hydroxyl or methoxy, or i hydroxyl or Cl-C3-alkoxy, in particular R5 is C1-C3-alkoxy or Cl-C3-alkyl, with methoxy and methyl being particularly preferred.
R6 is preferably methyl, methoxy, fluorine, chlorine or bromine, in particular hydrogen.
O.Z. 0050/40846 The compounds according to the invention are prepared by reacting a quinoline of the formula II
~N~R I ( I I ), R~
where X is a nucleofugic leaving group such as chlorine or bromine or phenoxy, and Rl, R2, R5 and R6 have the above meanings, and where, if R1 or R5 is a hydroxyl-substituted Cl-C4-alkyl or/and R5 is primary or secondary amino, the hydroxyl and amino can be modified by a suitable conven-tional protective group, with an amine of the formula R3-CH2-NH-R4 where R3 and R4 have the above meanings, in a conventional manner, and eliminating the hydroxyl- or amino-protective group, where present.
The reaction can be carried out in the presence of a solvent such as toluene, xylene, phenol, ethanol, butanol, dimethyl sulfoxide, dimethylethyleneurea, dimethylpropyleneurea, pyrrolidone or N-methyl-pyrrolidone, in mixtures of the~e solvents or in the absence of solvents, in the presence or absence of a cataly~t such as copper or bronze powder or copper(I) chloride, at from 50 to 250C, under atmospheric or superatmospheric pressure. The amines R3CH2NHR4 can be used in equimolar amounts or in excess.
The reaction of the compounds of the formula II
with the amine~ R3CH2NHR4 is preferably carried out in the ratio 1:1 to 1:10 in the presence of phenol at from 60 to 160~C.
The preparation of 4-aminoquinolines by the above process has been described, inter alia, in the following citations:
G. Jones, Quinolines, Part I, John Wiley & Sons, London, New York, 1977, pp. 547-550 and literature cited therein;
J. Indian Chem. Soc. 51 (1974) 880-882; J. Med. Chem. 14 (1971) 1060-1066; Chim. Therap. 1 (1966) 339-346;
o.z. 00S0~40846 Eur. J. Med. Chem. 11 (1976) 561-565.
The compounds of the general formula II can be obtained in a similar manner to known compounds. For the preparation of compounds of the formula Il, see, for example, J. Indian Chem. Soc. 51 (1974), 880-882 and G. Jones (Ed.) Quinolines, Part I, John Wiley & Sons, London, 1977: X = Cl: pp. 391-398, X = Br: pp. 404-406, X = OC6H5: pp. 577-579. 4-Phenoxyquinolines can also be detected as intermediates in the reaction of 4-chloro-quinolin~s with amines R3CH2NHR4 in the presence of phenol.
The amines R3CH2NHR4 are known from the literature or can be prepared in a similar manner to known compounds (Houben Weyl, ~ethoden der Organischen Chemie vol. 11/1, 4th edition 1957, G. Thieme-Verlag Stuttgart).
The compounds according to the invention can be converted into the addition salt with a physiologically tolerated acid. A compilation of conventional physio-logically tolerated acids is to be found in Fortschritte der Arzneimittelforschung 1966, Germany, Switzerland, BirXhauser Verlag, vol. 10, pp. 224-285 and J. Pharm. Sci. 66 (1977) 1-5.
The acid addition salts are usually obtained in a conventional manner by mixing the free base or solu-tions thereof ~ith the appropriate acid or soIutions thereof in an organic solvent, for example a lower alcohol such as methanol, ethanol or propanol, or a lower ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or an ether such as diethyl ether, tetrahydrofuran or dioxane. Mixtures of these solvents can be used to improve crystallization. It is also possible to prepare pharmaceutically acceptable aqueous solutions of acid addition compounds of the amino com-pounds of the formula I by dissolving the free bases in an aqueous acid solution.
The compounds according to the invention and the salts thereof with physiologically tolerated acids have valuable pharmacological actions. In particular, they - 6 - ~90307 O.Z. 005~40846 inhibit gastroitltestinal K~/H -A'rPase and gastric acid secretiQn~ The compounds according to the invention c~n ~herefore be used for the therapy of all disorders in which a reduction in gastric acid secretion has a bene-S ficial effect on healing, e.g. gastric ulcer, duodenalulcer, gastritis, reflux esoph~gitis and Zollinger-Ellison syndrome (cf. re~iew on inhibitors of R+/H+-ATPase, G. Sachs et al., Ann. Rev. Pharmacol.
Toxicol. 28 (88) 269-284 and literature cited therein).
The present invention also relates to drugs for oral, re~tal or intxa~enous administration, which contain the compounds of the formula I or the acid addition salts thereof as active substance, in addition to conventional carriers and dil~ents, and to the use of the noYe compounds and the physiologically tolerated salts thereof for the treatment of ~he said diseases.
The drugs of the present invention are prepared with ~he conventional solid ox liquid carriers or dilu-ents and the auxiliaries conventionally used in pharma-ceutical technology, in accordance with the desired modeof administration, with a suitable dosage, in a con-ventional manner. The preferred presentations are suitable for oral administration. ~xamples of such presentations are tablets, which may be (film) coated, capsules, pill5, powders~ solutions or su~pensions, or depot fonms. Also suitable, of course, are parenteral formulations such as solutions for injection. An example of another formul~tion is the suppository.
Appropriate tablets can be obtained, for example, b~ mixing the acti~e substance with conventional auxili-aries/ for example inert diluents such as dextrose, sucro~, sorbitol, mannitol and polyvinylpyrrolidone, disintegran~s such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents to achieve a depot effect such as carboxypolymethylene, carboxymethyl-ce lulose, cellulose acetate phthalate or polyvinyl acetateO The tablets can also be composed of several - 7 - ~90307 o.Z 0050/40B46 la~e~-s.
Appropriate coated tablets can be prepared from cores which are prepared in a similar mannex to the tablets and coated with the material conventionally used for this purpose, e.g. polyvinylpyrrolidone or shallac, gum arabic, talc, titanium dioxide or sucrose. This coating can al~o be composed of several layers, and it is possible to use the auxiliaries mentioned above for the tablets.
Solutions or suspensions containing the acti~e substance according to the invention can additionally contain flavor-improvers such as saccharin, cyclamate or suc~ose and, for examp1e, flavorings s~ch as vanillin or orange extract. They can additionally contain suspending auxiliaries such as sodi~m carbo~ym~thylcellulose or preservatives such as p-hydro~ybenzoates. Capsules containing active substances can bP prepared, for ex~
ample, by the active substance being mixed with an inert carrier, such as lactose or ~orbitol, and encapsulated in ?0 gelatin capsules.
