GB2151619A - Imidazoquinoline and analogues derivatives of - Google Patents

Imidazoquinoline and analogues derivatives of Download PDF

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GB2151619A
GB2151619A GB08431656A GB8431656A GB2151619A GB 2151619 A GB2151619 A GB 2151619A GB 08431656 A GB08431656 A GB 08431656A GB 8431656 A GB8431656 A GB 8431656A GB 2151619 A GB2151619 A GB 2151619A
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compound
formula
acid addition
imidazo
addition salt
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Roger Crossley
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John Wyeth and Brother Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Description

1 GB 2 15161 9A 1
SPECIFICATION
Imidazoquinoline derivatives The invention relates to novel heterocyclic compounds useful for the treatment of ulcers or hypersecretion in mammals and pharmaceutical compositions containing the novel compounds.
In our GB Patent 2039218 B we have described inter alia phenylalkylthiopyridines which are useful in the treatment of ulcers or hypersecretion in mammals. We have now found that by modifying the molecule to replace the pyridine group by an imidazoquinoline group novel compounds are obtained which have one or more of the following activities, anti-ulcer, antisecretory or H+ /K+ ATPase inhibitory activity.
The invention provides a compound of formula 1 Rf 1 B) 20R2 N N S-A-Ar (1) wherein A is a Cl-C, straight or branched alkylene chain which may be saturated or 25 unsaturated, B is a C2-Cl straight or branched alkylene chain which may be saturated or unsaturated, Ar is a phenyl or naphthyl group which may be substituted or unsubstituted, R' and R 2 are the same or different and are hydrogen, alkyl, alkoxy, aikoxyalkyi, hydroxyalkyl, hydroxy, halogen, nitro, carboxy, carboxylic ester, carbamoyl, carbamoyloxy, cyano, acyl, acylamino eg. loweralkanoylamino such as acetamino or trifl uo ro methyl, and acid addition salts 30 thereof.
Examples of A are CH, CH(CH3), CH(CH3)CH2, CH,Cl-12, CH2CH2CH21 CH CH, and CH = CHCH, CH2 is preerred.
B may be for example CH,Cl-l.,, GH(CH,)C1-12, CH2CH2CH2, CH = CH, CH CHCH, or (CH2)l The group Ar may be mono or polysubstituted but is preferably mono or disubstituted by any 35 of the following; halogen, alkoxy, aralkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, trif 1 uoro methyl, alkyl, aryl or aralkyl eg of 7 to 12 carbon atoms or disubstituted by a loweralkylene dioxy radical of 1 to 6 carbon atoms.
In this specification an alkyl group is preferably lower alkyl i.e. of 1 to 6 carbon atoms eg methyl, ethyl, n-propyl, isopropyl, n-butyi, s-butyi, t-butyi, n-pentyl or n-hexyi. An alkoxy group 40 is preferably lower alkoxy in which the alkyl portion is as defined for a lower alkyl group.
Whenever the term lower alkyl or lower alkoxy is used as part of another group eg arylloweralkyl, the lower alkyl or lower alkoxy portion has 1 to 6 carbon atoms unless otherwise stated. An aralkyl radical is preferably aryllower alkyl eg benzyi, phenethyl or phenpropyl.
The acid addition salts of compounds of formula 1 may be of any pharmaceutically acceptable 45 organic or inorganic acid eg hydrochloric, hydrobromic, hydroiodic, phosphoric, sulphuric, nitric, citric, acetic, formic, fumaric, maleic, tartaric, embonic, malonic, alkylsulphonic, eg methanesul phonic, aryisulphonic eg p-toluene sulphonic acids.
The invention includes methods of preparing the compounds of formula 1. The preferred method comprises reacting a compound of formula 11, Ar-A-Hal (11) wherein Ar and A are as defined above and Hal is a halogen atom especially chlorine, bromine or iodine, with a thiol of formula Ill, or an alkali metal salt thereof, 2 GB 2 151 619A 2 R1 2 CN) R N=j-SH B 2;:
N HD wherein B, R' and R' are as defined above.
