IE43978B1 - 1,3-dialkyl-7-oxoalkylaxanthines - Google Patents
1,3-dialkyl-7-oxoalkylaxanthinesInfo
- Publication number
- IE43978B1 IE43978B1 IE183/76A IE18376A IE43978B1 IE 43978 B1 IE43978 B1 IE 43978B1 IE 183/76 A IE183/76 A IE 183/76A IE 18376 A IE18376 A IE 18376A IE 43978 B1 IE43978 B1 IE 43978B1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- compound
- group
- composition according
- reaction
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
Abstract
By reaction of a compound of the formula II or a salt thereof with an agent introducing a radical of the formula -A-CO-CH3 (III> in particular by reaction of a compound of the formula II with a ketone of the formula CH2=CR-CO-CH3 (V> wherein in the above formulae the radicals R1, A and R have the meanings given in Patent Claims 1 and 4, the corresponding 7-substituted xanthine derivatives are obtained. During the reaction, the carbonyl group of the radical of the formula III or of the compound of the formula V is optionally intermediately protected. The novel compounds are useful medicaments for the treatment of disorders of the cardiovascular system, since they improve the circulation of the skeletal musculature and/or decrease or prevent arrhythmias.
Description
The present invention relates to pharmaceutical compositions useful for treating disorders of the cardiovascular system containing xanthine derivatives, to certain novel xanthines and to their preparation.
West German Specifications Bos. 1,235,5°4, 1,255,320, 932,489 and 2,234,202 and Swiss Specification Bo. 325,292 disclose various xanthine derivatives. However none of the prepared compounds were shown to possess anti-arrythmic or blood flow improving properties.
It has now been found, that certain hitherto unprepared xanthine derivatives have the ability to improve the flow of blood through ' skeletal muscles and some of which possess anti-arrythmic activity.
Accordingly the present invention provides pharmaceutical compositions which comprise a pharmaceutically acceptable carrier and a compound of the formula (i):
«1 wherein A is methylene, 1,1 ethylene or 1,2 ethylehe; and R| is an alkyl, hydroxyalkyl or alkoxyalkyl group of 3 or 4 carbon atoms.
- 2 Suitable groups A include the -CEL^-, —Cf-XiCH-) - an - groups.
Particularly suitable groups A include those coucr or 2 carbon atoms.
One highly favourable group A is the -CH^- grout.
Another highly favourable group A is the -CH (CK-, group.
An especially favourable group A is the -CK?“CHn group.
Preferred groups include alkyl groups of 3 or carbon atoms such as the n-projyl and iso-butyl groups,· 1iso-butyl group being particularly suitable.
Particularly suitable compounds of the formula '1' for inclusion in the compounds of this invention include those described in the Examples herein, for example, 1-met
3-isobutyl-7-(2-oxopropyl)-xanthine.
The compositions of the present invention are norm adapted for administration to humans, for example in the form or oral or parenteral compositions.
- 3 43S78
Typical oral formulations will include tablets, capsules, sachets, granules, powders, suspensions, emulsions and solutions.
The formulations may include conventional diluents, binding agents, dispersing agents, surface-active agents, lubricating agents, coating materials, flavouring agents, colouring agents, solvents, thickening agents, suspending agents, sweeteners or any other pharmaceutically acceptable additives, for example, gelatin, lactose, starch, talc, magnesium stearate, hydrogenated oils, polyglycola and syrups. Where the formulations are e;g. tablets-or capsules, they represent‘pre-measured unit doses but ih the case of e.g. granules, powders and suspensions the formulations may be presented as pre-measured unit doses or in multi-dose containers from which the appropriate unit dose may be withdrawn.
Injectable compositions may be as solutions, suspensions or emulsions in a pharmaceutically acceptable liquid or as a solid form or concentrate which can be used to quickly prepare an injectable formulation.
The compositions of the invention may be prepared hy conventional methods of mixing, blending, tabletting and the like.
The preferred compositions of this invention are orallyadministrable compositions especially unit-dose compositions such as tablets and capsules.
- 4 Most suitably the compositions of this invention will ba administered once or more times a day so that the total daily dooo will bo in the region of 1 to 1000 mg for a 70 kg adult, for examplii from 20 to 5θθ “E· Unit dosage forms according to this invention will frequently contain from 5 to 50θ mg, for example from 25 to 250 mg.