Suitable suppositories can be prepared, for example, by mi~ing with carriers intended for ~his purpose, such as neutral fats or polyethylene glycol or deri~atives thereof.
The single dose for h~mans on oral or rectal administration is from 10 to 1000 mg and on i.Y. ad-ministration is from 0.01 to 1.0 mg/kg of body weight.
The action of the compounds according to the invention has been determined in the following design of assayo The mucosa of a freshly removed pig stomach was nomogenized in 0.25 M sucrose, 20 ~ tris (tris(hydroxy-methylamino)methane), 1 I~MEGTA ~ethyl~nebis(oxyethylene-nitrilo~etraacetic acid), pH 7.0, in an ice bath and centrifuged at 20,000 xg for 20 minO The supern~tant was centrifuged at 100,000 xg for 60 min. The resulting microsomal pellet wa~ homogenized with 50 mM tris ~ 2 mM
MgCl2 + 0~1 mM E~TA, pH 7.5, and frozen in portions at y ~
O.~. 005~0846 -'0 C. The ~ /H -ATPase activity was assayed in 1 ml mixtures of the follo~ing composition: 50 mM
tris~HC1 buffer, pH 7.5, 2 mM MgCl2, 20 ~g of membrane protein with or without addition of 5 mM RCl. The ATPase reaction was started by addition of Na2ATP, final con-centration 2 mM, reaction time 15 min at 37 C. The reaction was then 5topped by adding 1 ml of 20 % tri-chloroacetic acid. The liberated phosphate was deter-mined by the method of Sanui (Analyt. Biochem. 60 (1974) 489-50~)~
The IC50 for inhibition of K~/H+-ATPase wa~ de~er-mined by adding ~arious concentrations of the compounds according to the invention in the above design of assay.
Examples General method:
A mixture of 1 equivalent of a compound of the formula II, 1 to 11 equivalents of an amine of the formula R3CH2NHR4 and 5 to 20 equivalents of phenol w~s heated at 60 to 140 C under reflux or in an autoclave for 2 ~o 8 h. The excess amine and the phenol were removed by distillation under reduced pressure, then ethyl ace~ate was added ~o the residue, and the mixture was extracted several times with aqueous tartaric acid solution. The aqueous phase was made alkaline with con-~5 centrated NH3 or dilute NaOH and extracted several times withethyl acet~te, and the orga~ic phase was washed seve-ral tLmes with dilute NaOH and H20, dried over Na2SO4 and evaporated in a rotary evaporator. The crude products were boiled with ether, and th product was filtered off with suction.The products were further purified by recrystallization from a suitable solvent (see Table).
The compounds of Examples 1 to 6 were obtained by this method.
Example~ 1 ~o Ç, compounds of the general formula I, R1 =
CH3, R2 = R4 = R8 = H, R5 = OCH3 v 9~
9 .. 890307 E~mpl~ R Yield Recrystal~- M.p. ( C) in % lization of theory f~om 1 2-thieny~ 40 1) ethanol 2) ethyl ceta~e 233-234 3-thienyl 66 ethanol 201-202 3 3-methyl-2-thienyl 70 214-215 4 2-furyl 22 ~ 215-216 5-methyl-2-furyl lS~) ethanol 179-180 6 1-methyl-2-pyrroiyl 10a)b~ ethanol 219-220 a) Purification by colu~n chromatography on silica gel with 95/5 CH2Cl2/CH3OH
b~ The reaction was carried out in the presen~e of 3 equi~alents of N-methylmorpholine.
The following compounds of the formula I can be obtained similarly by reaction of the appropriate 4-chloro-, 4-b~omo- or 4-phenoxyquinolines with the amines R3_~HZ-NHR4 -Example 7 R4 = R~ 5 - OCH3 Ex. Rl RZ R3 7a C2H5 ~ 3-methyl-2-thienyl 7b i-C3H7 H 2-thie~yl 7c n-C4H9 H 2-methyl-3-thienyl 7d CH2OH H 3-methyl-2 thienyl 7e CH2OCH3 H l-methyl-2-pyrrolyl 7f CX2OCH3 H 3-methyl-2-thienyl 7g CHz~CH3 H 2~methyl-3-thienyl 7h CH3 CH3 2~thienyl E.';. R ! R2 R3 7 i c~3 CH3 3-thienyl 7j CH3 c~3 3-methyl-2-thienyl 7k CH3 CH3 5 methyl-2-furyl 71 CH3 CH3 2 - furyl-7m CH3 CH3 1-methyl-2-pyrrolyl 7n CH20CH3 CH3 3-thienyl ~H3 C2H5 2 thienyl 7p CH3 i-C3H7 2-thie~yl 7q CH3 n-C4Hg 3-methyl-2-thienyl 7r CH3 n-C6H13 3-thienyl 7s H CH3 3-methyl-2-thienyl 7t X C2Hs 2-methyl-3-thienyl 7u H i-C3H7 2-fu~yl 7v H n-C~Hg 2-thienyl 7w H n C6H13 3-methyl-2-thienyl 7x H H 3-methyl-2-thienyl 7y ~ H 1-methyl-2-pyrrolyl Exa~ple 8 R' = CH3 r R2 = H) R5 - CH30, R6 = H
Ex. R3 R~
8a 3- thienyl CH3 8D 2-thienyl 2-thienylmethyl 8c 2-methyl~3-thienyl CH3 8d 3-methyl-2-thienyl 3-methyl-2-thienyl-methyl 8e 1-methyl 2-pyrrolyl 1-methyl-2-pyrrolyl-methyl 8~ l~methyl-2-pyrrolyl 2-thienylmethyl 8g 1-methyl-2-pyrrolyl CH3 8h 3-methyl-2 thienyl CH3 Ex~ple ~