Alternatively a compound of formula Ar-A-SH (lia), an alkali metal salt thereof may be reacted with a halide of formula Ilia wherein R', R 2, B and Hal are as defined above.
The starting compounds of formula 11 and lia are known compounds or may be prepared by methods known for analogous compounds. The starting compounds of formula Ill or Ilia are known compounds described in for example J.Org.Chem. 1959, 25, 1138 or 1963, 28, 2581, J. Heterocyclic Chem. 1982, 19, 837 or may be prepared by methods known for analogous compounds. In the above mentioned reaction the compounds of formula 1 may be isolated in 20 free base form or as acid addition salts.
The compounds of formula 1 possess anti-ulcer and/or anti-secretory activity as measured by standard test procedures and accordingly are useful for the treatment of ulcers or hypersecretion in mammals.
Anti-ulcer activity was determined by the stress-induced erosion test of Senay and Levine, 25 Proc.Soc.Exp. Biol. Med., 124, 1221-3 (1967).
Anti-secretory activity was determined by the test of H. Shay, D_ Sun and H. Gruenstein, Gastroenterology, 1954, 26, 903-13 as exemplified by Beattie et al, J.Med. Chem. 20, 714 (1977).
Compunds of formula 1 were also tested for anti-secretory activity by their ability to inhibit the 30 highly specific proton transporting enzyme H /K+ ATPase.
Potential H -,- /K+ ATPase inhibitors are evaluated by a technique involving the measurement of aminopyrine accumulation in rabbit isolated gastric glands. Aminopyrine, which is a weak base, accumulates in acid-secreting cells; therefore, uptake of aminopyrine is increased by secretagogues and an inhibitor of acid secretion will reduce the response to one or more secretagogues depending upon its site of action. Compounds which reduce the response to dibutyryl cyclic adenosine monophosphate (DBcAMP) stimulation are assumed to have an intracellular site of action, and those which reduce the response to both DBcAMP and high potassium ion concentration (K+) are thought to have an intracellular site of action at the secretory surface of the parietal cell, involving the highly specific proton-transporting enzyme, 40 H+ /K+ ATPase. The following test procedure is used:
Rabbit gastric glands are isolated from gastric mucosa from the corpus region of the stomach by a method based on one described by Berglindh T_ Obrink KJ_ Acta Physiol.Scand. 96, 150-159 (1976). Measurement of aminopyrine uptake is carried out using a modification of the method described by Berglindh T_ Hellander H.F., Obrink K.J. (ibid, 97, 401-414,1976). 45 Compounds are tested at a concentration of 10-4M, initially, and in some cases at lower concentrations, for their ability to inhibit 1 4 C-aminopyrine uptake in gastric glands, stimulated by DBcAMP and high K+ respectively. Results are expressed as the % inhibition of the maximum response to the secretagogue induced by the test compound. An inhibitor of H +/K' ATPase would be expected to reduce the response to both secretagogues.
The pharmaceutical formulations include solids and liquids. Any suitable carrier known in the art can be used to prepare the pharmaceutical composition. In such a composition, the carrier is generally a solid or liquid, or a mixture of a solid and a liquid.
Solid form compositions include powders, granules, tablets, capsules (eg hard and soft gelatin capsules). A solid carrier can be, for example, one or more substances which may also act as 55 flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aids, binders, effervescent excipients or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size 60 desired. The powders and tablets preferably contain up to 99%, eg from 10 to 80%, preferably to 75% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.
3 GB 2 151 619A 3 The term -composition- is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.
Liquid form compositions include, for example, suspensions, emulsions, syrups and elixirs.
The active ingredient, for example, can be suspended ina pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubiliz ers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers or osmo- regulators. Suitable examples 10 of liquid carriers for oral administration include water (particularly containing additives as above eg cellulose derivatives, preferably sodium carboxymethyl cellulose solution) alcohols (including monohydric alcohois and polyhydric alcohols eg glycerol and glycols) and their derivatives, and oils (eg fractionated coconut oil and arachis oil).
Preferably the pharmaceutical composition is in unit dosage form, eg as tablets or capsules. In 15 such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. The quantity of the active ingredient in a unit dose of composition may be varied or adjusted from 10 mg or less to 500 20 mg or more, according to the particular need.