The compounds of the formula (i) are novel and as such fora ea important part of this invention. Preferred novel compounds of the· formula (l) are those previously described as being particularly useful for inclusion in the compositions of this invention.
The present invention also provides process for the preparation of the compounds of the invention which process comprise either (a) the reaction of an alkali metal salt of a compound of the formula (l
*1 wherein is as defined in relation to formula (I) with a compound of the formula (ill):
X - A - CO - CHj (ΙΠ) wherein A is as defined in relation to formula (i) and X is a halogen atom such as a chlorine or bromine atom or, when A is a _ 5 _
43078
-CH., - CH2 - group, (b) the reaction of a compound of the formula (II) with a compound of the formula (IV):
ch2 = C.H - CO - ch3 (IV) in an alkaline medium at an elevated temperature.
The described reactions are preferably carried out at temperatures in the range from 40 to 80°C, optionally under elevated or reduced pressures, but usually at atmospheric pressure. The individual starting compounds may be used either in stoichiometric quantities or in excess. The alkali salts in reaction (b) may either be prepared beforehand or in the reaction itself.
Suitable solvents are water-miscible compounds, preferably lower alcohols containing 1 to 6 carbon atoms, such as methanol, propanol, isopropanol and various butanols, also acetone, pyridine, triethylamine, polyhydric alcohols such as ethylene glycol, and ethylene glycol monomethyl ether or ethylene glycol monoethyl ether.
The compounds of this invention do not normally have aLDjof less than lg/kg/po.
When tested on the urethane-chloralose anaesthetised cat model described in German Offenlegungsschrift No. 2,402,908 it was found that l-methyl-3-isobutyl-7-(2-oxopropyl)xanthine was effective at promoting the blood flow through skeletal muscles at doses from 5mg/kg to about 31mg/kg/id.
The invention is illustrated by the following specific Examples
Example 1
1-ife thyl-5-isobutyl-7- (2-oxopropyl) xanthine l-Bromopropan-2-one (13-7 ff) was dissolved, in absolute ethanol (70 ml) and the solution introduced into a 500 ml three necked flask. To this was slowly added at boiling temperature a solution of l-nethyl-3isobutylxanthine sodium salt (22 g) in absolute ethanol (200 ml)» The reaction was heated under reflux for 5 hours. After cooling the precipitated sodium bromide was removed by filtration and the resulting solution evaporated in a rotary evaporator. The resulting material was dissolved in chloroform and washed with 2N NaOH to extract any unreacted starting materials. The chloroform phase was dried with sodium sulphate, filtered and the solvents removed in vacuo to yield the material which on crystallisation in ethanol gave l~methyl~3-isobutyl-7-(2-oropropyl)xanthine (10 g), m.p. 147°C.
Analysis: Calculated: C: 56.10, H: 6.52, H: 20.13, 0: 17.25
Found: C: 56.00, Ξ: 6.30, Bs 19.71. 0: 18.00
C: 55-88, Hs 6.22, Ns 19.84, 0: 17-96
- 7 439*8
Example 2 l-Methyl-5-iBotu.tyl-7-(l-methyl-2-oxopropyl)xan.thine
The title compound. was prepared by the method described in
Example 1 in a yield of 62%. After recrystallisation from ether/ petrolether had a m.p. 104°C. The analysis figures were: Calculated: C: 57-52, H: 6.90, N: 19.16, 0: 16.42
Found: C: 57.33, H: 6.54, »: 19.17, 0: I6.97
C: 57.4Ο, H: 6.48, N: I9.I6, 0: 16.93
- 8 43S78
Example 3 l-Methyl-3-isobutyl-7-(3-oxobutyl)xanthine l-Methyl-3-isobutylxanthine (l6.6g), methylvinylketone (6.3 g), triethylamine (5-75 ml) and methanol (85 ml) were introduced into a 5 250 ml three necked flask and the mixture slowly warmed to 4θ to 45°C·
The reaction was maintained at this temperature for 10 hours at which time the reaction was substantially complete. The solvents were distilled off in vaouo and the residue dissolved in chloroform. The solution was washed twice with cold sodium carbonate solution to 10 extract any unreacted starting materials. The chloroform phase was dried and the solvents removed under vacuo. The remaining material was crystallised from ethyl acetate/ether t<* yield l-methyl-3-isobutyl7-(3-°xobutyl)xanthine (12 g), m.p. 111°C.