R~ = CH3, Ri = R~ = H~ R5 = CH30 Ex. ~?. R3 9a EI 4 methyl-2 thienyl 9b H 5-methyl-2-thienyl 9c CH3 5-rnethyl-2-thienyl 9d H 4,5-dimethyl-2-thienyl 9e H 4,5-dichloro-2-thienyl 9f CH3 2-chloro-3-thienyl 9g H 2-chloro-3-thienyl 9h H 3-methyl-2-furyl 9i CH3 3-methyl-2-furyl 9j H 4-methyl-2-furyl 9k El 2~methyl-4-furyl 91 CH3 2-methyl-4-furyl 9m H 2-methyl-3-furyl 9n H 2,5~dimethyl-3-:Euryl 9o CH3 2,5-dimethyl-3-furyl 9p CH3 1-methyl-2-pyrrolyl 9q H l-isopropyl-2-pyrrolyl 9r H l-n~butyl-2-pyrrolyl 9s H l-benzyl-2-pyrrolyl 9t H l-phenyl 2-pyrrolyl 9u H 1-(4-chlorophenyl)-2-pyrrolyl 9v H 1 ( 2-methoxyphenyl ~ -2-pyrrolyl 9w H 1,3-dimethyl 2-pyrrolyl 9x H 1,2-dirnethyl-3-pyrrolyl 9y H 1-methyl-3-pyrrolyl 9z CH3 1-me~hyl-3-pyrrolyl 9z~ H l-isopropyl-3-pyrrolyl 9zb H 1-phenyl-3 -pyrrolyl 9zc H 1-benzyl-3-pyrrolyl gzd H 2-benzofuranyl 3ze H 3-benzofuranyl 9zf H 3-methyl-2-ben~ofuranyl O. Z . OOS0/40846 E.~. R- R3 9æg H 2-benzothienyl 9 zh H 3-benzothienyl 9~i H 3-methyl-2-ben~othienyl 3 z j H 3 - indo lyl 9z)i ~ l-methyl-3-indolyl 9zl CH3 2-benzothienyl 9zm H 2-methyl-3-benzothienyi 9zn H 3-chloro-2-benzothienyl 3~o H 3-bromo-2-benzothiellyl 9zp H 3-iodo-2-benzothienyl gzq ~ 2-bromo 3-benzothienyl 9~r H 2, 4, 5-trimethyl-3-thieny~
9zs H 3, 4, 5-trimethyl-2-thienyl 9zt H 2, 4, 5-trimethyl-3-furyl 9 ~ H 3, 4, 5 -trimethyl - 2 - f uryl 9zv }~ 1, 2, 5-trimethyl-3-pyrrolyl 9zw H 1, 2, 4-trimethyl-3~pyrrolyl 9zx H 1, 2, 4, 5-tetramethyl-3-pyrrolyl 9zy ~ 1, 3, 4-t:rimethyl-2-pyrrolyl 9~z H 1, 3 / 5-trime~hyl-2-pyrrolyl Exa.nple 1 0 ~ = ~H3, ~ = ~
2 5 Ex . R2 ~3 R5 R6 lOa H 3-methyl-2-thienyl O~2H5 H
lQb c~3 3-methyl-2-thienyl OC2H5 H
lOc H 3-methyl-2-thienyl O-nC4H9 H
lOd H 2- thienyl O-nC6~13 H
lOe H l-methyl-2-pyrrolyl OCH2C6H5 H
lOf CH3 1-methyl-2-pyrrolyl OCH2C6H5 lOg H 5-methyl-2-furyl OCH2C6~I5 lOh ~H3 ~methyl-2-thienyl Oc:H2c6H5 H
lQi H 3-methyl-2-thienyl OcH2c6~ls H
- 13 - ~90307 0050/a~0846 E ~ . R- ~' R5 R6 10i H 3-thienyl SCH3 H
lOk H 3-methyl-2-thienyl N(CH3) 2 H
101 H 3-methyl-2-thienyl NHCH2C6H5 lOm H 3-methyl 2-thienyl NHCOC6Hs ~I
lOn H 2-thienyl CF3 H
lOo H 3-methyl-2-thienyl Cl ~
lCp CH3 3-methyl-2-thienyl Cl H
lOq H 1-methyl-2-pyrxolyl Br H
lOr H ~-methyl-2-thienyl OCH3 6-OCH3 105 H 3-methyl-2-thienyl OCH3 5-OCH3 lOt H 2-methyl-3-thienyl OCH3 5-OC~3 lOu H 3-methyl-2-thienyl OCH3 6-Cl lOv H 3-methyl-2-thienyl OCH3 5-CH3 lOw ~ 3-methyl-2-thienyl OCH3 6-~h3 lOx H 3-methyl-2-thienyl OCH3 7-C~3 lOy H 2-methyl-3-thienyl OCH3 5-CH3 10~ H 2-methyl-3-thienyl oc~3 6-CH3 Example 11 Rl = CH3/ R2 _ R4 = ~6 = H, ~5 = OCH3 Ex, ~3 lla 3-ethyl-2-thienyl llb 3-isopropyl-2-thienyl llc 3 cyclopropyl-2-thienyl lld 5-ethyl-2 thienyl lle 5-isopropyl-2-thienyl llf 5-tert. butyl 2-thienyl llg 3,5-di~lethyl-2-thienyl llh 3,4-dimethyl-2-thienyl lli 3,4,5-trimethyl 2-thienyl llj 2~methyl~3-thienyl llk 4~methyl-3-thienyl 111 5-methyl-3-thienyl llm 2,4-dLm~thyl-3-thienyl lln 2,5 d~nethyl-3-thienyl E`;. R3 llo 4,5~dimethyl-3 thienyl llp 2,4,5-trimethyl-3-thienyl Example 12 Rl = CH3, R2 - R4 = R = H, R5 = OCH3 Ex. R3 12a 3-chloro-2-thienyl 12b 4-chloro-2-thienyl 12c 5-chloro-2-thienyl 12d 3,4-dichloro-2-~hienyl 12e 3,4,5-trichloro-2-thienyl 12f 5-chloro-3-methyl-thienyl 12g 2-chloro-3-thienyl 12h 4-chloro-3-thienyl 12i 5-chloro-3-thienyl 12j 2,5-dichloro-3-thienyl 12k 4,5~dichloro-3-thienyl 121 4-chloro-2,5-dimethyl-2-thienyl 12m 2 chloro-5-methyl-2-thienyl 12n 3-bromo-2-thienyl 120 4~bromo-2-thienyl 12p 5-bromo-2-thienyl 12q 3,4-dibromo-2-thienyl 12r 3,5-dibromo-2-thienyl 12s 4,5-dibromo-2-thienyl 12t 3 bromo-5-methyl-2-thienyl 12u 4-bromo-3-methyl-2-thienyl 12v 5-bromo-3-methyl-2-thienyl 12w 2-bromo-3-thienyl 12x 4-bromo-3-thienyl 12y 5-bromo-3-thienyl 12z 2,4-dibromo-3-thienyl 12za 2,5-dibromo-3-thienyl 12zb 4,5-dibromo-3-thierlyl 12zd 2,4,5 tribromo-3-thienyl .Y, ~,~
l~e 5-bromo-~-methyl-3-thienyl 12~f 2-bromo-5-methyl-3-thienyl 12~g 4-bromo-2-methyl-3 thienyl 12zh 2-bromo-4-methyl-3-thienyl 12~i 3-iodo-2~hienyl 12zj 4-iodo-2-thienyl 12zk 5-iodo-2-thienyl 12zl 3-iodo-5-methyl-2~thienyl 12zm 5-iodo-3 methyl-2-thienyl 12~n 2-iodo-3-thienyl l~o 5-iodo-3-thienyl 12~p ~-iodo-4-methyl-3-thienyl 12z~ 4-iodo-2-methyl-3-thienyl 12zr 5-iodo-2-methyl-3-thienyl 12~s 2,5~dimethyl-4-iodo-3-thienyl Example 13 Rl = CH3, R2 - R~ - R6 = H
Ex, R3 R5 13a 3-methyl-2-thienyl NHCOcH3 13b 3 methyl-2-thienyl o-iC3~7 13c 3-methyl-2-thienyl o-nC3~7 13d 3 methyl-2-thienyl NHCH3 13e 3-methyl 2-thienyl COCH3 13f 3-methyl-~-thienyl COOH
13g 3-methyl-2-thienyl COOC2H5 13h 3-methyl-2-thienyl CONH2 13i 3-methyl-2-thienyl CON(cH3)z 13j 3-methyl-2-thienyl CH2OH
13k 2 methyl-3-thlenyl CH2OH
131 1-methyl-2-pyrrolyl CH2OH