The anti-ulcer compositions of the invention will be administered orally on either liquid or solid composition form. These compositions may include one or more antacid ingredients, eg aluminium hydroxide, magnesium hydroxide or bismuth carbonate, aluminium glycinate, cal cium carbonate, magnesium trisilicate, sodium bicarbonate or the alumina gel described in British Specification No. 1,284,394.
In another aspect the invention provides as pharmaceutical, eg. an antiulcer agent a compound of formula 1 or a pharmaceutically acceptable salt thereof as defined above.
The compounds of the invention may be used in treating ulcers or hypersecretion in a mammal in need of such treatment by administering to said mammal an effective amount of a 30 compound of formula 1 or a pharmaceutically acceptable salt thereof. The amount of compound used will depend on the activity of the compound and the needs of the mammal being treated.
Doses may range from 0.1 to 30 mg/kg.
The following examples illustrate the invention:
Example 1 2-Benzyithio-5,6-dihydro-[4H]-imidazo [4,5, 1-ijlquinolin A solution of 5,6-dihydro-2-mereapto-[4H]-imidazo[4,5,1,ijlquinotine (3. 59) in ethanol (50mi) at reflux was treated with benzyl chloride (3.5mi) and heated at reflux for 3 hours. The solution was cooled and induced to crystallise. The crystals which formed were filtered, washed with ether and dried to give the title compound as the hydrochloride (5.6g) mp 1 68-WC (Found: C, 64.2; H, 5A N, 8.7 C,^^SMC1 requires C, 64.4; H, 5.4; N, 8.3%.
Example 2 45 2-(3-Chlorobenzylthio)-5,6,-dihydro-[4H]-imidazo[4,5, 1, ij]quinoline A solution of 5,6-dihydro-2-mercapto-[4H]-imidazo[4,5, 1 Aj]quinoline (3. 59) in ethanol (50mi) at reflux was treated with m-chlorobenzyl chloride (3.5mi) and was heated at reflux for 3 hours. Crystals which formed on cooling were removed by filtration, washed with Et20 and dried to give the title compound as the hydrochloride (5.39) mp 1 72-WC. (Found: C, 58. 1; N, 4.6; N, 8.0 C,Hi,CiN,S.HO requires C, 57.8; H, 4.65; H, 8.1%).
Example 3
5,6-Dihydro-2-(4-fluorophenyimethytthio)-[4H]-imidazo-[4,5, 1,ijlquinoline A suspension of 5,6-dihydro-2-rnereapto-[4H]-imidazo-[4,5, 1 AJ1quinoline in refluxing ethanol (25m[) was treated with 4-fluorobenzyl chloride (1.45g) in ethanol (5mi). The solid rapidly went 55 into solution and the mixture was heated at reflux for 1 hour and cooled. Et,0 (1 50mi) was added and the product allowed to crystallise. The crystals were removed by filtration, washed with Et,0 and dried to give the title compound as the hydrochloride, hemihydrate (2.5g, 73%) mp 11 8-20'C. (Found: C, 59.5; H, 5.2; N, 8.3 Cl,H,,FN,S.HCI.IH,0 requires C, 59.4; H, 5.0; N, 8.15%).
Example 4
2-(2-Chlorophenyimethylthio)-5,6-dihydro-[4H]-imidazo[4,5, 1-ijlquinoline A suspension of 5,6-dihydro-2-methyl-[4H]-imidazo-[4,5,1-i,j]quinoline (1. 9g) in refluxing ethanol (25mi) was treated with o-chlorobenzyl chloride (1.61 g) in ethanol. The suspension 65 4 GB 2 151 619A 4 rapidly went into solution and the mixture was heated at reflux for 2 hours, filtered, cooled and diluted with ether (1 50mi). The crystals which formed were removed by filtration, washed with ether and dried to give the title compound as the hydrochloride (2.69, 74%) mp 1 57-WC (Found: C, 58.4; H, 4.7; N, 8.0 C,H,CiN,S.I-IC1 requires C, 58.1; H, 4.6; N, 8.0%).