Analysis: Calculated: C: 57.52, Hi 6.90, Hi 19.16, 0: 16.42 15 found: C: 57.60, Hi 6.85, Hi I8.45, 0: 17.08
Claims (15)
1. A pharmaceutical composition which comprises a pharmaceut ically acceptaiiSe carrier and a compound of the formula (I):
CH,
A - CO - CH, (I) wherein A is methylene, 1,1 ethylene or 1,2 ethylene; and is an alkyl, hydroxyalkyl or alkoxyalkyl group of 3 or 4 carbon atoms.
2. A composition according to claim 1 wherein A is a -CH 2 -group.
3. A composition according to claim 1 wherein A is a -CH (CH 3 ) - group.
4. A composition according to claim 1 wherein A is a -CH 2 -CH 2 -group.
5. A composition according to any of claims 1-4 wherein R-^ is an alkyl group of 3 or 4 carbon atoms.
6. A composition according to any of claims 1-4 wherein R^ is an iso-butyl group.
10 43873
7.
8.
5 9.
10.
11.
10 12.
13.
14.
7.
8.
5 9.
10.
11.
10 12.
13.
14.
A composition according to claim 1 wherein the compound of formula (i) is l-methyl-3“lsobutyl-V-(2-oxopropyl) xanthine
A composition acoording to any of claims 1-7 adapted for oral administration to humans.
A unit dose composition according to claim 8 which contains 25 to 25Ο mg of a compound of the formula (i).
A compound of the formula (I) as defined in claim 1.
A compound according to claim 10 wherein is an alkyl group of J or 4 carbon atoms.
The compound according to claim 10 wherein Εχ is an isobutyl group.
1-Methyl-3-isobutyl-7-(2-oxopropyl)xanthine,
A process for the preparation of the compounds claimed in claim 11 which prooess comprises either:
(a) the reaction of an alkali metal salt of a compound of the formula (il):
CH.
Ν'
R.
wherein R^ is as defined in Claim 1 with a
- 11 4S978 compound of the formula (III):
X - A - CO - CH 3 (III) wherein A is as defined in relation to formula halogen atom or, when A is a -CH 2 -CH 2 ~ .group, (b) the reaction of a compound of the formula compound of the formula (IV):
(I) and X is a (II) with a ch 2 = CH - CO - CH 3 (IV) in an alkaline medium at an elevated temperature.
15. A process according to claim 15 wherein X is a chlorine or bromine atom.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19752507555 DE2507555A1 (en) | 1975-02-21 | 1975-02-21 | 7- (OXOALKYL) -1,3-DIALKYLXANTHINE, THE METHOD OF MANUFACTURING THEREOF AND MEDICINAL PRODUCTS CONTAINING THIS COMPOUND |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE43978L IE43978L (en) | 1976-08-21 |
| IE43978B1 true IE43978B1 (en) | 1981-07-15 |
Family
ID=5939491
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE183/76A IE43978B1 (en) | 1975-02-21 | 1976-01-30 | 1,3-dialkyl-7-oxoalkylaxanthines |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS51110598A (en) |
| AR (2) | AR208755A1 (en) |
| AT (1) | AT342617B (en) |
| AU (1) | AU506542B2 (en) |
| BE (1) | BE838466A (en) |
| CH (1) | CH621789A5 (en) |
| DE (1) | DE2507555A1 (en) |
| DK (1) | DK72676A (en) |
| ES (1) | ES445301A1 (en) |
| FI (1) | FI760418A (en) |
| FR (1) | FR2301258A1 (en) |
| GB (1) | GB1496316A (en) |
| HU (1) | HU174656B (en) |
| IE (1) | IE43978B1 (en) |
| NL (1) | NL7601622A (en) |
| SE (1) | SE7601455L (en) |
| YU (1) | YU37276A (en) |