13m 3-methyl-2~thienyl CH(OH~ C~3 13n 2-methyl-3-thienyl CH(OH) C~3 13O 2-thienyl CH3 O.Z~ 00.50~4~5 E~. R3 ~5 13p 3 -thienyl C~13 13q 3-methyl-2-thienyl CH3 13r 2-methyl-3 thienyl CH3 13s 1-methyl-2-pyrrolyl CH3 13t 1-isopropyl-2-pyrrolyl CH3 13u 1, 2,5-tri.~ethyl-3-pyrrolyl CH3 13v 3-methyl-2-thienyl C2Hs 13w 2~methyl-3thienyl C2H5 13x 3-methyl-2-thienyl nC3~7 13y 3-methyl 2-thienyl iC3~1 13z 3 rnethy~-2-thienyl CH2OCH3 13~a 3 methyl-2-thienyl CH2OC2~5 13~b 3~methyl-2~thienyl CH2OiC3~7
The compounds of the general formula II can be obtained in a similar manner to known compounds. For the preparation of compounds of the formula Il, see, for example, J. Indian Chem. Soc. 51 (1974), 880-882 and G. Jones (Ed.) Quinolines, Part I, John Wiley & Sons, London, 1977: X = Cl: pp. 391-398, X = Br: pp. 404-406, X = OC6H5: pp. 577-579. 4-Phenoxyquinolines can also be detected as intermediates in the reaction of 4-chloro-quinolin~s with amines R3CH2NHR4 in the presence of phenol.
The amines R3CH2NHR4 are known from the literature or can be prepared in a similar manner to known compounds (Houben Weyl, ~ethoden der Organischen Chemie vol. 11/1, 4th edition 1957, G. Thieme-Verlag Stuttgart).
The compounds according to the invention can be converted into the addition salt with a physiologically tolerated acid. A compilation of conventional physio-logically tolerated acids is to be found in Fortschritte der Arzneimittelforschung 1966, Germany, Switzerland, BirXhauser Verlag, vol. 10, pp. 224-285 and J. Pharm. Sci. 66 (1977) 1-5.
The acid addition salts are usually obtained in a conventional manner by mixing the free base or solu-tions thereof ~ith the appropriate acid or soIutions thereof in an organic solvent, for example a lower alcohol such as methanol, ethanol or propanol, or a lower ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, or an ether such as diethyl ether, tetrahydrofuran or dioxane. Mixtures of these solvents can be used to improve crystallization. It is also possible to prepare pharmaceutically acceptable aqueous solutions of acid addition compounds of the amino com-pounds of the formula I by dissolving the free bases in an aqueous acid solution.
The compounds according to the invention and the salts thereof with physiologically tolerated acids have valuable pharmacological actions. In particular, they - 6 - ~90307 O.Z. 005~40846 inhibit gastroitltestinal K~/H -A'rPase and gastric acid secretiQn~ The compounds according to the invention c~n ~herefore be used for the therapy of all disorders in which a reduction in gastric acid secretion has a bene-S ficial effect on healing, e.g. gastric ulcer, duodenalulcer, gastritis, reflux esoph~gitis and Zollinger-Ellison syndrome (cf. re~iew on inhibitors of R+/H+-ATPase, G. Sachs et al., Ann. Rev. Pharmacol.
Toxicol. 28 (88) 269-284 and literature cited therein).
The present invention also relates to drugs for oral, re~tal or intxa~enous administration, which contain the compounds of the formula I or the acid addition salts thereof as active substance, in addition to conventional carriers and dil~ents, and to the use of the noYe compounds and the physiologically tolerated salts thereof for the treatment of ~he said diseases.
The drugs of the present invention are prepared with ~he conventional solid ox liquid carriers or dilu-ents and the auxiliaries conventionally used in pharma-ceutical technology, in accordance with the desired modeof administration, with a suitable dosage, in a con-ventional manner. The preferred presentations are suitable for oral administration. ~xamples of such presentations are tablets, which may be (film) coated, capsules, pill5, powders~ solutions or su~pensions, or depot fonms. Also suitable, of course, are parenteral formulations such as solutions for injection. An example of another formul~tion is the suppository.
Appropriate tablets can be obtained, for example, b~ mixing the acti~e substance with conventional auxili-aries/ for example inert diluents such as dextrose, sucro~, sorbitol, mannitol and polyvinylpyrrolidone, disintegran~s such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or agents to achieve a depot effect such as carboxypolymethylene, carboxymethyl-ce lulose, cellulose acetate phthalate or polyvinyl acetateO The tablets can also be composed of several - 7 - ~90307 o.Z 0050/40B46 la~e~-s.
Appropriate coated tablets can be prepared from cores which are prepared in a similar mannex to the tablets and coated with the material conventionally used for this purpose, e.g. polyvinylpyrrolidone or shallac, gum arabic, talc, titanium dioxide or sucrose. This coating can al~o be composed of several layers, and it is possible to use the auxiliaries mentioned above for the tablets.