Example 5 2-(4-Chlorophenylmethytthio)-5.6-dihydro-[4H]-imidazo-[4,5, 1ij]quinoline A suspension of 5,6-dihydro-2-mercapto-[4H]-imidazo-[4,5, 1 Aj]quinoline (1.9g) in refluxing ethanol (25mi) was treated with 4chlorobenzyl chloride (1.6g) in ethanol (5mi). The suspended solid rapidly went into solution and this was heated at reflux for 1 hour, filtered, cooled and 10 diluted with ether (75mi). The crystals which formed were removed by filtration, washed with ether and dried to give the title compound as the hydrochloride hemihydrate (1.8g, 50%) mp 107-WC (Found: C, 56.8; H, 5.0; N, 7.7. C,^,CiN,S HO -11-1,0 requires C, 56.7; H, 4.8; N, 7.8%).
Example 6 o,6-Dihydro-2-(2-fluorophenyimethylthio)-[4H]-imidazo-[4,5, lijlquinoline A suspension of 5,6-dihydro-2-rnercapto-[4H]-imidazo-[4,5,1-i,j]quinoline (1.9g) in refluxing ethanol (25mi) was treated with 2-fluorobenzyl chloride (1.45g) in ethanol (5m]) and the mixture was heated at reflux for 1 hour. The resulting solution was filtered and ether (75mi) was added. 20 The crystals which formed on cooling were removed by filtration, washed with ether and dried to give the title compound as the hydrochloride (2.2g, 65%) mp 167-9'C (Found: C, 60.9; H, 4.9; N, 8.35. C,^JN,S.HU requires C, 61.0; H, 4.5; N, 8.4%).
-5 Example 7
2-Benzylthio-[4H]-imidazo[4,5, 1-ij]quinoline 2-Mercapto-[4H]-imidazo[4,5,1-ij]quinoline (1.889) in ethanol (20mi) at reflux was treated with benzylchloride (1.2mi) and the mixture was heated at reflux for 31 hours and cooled. The resulting mixture was diluted with ether (20mi) and the cream coloured solid washed with ether and dried to give the title compound as the hydrochloride (2.79, 86%) mp 1 95-8'C (Found: C, 30 64.6; H, 4.9; N, 9.2. C,^,N2S.HO requires C, 64.85; H, 4.8; N, 8.9%).
Example 8
Following the general procedure of Example 1 the following products are prepared:- GB 2 151 619A 5 Starting.Material Final Product R R + ArAHal 2 nN R 1 R N) N L SH N LS-A-Ar 10 IIIb IIb Ib 1 1 15 8a) IJIb R = 8-Me PhCH2C1 R 8-Me R 2= H R 2 H A CH 2 Ar Ph 20 8b) Mb R 1= 8-MP-0 PhCH 2 cl R 1 = 8MeO R 2= H R 2 H A CH 2 2 Ar Ph 8c) Mb R 1= 9-Me PhCH2C1 R 1 9Me R 2= H R 2 H 30 A CH 2 Ar = Ph 8d) Mb R 1= 7-MeO PhCH 2 cl R 1 = 7-Meo 35 R 2= H R 2 H A CH 2 Ar Ph 40 8e) Mb R 1= 8-cl PhCH 2 cl R 1 = 8Cl R 2= H R 2 H A CH 2 45 Ar Ph 8f) Mb PhCH 2 cl 50 N J N LSH N LSCH 2 Ph 55 Sg) Mb PhCH 2 cl 60 N LSH N LSCH 2 Ph 6 GB 2 151 619A 6 Example 9
The starting material PhCH2C1 in Examples 8a to 8g is replaced by 4chlorobenzylchloride to obtain the corresponding final products.
Example 10
The starting material PhCH,Cl in Examples 8a to 89 is replaced by PhCH(CHjC1 to obtain the corresponding final products.
Example 11
The starting material PhCH2C1 in Examples 8a to 89 is replaced by 'I naphthyimethylchloride 10 to obtain the corresponding final products.