| ZA (1) | ZA76568B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0570831A2 (en) * | 1992-05-20 | 1993-11-24 | Hoechst Aktiengesellschaft | Use of Xanthinderivatives for treatment of cerebral nerve dammages after disruption of the blood circulation |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2761863A (en) * | 1956-09-04 | Lower-alkyl | ||
| DE932489C (en) * | 1953-09-11 | 1955-09-01 | Hoffmann La Roche | Process for the production of new xanthine bases and their salts |
| CH325292A (en) * | 1953-10-21 | 1957-10-31 | Geigy Ag J R | Process for the preparation of 7-oxyalkyl-xanthine derivatives |
| DE1233405B (en) * | 1964-09-05 | 1967-02-02 | Albert Ag Chem Werke | Process for the preparation of 7- (oxoalkyl) -1, 3-dimethylxanthines |
| US3422107A (en) * | 1964-09-05 | 1969-01-14 | Albert Ag Chem Werke | Certain oxoalkyldimethylxanthines and a process for the preparation thereof |
| DE2234202A1 (en) * | 1972-07-12 | 1974-01-24 | Albert Ag Chem Werke | Prep. of oxoalkylxanthine - this has e.g. broncholytic and fibrinolytic activity |
| DE2330742C2 (en) * | 1973-06-16 | 1982-07-29 | Hoechst Ag, 6000 Frankfurt | 1- (Oxoalkyl) -3-methyl-7-alkylxanthines, process for their preparation and pharmaceuticals containing them |
| CH608236A5 (en) * | 1974-01-22 | 1978-12-29 | Wuelfing J A Fa |
-
1975
- 1975-02-21 DE DE19752507555 patent/DE2507555A1/en not_active Withdrawn
-
1976
- 1976-01-30 IE IE183/76A patent/IE43978B1/en unknown
- 1976-02-02 ZA ZA568A patent/ZA76568B/en unknown
- 1976-02-09 FR FR7603413A patent/FR2301258A1/en active Granted
- 1976-02-10 SE SE7601455A patent/SE7601455L/en unknown
- 1976-02-10 AT AT89776A patent/AT342617B/en not_active IP Right Cessation
- 1976-02-11 BE BE164248A patent/BE838466A/en not_active IP Right Cessation
- 1976-02-11 GB GB5326/76A patent/GB1496316A/en not_active Expired
- 1976-02-12 HU HU76WU22A patent/HU174656B/en unknown
- 1976-02-13 AR AR262265A patent/AR208755A1/en active
- 1976-02-17 YU YU00372/76A patent/YU37276A/en unknown
- 1976-02-18 ES ES445301A patent/ES445301A1/en not_active Expired
- 1976-02-18 NL NL7601622A patent/NL7601622A/en not_active Application Discontinuation
- 1976-02-19 FI FI760418A patent/FI760418A/fi not_active Application Discontinuation
- 1976-02-20 JP JP51017837A patent/JPS51110598A/ja active Pending
- 1976-02-20 DK DK72676*#A patent/DK72676A/en unknown
- 1976-02-20 CH CH210676A patent/CH621789A5/en not_active IP Right Cessation
- 1976-02-23 AU AU11338/76A patent/AU506542B2/en not_active Expired
- 1976-09-29 AR AR264907A patent/AR210168A1/en active
Also Published As
| Publication number | Publication date |
|---|---|
| BE838466A (en) | 1976-08-11 |
| ZA76568B (en) | 1977-01-26 |
| AR210168A1 (en) | 1977-06-30 |
| NL7601622A (en) | 1976-08-24 |
| IE43978L (en) | 1976-08-21 |
| GB1496316A (en) | 1977-12-30 |
| CH621789A5 (en) | 1981-02-27 |
| FR2301258A1 (en) | 1976-09-17 |
| JPS51110598A (en) | 1976-09-30 |
| ATA89776A (en) | 1977-08-15 |
| DE2507555A1 (en) | 1976-09-02 |
| FI760418A (en) | 1976-08-22 |
| DK72676A (en) | 1976-08-22 |
| HU174656B (en) | 1980-02-28 |
| FR2301258B1 (en) | 1978-11-17 |
| AT342617B (en) | 1978-04-10 |
| AU1133876A (en) | 1977-09-01 |
| AU506542B2 (en) | 1980-01-10 |
| ES445301A1 (en) | 1977-06-01 |
| YU37276A (en) | 1982-08-31 |
| AR208755A1 (en) | 1977-02-28 |
| SE7601455L (en) | 1976-08-22 |
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