Solutions or suspensions containing the acti~e substance according to the invention can additionally contain flavor-improvers such as saccharin, cyclamate or suc~ose and, for examp1e, flavorings s~ch as vanillin or orange extract. They can additionally contain suspending auxiliaries such as sodi~m carbo~ym~thylcellulose or preservatives such as p-hydro~ybenzoates. Capsules containing active substances can bP prepared, for ex~
ample, by the active substance being mixed with an inert carrier, such as lactose or ~orbitol, and encapsulated in ?0 gelatin capsules.
Suitable suppositories can be prepared, for example, by mi~ing with carriers intended for ~his purpose, such as neutral fats or polyethylene glycol or deri~atives thereof.
The single dose for h~mans on oral or rectal administration is from 10 to 1000 mg and on i.Y. ad-ministration is from 0.01 to 1.0 mg/kg of body weight.
The action of the compounds according to the invention has been determined in the following design of assayo The mucosa of a freshly removed pig stomach was nomogenized in 0.25 M sucrose, 20 ~ tris (tris(hydroxy-methylamino)methane), 1 I~MEGTA ~ethyl~nebis(oxyethylene-nitrilo~etraacetic acid), pH 7.0, in an ice bath and centrifuged at 20,000 xg for 20 minO The supern~tant was centrifuged at 100,000 xg for 60 min. The resulting microsomal pellet wa~ homogenized with 50 mM tris ~ 2 mM
MgCl2 + 0~1 mM E~TA, pH 7.5, and frozen in portions at y ~
O.~. 005~0846 -'0 C. The ~ /H -ATPase activity was assayed in 1 ml mixtures of the follo~ing composition: 50 mM
tris~HC1 buffer, pH 7.5, 2 mM MgCl2, 20 ~g of membrane protein with or without addition of 5 mM RCl. The ATPase reaction was started by addition of Na2ATP, final con-centration 2 mM, reaction time 15 min at 37 C. The reaction was then 5topped by adding 1 ml of 20 % tri-chloroacetic acid. The liberated phosphate was deter-mined by the method of Sanui (Analyt. Biochem. 60 (1974) 489-50~)~
The IC50 for inhibition of K~/H+-ATPase wa~ de~er-mined by adding ~arious concentrations of the compounds according to the invention in the above design of assay.
Examples General method:
A mixture of 1 equivalent of a compound of the formula II, 1 to 11 equivalents of an amine of the formula R3CH2NHR4 and 5 to 20 equivalents of phenol w~s heated at 60 to 140 C under reflux or in an autoclave for 2 ~o 8 h. The excess amine and the phenol were removed by distillation under reduced pressure, then ethyl ace~ate was added ~o the residue, and the mixture was extracted several times with aqueous tartaric acid solution. The aqueous phase was made alkaline with con-~5 centrated NH3 or dilute NaOH and extracted several times withethyl acet~te, and the orga~ic phase was washed seve-ral tLmes with dilute NaOH and H20, dried over Na2SO4 and evaporated in a rotary evaporator. The crude products were boiled with ether, and th product was filtered off with suction.The products were further purified by recrystallization from a suitable solvent (see Table).
The compounds of Examples 1 to 6 were obtained by this method.
Example~ 1 ~o Ç, compounds of the general formula I, R1 =
CH3, R2 = R4 = R8 = H, R5 = OCH3 v 9~
9 .. 890307 E~mpl~ R Yield Recrystal~- M.p. ( C) in % lization of theory f~om 1 2-thieny~ 40 1) ethanol 2) ethyl ceta~e 233-234 3-thienyl 66 ethanol 201-202 3 3-methyl-2-thienyl 70 214-215 4 2-furyl 22 ~ 215-216 5-methyl-2-furyl lS~) ethanol 179-180 6 1-methyl-2-pyrroiyl 10a)b~ ethanol 219-220 a) Purification by colu~n chromatography on silica gel with 95/5 CH2Cl2/CH3OH
b~ The reaction was carried out in the presen~e of 3 equi~alents of N-methylmorpholine.
The following compounds of the formula I can be obtained similarly by reaction of the appropriate 4-chloro-, 4-b~omo- or 4-phenoxyquinolines with the amines R3_~HZ-NHR4 -Example 7 R4 = R~ 5 - OCH3 Ex. Rl RZ R3 7a C2H5 ~ 3-methyl-2-thienyl 7b i-C3H7 H 2-thie~yl 7c n-C4H9 H 2-methyl-3-thienyl 7d CH2OH H 3-methyl-2 thienyl 7e CH2OCH3 H l-methyl-2-pyrrolyl 7f CX2OCH3 H 3-methyl-2-thienyl 7g CHz~CH3 H 2~methyl-3-thienyl 7h CH3 CH3 2~thienyl E.';. R ! R2 R3 7 i c~3 CH3 3-thienyl 7j CH3 c~3 3-methyl-2-thienyl 7k CH3 CH3 5 methyl-2-furyl 71 CH3 CH3 2 - furyl-7m CH3 CH3 1-methyl-2-pyrrolyl 7n CH20CH3 CH3 3-thienyl ~H3 C2H5 2 thienyl 7p CH3 i-C3H7 2-thie~yl 7q CH3 n-C4Hg 3-methyl-2-thienyl 7r CH3 n-C6H13 3-thienyl 7s H CH3 3-methyl-2-thienyl 7t X C2Hs 2-methyl-3-thienyl 7u H i-C3H7 2-fu~yl 7v H n-C~Hg 2-thienyl 7w H n C6H13 3-methyl-2-thienyl 7x H H 3-methyl-2-thienyl 7y ~ H 1-methyl-2-pyrrolyl Exa~ple 8 R' = CH3 r R2 = H) R5 - CH30, R6 = H