Pharmacological Test Results 15 2 0 CUnd Stress Induced Anti-Secretory % Inhibition to 20 Ex " le Erosion (Shay et al) Stimulation by No. (Senay & Levine) DBcAMP K + Dose % Inhib- at 10-4 at 10-4 25 mg/kg ition 1 100 83 30 N/A 70 111 30 2 100 N/A 30 N/A 69 54 3 100 62% 30 N/A 6.7 76 4 100 55% 30 N/A 32.9 83.5 35 100 N/A 30 N/A 53 109 6 100 N/A 30 N/A 40.6 93 7 100 54 30 N/A 40 63 40 N/A = No significant Activity.

Claims (20)

1. A compound of formula 1 2 N) R -S-A-Ar wherein A is a C,-C4 straight or branched alkylene chain which may be saturated or unsaturated, B is a C2-C4 straight or branched alkylene chain which may be saturated or unsaturated, 65 Ar is a phenyl or naphthyl group which may be substituted or unsubstituted, 66 7 GB 2 151 61 9A 7 R' and R 2 are the same or different and are hydrogen, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, hydroxy, halogen, nitro, carboxy, carboxylic ester, carbamoy], carbamoyloxy, cyano, acyi, acylamino or trifluoromethyl, or an acid addition salt thereof.
2. A compound as claimed in Claim 1, wherein Ar is phenyl or halophenyl.
3. A compound as claimed in Claim 1, or Claim 2, wherein B is (CH2)1.
4. A compound as claimed in any one of claims 1-3, wherein R' and R 2 are hydrogen.
5. 2-Benzyithio-5,6,-dihydro-[4H]-imidazo[4,5, 1 Aflquinoline, or an acid addition salt thereof.
6. 2-(3-Chlorobenzyithio)-5,6,-dihydro-[4H]-imidazo[4,5, 1 Aj]quinoline, or an acid addition salt thereof.
7. 5,6-Dihydro-2-(4-fluorophenyimethyithio)-[4H]-imidazo-[4,5,1ij]quinoline, or an acid ad- 10 dition salt thereof.
8. 2-(2-Chlorophenyimethyithio)-5,6-dihydro-[4H]-imidazo[4,5,1ijlquinoline, or an acid addi tion salt thereof.
9. 2-(4-Chlorophenyimethyithio)-5,6-dihydro-[4H]-imidazo-[4,5, 1 iflquinoline, or an acid ad- dition salt thereof.
10. 5,6-Dihydro-2-(2-fluorophenyimethyithio)-[4H]-imidazo-[4,5, 1 iflquinoline, or an acid addition salt thereof.
11. 2-Benzyithio-[4H]-imidazo[4,5, 1 Aj]quinoline, or an acid addition salt thereof.
12. A compound as claimed in any one of the preceding claims, or an acid addition salt thereof for use as a pharmaceutical.
13. A compound as claimed in any one of claims 1 - 11, or an acid addition salt thereof for use as an anti-ulcer agent or for the treatment of hypersecretion.
14. A pharmaceutical composition comprising a compound of formula 1 as claimed in any one of claims 1 - 11, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutical carrier.
15. A pharmaceutical composition as claimed in claim 14, in unit dosage form.
16. A method of preparing a compound of formula 1 as claimed in any one of claims 1 - 11, or an acid addition salt thereof, which method comprises reacting a compound of formula 11 Ar-A-Hal 11 wherein Ar and A are as defined in claim 1, and Hal is a halogen atom, with a thiol of formula Ill, or an alkali metal salt thereof, N -SH wherein B, R' and R' are as defined in claim 1.
17. A method of preparing a compound of formula 1, as claimed in any one of claims 1 -11, or an acid addition salt thereof, which method comprises reacting a compound of formula lia Ar-A-SH lla or an alkali metal salt thereof wherein Ar and A are as defined in claim 1, with a halide of formula Ilia B N) (111C1) R Ni 1 - ni- wherein B, R' and R' are as defined in claim 1, and Hal is a halogen atom.
18. A method as claimed in claim 16 or claim 17 wherein Ar-A in the compound of 65 8 GB 2 151 619A 8 formula 11 or lla is a benzyl group.