Ex. R3 R~
8a 3- thienyl CH3 8D 2-thienyl 2-thienylmethyl 8c 2-methyl~3-thienyl CH3 8d 3-methyl-2-thienyl 3-methyl-2-thienyl-methyl 8e 1-methyl 2-pyrrolyl 1-methyl-2-pyrrolyl-methyl 8~ l~methyl-2-pyrrolyl 2-thienylmethyl 8g 1-methyl-2-pyrrolyl CH3 8h 3-methyl-2 thienyl CH3 Ex~ple ~
R~ = CH3, Ri = R~ = H~ R5 = CH30 Ex. ~?. R3 9a EI 4 methyl-2 thienyl 9b H 5-methyl-2-thienyl 9c CH3 5-rnethyl-2-thienyl 9d H 4,5-dimethyl-2-thienyl 9e H 4,5-dichloro-2-thienyl 9f CH3 2-chloro-3-thienyl 9g H 2-chloro-3-thienyl 9h H 3-methyl-2-furyl 9i CH3 3-methyl-2-furyl 9j H 4-methyl-2-furyl 9k El 2~methyl-4-furyl 91 CH3 2-methyl-4-furyl 9m H 2-methyl-3-furyl 9n H 2,5~dimethyl-3-:Euryl 9o CH3 2,5-dimethyl-3-furyl 9p CH3 1-methyl-2-pyrrolyl 9q H l-isopropyl-2-pyrrolyl 9r H l-n~butyl-2-pyrrolyl 9s H l-benzyl-2-pyrrolyl 9t H l-phenyl 2-pyrrolyl 9u H 1-(4-chlorophenyl)-2-pyrrolyl 9v H 1 ( 2-methoxyphenyl ~ -2-pyrrolyl 9w H 1,3-dimethyl 2-pyrrolyl 9x H 1,2-dirnethyl-3-pyrrolyl 9y H 1-methyl-3-pyrrolyl 9z CH3 1-me~hyl-3-pyrrolyl 9z~ H l-isopropyl-3-pyrrolyl 9zb H 1-phenyl-3 -pyrrolyl 9zc H 1-benzyl-3-pyrrolyl gzd H 2-benzofuranyl 3ze H 3-benzofuranyl 9zf H 3-methyl-2-ben~ofuranyl O. Z . OOS0/40846 E.~. R- R3 9æg H 2-benzothienyl 9 zh H 3-benzothienyl 9~i H 3-methyl-2-ben~othienyl 3 z j H 3 - indo lyl 9z)i ~ l-methyl-3-indolyl 9zl CH3 2-benzothienyl 9zm H 2-methyl-3-benzothienyi 9zn H 3-chloro-2-benzothienyl 3~o H 3-bromo-2-benzothiellyl 9zp H 3-iodo-2-benzothienyl gzq ~ 2-bromo 3-benzothienyl 9~r H 2, 4, 5-trimethyl-3-thieny~
9zs H 3, 4, 5-trimethyl-2-thienyl 9zt H 2, 4, 5-trimethyl-3-furyl 9 ~ H 3, 4, 5 -trimethyl - 2 - f uryl 9zv }~ 1, 2, 5-trimethyl-3-pyrrolyl 9zw H 1, 2, 4-trimethyl-3~pyrrolyl 9zx H 1, 2, 4, 5-tetramethyl-3-pyrrolyl 9zy ~ 1, 3, 4-t:rimethyl-2-pyrrolyl 9~z H 1, 3 / 5-trime~hyl-2-pyrrolyl Exa.nple 1 0 ~ = ~H3, ~ = ~
2 5 Ex . R2 ~3 R5 R6 lOa H 3-methyl-2-thienyl O~2H5 H
lQb c~3 3-methyl-2-thienyl OC2H5 H
lOc H 3-methyl-2-thienyl O-nC4H9 H
lOd H 2- thienyl O-nC6~13 H
lOe H l-methyl-2-pyrrolyl OCH2C6H5 H
lOf CH3 1-methyl-2-pyrrolyl OCH2C6H5 lOg H 5-methyl-2-furyl OCH2C6~I5 lOh ~H3 ~methyl-2-thienyl Oc:H2c6H5 H
lQi H 3-methyl-2-thienyl OcH2c6~ls H
- 13 - ~90307 0050/a~0846 E ~ . R- ~' R5 R6 10i H 3-thienyl SCH3 H
lOk H 3-methyl-2-thienyl N(CH3) 2 H
101 H 3-methyl-2-thienyl NHCH2C6H5 lOm H 3-methyl 2-thienyl NHCOC6Hs ~I
lOn H 2-thienyl CF3 H
lOo H 3-methyl-2-thienyl Cl ~
lCp CH3 3-methyl-2-thienyl Cl H
lOq H 1-methyl-2-pyrxolyl Br H
lOr H ~-methyl-2-thienyl OCH3 6-OCH3 105 H 3-methyl-2-thienyl OCH3 5-OCH3 lOt H 2-methyl-3-thienyl OCH3 5-OC~3 lOu H 3-methyl-2-thienyl OCH3 6-Cl lOv H 3-methyl-2-thienyl OCH3 5-CH3 lOw ~ 3-methyl-2-thienyl OCH3 6-~h3 lOx H 3-methyl-2-thienyl OCH3 7-C~3 lOy H 2-methyl-3-thienyl OCH3 5-CH3 10~ H 2-methyl-3-thienyl oc~3 6-CH3 Example 11 Rl = CH3/ R2 _ R4 = ~6 = H, ~5 = OCH3 Ex, ~3 lla 3-ethyl-2-thienyl llb 3-isopropyl-2-thienyl llc 3 cyclopropyl-2-thienyl lld 5-ethyl-2 thienyl lle 5-isopropyl-2-thienyl llf 5-tert. butyl 2-thienyl llg 3,5-di~lethyl-2-thienyl llh 3,4-dimethyl-2-thienyl lli 3,4,5-trimethyl 2-thienyl llj 2~methyl~3-thienyl llk 4~methyl-3-thienyl 111 5-methyl-3-thienyl llm 2,4-dLm~thyl-3-thienyl lln 2,5 d~nethyl-3-thienyl E`;. R3 llo 4,5~dimethyl-3 thienyl llp 2,4,5-trimethyl-3-thienyl Example 12 Rl = CH3, R2 - R4 = R = H, R5 = OCH3 Ex. R3 12a 3-chloro-2-thienyl 12b 4-chloro-2-thienyl 12c 5-chloro-2-thienyl 12d 3,4-dichloro-2-~hienyl 12e 3,4,5-trichloro-2-thienyl 12f 5-chloro-3-methyl-thienyl 12g 2-chloro-3-thienyl 12h 4-chloro-3-thienyl 12i 5-chloro-3-thienyl 12j 2,5-dichloro-3-thienyl 12k 4,5~dichloro-3-thienyl 121 4-chloro-2,5-dimethyl-2-thienyl 12m 2 chloro-5-methyl-2-thienyl 12n 3-bromo-2-thienyl 120 4~bromo-2-thienyl 12p 5-bromo-2-thienyl 12q 3,4-dibromo-2-thienyl 12r 3,5-dibromo-2-thienyl 12s 4,5-dibromo-2-thienyl 12t 3 bromo-5-methyl-2-thienyl 12u 4-bromo-3-methyl-2-thienyl 12v 5-bromo-3-methyl-2-thienyl 12w 2-bromo-3-thienyl 12x 4-bromo-3-thienyl 12y 5-bromo-3-thienyl 12z 2,4-dibromo-3-thienyl 12za 2,5-dibromo-3-thienyl 12zb 4,5-dibromo-3-thierlyl 12zd 2,4,5 tribromo-3-thienyl .Y, ~,~
l~e 5-bromo-~-methyl-3-thienyl 12~f 2-bromo-5-methyl-3-thienyl 12~g 4-bromo-2-methyl-3 thienyl 12zh 2-bromo-4-methyl-3-thienyl 12~i 3-iodo-2~hienyl 12zj 4-iodo-2-thienyl 12zk 5-iodo-2-thienyl 12zl 3-iodo-5-methyl-2~thienyl 12zm 5-iodo-3 methyl-2-thienyl 12~n 2-iodo-3-thienyl l~o 5-iodo-3-thienyl 12~p ~-iodo-4-methyl-3-thienyl 12z~ 4-iodo-2-methyl-3-thienyl 12zr 5-iodo-2-methyl-3-thienyl 12~s 2,5~dimethyl-4-iodo-3-thienyl Example 13 Rl = CH3, R2 - R~ - R6 = H
Ex, R3 R5 13a 3-methyl-2-thienyl NHCOcH3 13b 3 methyl-2-thienyl o-iC3~7 13c 3-methyl-2-thienyl o-nC3~7 13d 3 methyl-2-thienyl NHCH3 13e 3-methyl 2-thienyl COCH3 13f 3-methyl-~-thienyl COOH
13g 3-methyl-2-thienyl COOC2H5 13h 3-methyl-2-thienyl CONH2 13i 3-methyl-2-thienyl CON(cH3)z 13j 3-methyl-2-thienyl CH2OH
13k 2 methyl-3-thlenyl CH2OH
131 1-methyl-2-pyrrolyl CH2OH
13m 3-methyl-2~thienyl CH(OH~ C~3 13n 2-methyl-3-thienyl CH(OH) C~3 13O 2-thienyl CH3 O.Z~ 00.50~4~5 E~. R3 ~5 13p 3 -thienyl C~13 13q 3-methyl-2-thienyl CH3 13r 2-methyl-3 thienyl CH3 13s 1-methyl-2-pyrrolyl CH3 13t 1-isopropyl-2-pyrrolyl CH3 13u 1, 2,5-tri.~ethyl-3-pyrrolyl CH3 13v 3-methyl-2-thienyl C2Hs 13w 2~methyl-3thienyl C2H5 13x 3-methyl-2-thienyl nC3~7 13y 3-methyl 2-thienyl iC3~1 13z 3 rnethy~-2-thienyl CH2OCH3 13~a 3 methyl-2-thienyl CH2OC2~5 13~b 3~methyl-2~thienyl CH2OiC3~7
Claims (10)
1. A compound of the formula I
(I), where R1 is hydrogen or C1-C4-alkyl which can be substituted by hydroxyl or C1-C4-alkoxy, R2 is hydrogen or C1-C6-alkyl, R3 is thienyl, which can be substituted by 1 to 3 C1-C4-alkyl groups and/or 1 to 2 halogen atoms, furyl which can be substituted by 1 to 3 C1-C4-alkyl groups, pyrrolyl which can have hydrogen, C1-C6-alkyl, phenyl-C1-C3-alkyl or phenyl on the nitrogen and can be substituted on the carbon atoms by 1 to 3 C1-C4-alkyl groups, it also being possible or the thienyl, furyl or pyrrolyl to be benzo-fused, R4 is hydrogen, C1-C4-alkyl or -CH2-R3 where R3 has the abovementioned meaning, R5 is C1-C6-alkyl which can be substituted by hydroxyl or C1-C3-alkoxy or is hydroxyl, C1-C6-alkoxy, phenoxy,phenyl-C1-C3-alkoxy,C1 C6-alkylthio,phenyl-thio,phenyl-C1-C3-alkylthio, amino,C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenylamino, N-phenyl-N-(C1-C4-alkyl)amino, pherlyl-C1-C4-alkylamino, N-phenyl-C1-C4-alkyl-N-(C1-C4-alkyl) amino, C1-C4-alkanoylamino, benzoylamino, phenyl-C1-C3-alkanoylamino, C1 C6-alkanoyl, hydroxycarbonyl, C1-C6-alkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, di- ( C1-C6-alkyl)aminocarbonyl, trifluoromethyl or halogen, and R6 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy or halogen and tna physiologically tolerated salts thereof.
(I), where R1 is hydrogen or C1-C4-alkyl which can be substituted by hydroxyl or C1-C4-alkoxy, R2 is hydrogen or C1-C6-alkyl, R3 is thienyl, which can be substituted by 1 to 3 C1-C4-alkyl groups and/or 1 to 2 halogen atoms, furyl which can be substituted by 1 to 3 C1-C4-alkyl groups, pyrrolyl which can have hydrogen, C1-C6-alkyl, phenyl-C1-C3-alkyl or phenyl on the nitrogen and can be substituted on the carbon atoms by 1 to 3 C1-C4-alkyl groups, it also being possible or the thienyl, furyl or pyrrolyl to be benzo-fused, R4 is hydrogen, C1-C4-alkyl or -CH2-R3 where R3 has the abovementioned meaning, R5 is C1-C6-alkyl which can be substituted by hydroxyl or C1-C3-alkoxy or is hydroxyl, C1-C6-alkoxy, phenoxy,phenyl-C1-C3-alkoxy,C1 C6-alkylthio,phenyl-thio,phenyl-C1-C3-alkylthio, amino,C1-C4-alkylamino, di-(C1-C4-alkyl)amino, phenylamino, N-phenyl-N-(C1-C4-alkyl)amino, pherlyl-C1-C4-alkylamino, N-phenyl-C1-C4-alkyl-N-(C1-C4-alkyl) amino, C1-C4-alkanoylamino, benzoylamino, phenyl-C1-C3-alkanoylamino, C1 C6-alkanoyl, hydroxycarbonyl, C1-C6-alkoxycarbonyl, aminocarbonyl, C1-C6-alkylaminocarbonyl, di- ( C1-C6-alkyl)aminocarbonyl, trifluoromethyl or halogen, and R6 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy or halogen and tna physiologically tolerated salts thereof.