19. A method as claimed in claim 16, substantially as hereinbefore described in any one of Examples 1 to 7.
20. A compound of formula 1, whenever prepared by a method as claimed in any one of claims 16 to 19.
Printed in the United Kingdom for Her Majesty's Stationery Office. Dd 8818935. 1985. 4235 Published at The Patent Office. 25 Southampton Buildings, London. WC2A I AY. from which copies may be obtained
GB08431656A 1983-12-16 1984-12-14 Imidazoquinoline and analogues derivatives of Expired GB2151619B (en)

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JP (1) JPS60152486A (en)
KR (1) KR910005852B1 (en)
AR (1) AR240938A1 (en)
AT (1) ATE38037T1 (en)
AU (1) AU578055B2 (en)
CA (1) CA1229598A (en)
DE (1) DE3474664D1 (en)
DK (1) DK168215B1 (en)
ES (2) ES8604958A1 (en)
FI (1) FI78092C (en)
GB (2) GB8333581D0 (en)
GR (1) GR82452B (en)
IE (1) IE57647B1 (en)
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US4761411A (en) * 1983-05-18 1988-08-02 Hoechst-Roussel Pharmaceuticals Inc. Dihydrobenzopyrrolobenzodiazepines useful for treating pyschoses
IE57646B1 (en) * 1983-12-16 1993-02-10 Wyeth John & Brother Ltd Derivatives of imidazoquinolines and analogues thereof
IL93136A (en) * 1989-02-23 1995-01-24 Janssen Pharmaceutica Nv Tetrahydroimidazo (1,4) benzodiazepin-2-thione derivatives, their preparation and pharmaceutical compositions containing them
JP2899757B2 (en) * 1989-06-26 1999-06-02 持田製薬株式会社 Dihydroimidazoquinolinone oxime sulfonic acid derivative

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US3200123A (en) * 1962-01-26 1965-08-10 Richardson Merreil Inc Imidazoquinolines
GB2039218B (en) * 1978-11-30 1983-07-27 Wyeth John & Brother Ltd Pharmaceutical compositions
GB2069492B (en) * 1980-02-20 1984-02-29 Wyeth John & Brother Ltd Sulphur compounds
US4409226A (en) * 1981-10-05 1983-10-11 Schering Corporation Imidazo[1,5-a]pyridines
US4478834A (en) * 1983-02-11 1984-10-23 Usv Pharmaceutical Corporation Dihydropyridines and their use in the treatment of asthma
IE57646B1 (en) * 1983-12-16 1993-02-10 Wyeth John & Brother Ltd Derivatives of imidazoquinolines and analogues thereof

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DK168215B1 (en) 1994-02-28
AR240938A1 (en) 1991-03-27
ES549071A0 (en) 1986-09-01
US4609655A (en) 1986-09-02
KR910005852B1 (en) 1991-08-05
AU578055B2 (en) 1988-10-13
JPH0449554B2 (en) 1992-08-11
DK602184D0 (en) 1984-12-14
EP0146369A2 (en) 1985-06-26
CA1229598A (en) 1987-11-24
IE843119L (en) 1985-06-16
FI844932A0 (en) 1984-12-13
FI78092C (en) 1989-06-12
GB8333581D0 (en) 1984-01-25
GB2151619B (en) 1987-01-21
GB8431656D0 (en) 1985-01-30
ES8609322A1 (en) 1986-09-01
AR240938A2 (en) 1991-03-27
AU3669484A (en) 1985-06-20
ES8604958A1 (en) 1986-03-01
DE3474664D1 (en) 1988-11-24
ATE38037T1 (en) 1988-11-15
JPS60152486A (en) 1985-08-10
EP0146369B1 (en) 1988-10-19
ZA849484B (en) 1986-07-30
ES538592A0 (en) 1986-03-01
EP0146369A3 (en) 1986-04-16
DK602184A (en) 1985-06-17
KR850004760A (en) 1985-07-27
PT79689A (en) 1985-01-01
FI78092B (en) 1989-02-28
FI844932L (en) 1985-06-17
GR82452B (en) 1985-03-19
IE57647B1 (en) 1993-02-10

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