2. A compound as claimed in claim 1, wherein R2 is O.Z. 0050/40846 hydrogen, and the physiologically tolerated salts thereof.
3. A compound as claimed in claim 2, wherein R1 is C1-C3-alKyl which can be substituted by hydroxyl or C1-C3-alkoxy, R3 is thienyl which can be substituted by 1 to 3 C1-C3-alkyl groups and/or 1 to 2 halogen atoms or is furyl which can be substituted by 1 to 3 C1-C3-alkyl groups, or is pyrrolyl which is substituted on the nitrogen by C1-C4-alkyl, benzyl or phenyl and can be substituted on the carbon atoms by 1 to 3 methyl groups, R4 is hydrogen or methyl, R5 is C1-C3-alkyl which can be substituted by hydroxyl or methoxy, or is hydroxyl or C1-C3-alkoxy, and R6 is hydrogen, and the physiologically tolerated salts thereof.
4. A compound as claimed in claim 1, wherein R2 is C1-C3-alkyl, and the physiologically tolerated salts thereof.
5. A process for the preparation of a compound of the formula I
(I), as claimed in claim 1, which comprises reacting a quino-line of the formula II
(II).
where X is a nucleofugic leaving group, and R1, R2, R5 and R6 have the meanings specified in claim 1, with an amine of the formula R3CH2NHR4 in the presence or absence of a solvent at from 50 to 250°C.
(I), as claimed in claim 1, which comprises reacting a quino-line of the formula II
(II).
where X is a nucleofugic leaving group, and R1, R2, R5 and R6 have the meanings specified in claim 1, with an amine of the formula R3CH2NHR4 in the presence or absence of a solvent at from 50 to 250°C.
6. The use of a compound of the formula I as claimed in any of claims 1 to 4 for the preparation of a drug.
7. The use of a compound of the formula I as claimed O.Z. 0050/40846 in claim 1 for the preparation of a drug for diseases where a reduction in gastric acid secretion has a beneficial effect on healing.
8. A drug for oral or rectal administration, which contains as active substance from 10 to 1000 mg of a compound of the formula I as claimed in claim 1 per single dose in addition to conventional pharma-ceutical auxiliaries.
9. A drug for intravenous administration, which contains as active substance from 0.01 to 1.0 mg/kg of body weight of a compound of the formula I as claimed in claim 1, in addition to conventional pharma-ceutical auxiliaries.
10. A drug for diseases in which a reduction in gastric acid secretion has a beneficial effect on healing, which contains as active substance an effective amount of a compound of the formula I as claimed in claim 1, in addition to conventional pharma-ceutical auxiliaries.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3917233A DE3917233A1 (en) | 1989-05-26 | 1989-05-26 | 8-SUBSTITUTED 4- (HETEROCYCLYLMETHYLAMINO) -INCHINOLINES, THEIR USE AND DRUGS DERIVED THEREFROM |
| DEP3917233.3 | 1989-05-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2016141A1 true CA2016141A1 (en) | 1990-11-26 |
Family
ID=6381484
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002016141A Abandoned CA2016141A1 (en) | 1989-05-26 | 1990-05-07 | 8-substituted 4-(heterocyclylmethylamino) quinolines, the use thereof and drugs prepared therefrom |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0399267A3 (en) |
| JP (1) | JPH0317078A (en) |
| CA (1) | CA2016141A1 (en) |
| DE (1) | DE3917233A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8536206B2 (en) | 2003-03-08 | 2013-09-17 | Takeda Gmbh | Process for the preparation of roflumilast |
| US8663694B2 (en) | 2005-03-16 | 2014-03-04 | Takeda Gmbh | Taste masked dosage form containing roflumilast |
| US9468598B2 (en) | 2002-02-20 | 2016-10-18 | Astrazeneca Ab | Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IS4164A (en) * | 1993-06-11 | 1994-12-12 | Ab Astra | Compounds that inhibit gastric acid flow |
| US5556863A (en) * | 1993-06-11 | 1996-09-17 | Astra Aktiebolag | Compound for gastric acid secretion inhibition |
| UA80393C2 (en) | 2000-12-07 | 2007-09-25 | Алтана Фарма Аг | Pharmaceutical preparation comprising an pde inhibitor dispersed on a matrix |
| AU2003252315A1 (en) * | 2002-08-09 | 2004-02-25 | Kyorin Pharmaceutical Co., Ltd. | 4-substituted-quinoline-8-carboxylic amide derivatives and pharmacologically acceptable addition salts thereof |
| EP1746092A1 (en) * | 2005-07-22 | 2007-01-24 | Exonhit Therapeutics SA | Compounds and methods for treatment of amyloid-B-peptide related disorders |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2652398A (en) * | 1949-11-17 | 1953-09-15 | Endo Products Inc | N-substituted-2-amino (methyl) quinolines |
| US4343804A (en) * | 1979-03-26 | 1982-08-10 | A. H. Robins Company, Inc. | 4-Amino-3-quinolinecarboxylic acids and esters-antisecretory anti-ulcer compounds |
| IL89028A0 (en) * | 1988-01-29 | 1989-08-15 | Lilly Co Eli | Quinoline,quinazoline and cinnoline derivatives |
-
1989
- 1989-05-26 DE DE3917233A patent/DE3917233A1/en not_active Withdrawn
-
1990
- 1990-05-07 CA CA002016141A patent/CA2016141A1/en not_active Abandoned
- 1990-05-07 EP EP19900108496 patent/EP0399267A3/en not_active Withdrawn
- 1990-05-28 JP JP2135537A patent/JPH0317078A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9468598B2 (en) | 2002-02-20 | 2016-10-18 | Astrazeneca Ab | Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient |
| US8536206B2 (en) | 2003-03-08 | 2013-09-17 | Takeda Gmbh | Process for the preparation of roflumilast |
| US8604064B2 (en) | 2003-03-10 | 2013-12-10 | Takeda Gmbh | Process for the preparation of roflumilast |
| US8618142B2 (en) | 2003-03-10 | 2013-12-31 | Takeda Gmbh | Process for the preparation of roflumilast |
| US8663694B2 (en) | 2005-03-16 | 2014-03-04 | Takeda Gmbh | Taste masked dosage form containing roflumilast |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3917233A1 (en) | 1990-11-29 |
| JPH0317078A (en) | 1991-01-25 |
| EP0399267A3 (en) | 1991-12-18 |
| EP0399267A2 (en) | 1990-11-28 |
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