AU604767B2 - 1-hydroxyalkylxanthines, processes for their preparation and medicaments containing them - Google Patents
1-hydroxyalkylxanthines, processes for their preparation and medicaments containing them Download PDFInfo
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- AU604767B2 AU604767B2 AU79980/87A AU7998087A AU604767B2 AU 604767 B2 AU604767 B2 AU 604767B2 AU 79980/87 A AU79980/87 A AU 79980/87A AU 7998087 A AU7998087 A AU 7998087A AU 604767 B2 AU604767 B2 AU 604767B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
- C07D473/08—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 with methyl radicals in positions 1 and 3, e.g. theophylline
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- C—CHEMISTRY; METALLURGY
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- 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
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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Abstract
Compound of formula: <IMAGE> or a physiologically acceptable salt of this compound, in which formula R1 is a C2-C5 omega -hydroxy-n-alkyl or C3-C5 ( omega -1)-hydroxy-n-alkyl, R3 is a C1-C4 alkyl group, R8 is H, methyl or ethyl, and the sum of the carbon atoms in R1 and R3 is between 4 and 9. Pharmaceutical composition containing this compound.
Description
604 76 COMMONWEALTH OF AUSTRALIA FORM PATENTS ACT 1952 COMPLETE S P E C IF I CAT ION FOR OFFICE USE: Class Int.Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art: This document contains the amendments made t.nder Section 49 and is corrcct for prioting.
I
Name of Applicant: Address of Applicant: Actual Inventor: SOCIETE DES PRODUITS NESTLE S.A.
Vevey, Switzerland Rene Fumeaux and Georges Philippossian S Address for Service: SHELSTON WATERS, 55 Clarence Street, Sydney Complete Specification for the Invention entitled: "I1-IYDROXYALKYLXANTHINES, PROCESSES FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM" The following statement is a full description of th invention, including the best method of performing it known to me/us:- 1A
ABSTRACT
1-Hydroxyalkyl xanthines, processes for their preparation and medicaments containing them A compound corresponding to the following formula in which R1 is a C 2
-C
5 w-hydroxy-n-alkyl group or a C3-C (uj-l)-hydroxy-n-alkyl group, R 3 is a C 1
-C
4 alkyl group,
R
8 is H, methyl or ethyl and the sum of the carbon atoms in
R
1 and R 3 is between 4 and 9, or a physiologically acceptable salt of this compound.
A pharmaceutical composition containing this compound.
1 1B 1-Hydroxyalkylxanthines, processes for their preparation and medicaments containing them 1 This invention relates to a new. class of xanthines, namely 1-hydroxyalkyl xanthines, to processes for their preparation and to a medicament containing them.
EP39780 relates to 1,3- or 1,3,8-substituted xanthines showing sedative and anxiolytic properties. These compounds were developed with a view to enhancing or making more specific certain therapeutically useful physiological effects of natural xanthines, such as caffeine or theophylline. Despite their undeniable neuroleptic and anxiolytic character, the compounds according to the abovementioned patent show- side effects, particularly on the cardiovascular function. By contrast, the cardiostimulant activity of these compounds, taken on its own, opened up a new channel of investigation in that direction.
The present invention relates to a new class of xanthines, namely 1-hydroxyalkyl xanthines, which show in particular cardiovascular activity. The compounds according to the invention are xanthines corresponding to the following general formula 0
R
1
N
RII) R 8
(I)
N
R3 in which
R
1 is a C 2
-C
5 W, 'ydroxy-n-alkyl group or a C3-C 5 15 2- 1 hydroxy-n--alkyl group, R 3 is a C C4 al kyl group, R8is H, methyl or ethyl and the sum of the carbr-, atoms in Rand R 3is between 4 and 9, or physiologically acceptable salts thereof.
More precisely, the following compounds are more specifically claimed: 1- (2-Hydroxyethyl)-3-propyl xanthine, 1- (2-Hydroxyethyl)-3-isobutyl xanthine, 1- (2-Hiydroxyethyl)-3--isobutyl-8-methyl xanthine, 1- (2-Hydroxypropyl)-3-propyl xanthine, 1- (2-Hydroxypropyl)-3--propyl-8-rnethyl xanthine, 1- (2-Hydroxypropyl)-3-butyl xanthine, 1- (3-Hydroxypropyl)-3-propyl xanthine, 1- (3-Hydroxypropyl)-3--propyl-8-.methyl xanthine, 1- -Hydroxypropyl)-3-propyl-8-ethyl xanthine, 1- (3-Hydroxypropyl)-3-butyl xanthine, 1- (3-IHydroypropyl)-3-isobutyl xanthine, 1- (3-Hydroxypropyl)-3--isobutyl--8-methyl xanthine, 1- (3-Hydroxybutyl)-3-methy. xanthine, 1- (3-Hydroxybutyl)-3-ethyl xanthine, 1- (3-Hydroxybutyl)-3--ethyl-8-methyl xanthine, 1- (3-Hydroxybutyl)-3-propyl xanthine, 1- (3-lydroxybutyl)-3-isobutyl xanthlne, 1- (4-Hydroxybutyl)-3-ethyl xanthine, 1- (4-Hydroxybutyl)-3-propyl xanthine, 1- (4-Hydroxybutyl)-3-propyl-8--methyl xanthine, 1- (4-fydroxybutyl) -3-butyl xanthine, 1- (4-Hydroxybutyl)-3-isobutyl-8-methyI xanthine, 1- (4-H-ydroxypentyl)-3-methyl xanthine
L~"F~I;
3 1 1-(4-Hydroxypentyl)-3-propyl xanthine, 1-(5-Hydroxypentyl)-3-methyl xanthine, 1-(5-Hydroxypentyl-3-propyl xanthine et 1- (5-Hydroxypentyl)-3-propyl-8-methyl xanthine.
Physiologically acceptable salts of the compounds corresponding to general formula are understood to be the salts which these compounds form with pharmaceutically acceptable bases. The salts in question are salts of which the cations are harmless with respect to animal organisms and do not produce any side effects in therapeutic doses. Salts such as these include the salts of alkali metals, such as sodium, potassium, pharmaceutically acceptable salts of ammonium and amines known to the expert.
These salts are prepared by heating the compound corresponding to general formula in the presence of the appropriate base and in the presence or a sence of a solvent, preferably followed by recrystallization.
The compounds according to the invention are prepared by one of the following processes: A) A uracil corresponding to the following formula 0 11 H NH-C-R
N
SNH2 R3 is reacted with an alkylating agent of the formula R1-X, wher R, R 3 and R 8 are as defined in general formula except that R 1 is not *J-hydroxybutyl, and where X is a halogen atom, preferably bromine, or monosulfate or disulfate or p-toluenesulfonate, 4 1 in a solvent suitable for all the reactants, such as for example dimethylformamide (DMF), dimethylsulfoxide (DMSO) or hexamethylphosphorotriamide (HMPT), at a temperature in the range from 20 to 40°C and in the presence of an alkali metal hydroxide, for example sodium hydroxide in solid form. The reaction is preferably carried out in DMF at 20°C in accordance with the following scheme: 0 0 H NH-C-R
NH-C-R
NH
2
NH
2 2 2
R
3 R3 The product corresponding to general formula (III) is then cyclized at 20 to 100°C in an alkali metal hydroxide solution in accordance with the following reaction scheme: NH-C "-R 8
N
S N 2 0 N (I)
R
3 R3 Although it is possible to isolate the derivative of general formula (III), it is preferred to carry out cycli4ation directly without isolating or purifying the derivative in question. To this end, the reaction medium is neutralized and the solvent evaporated, after which the residue is dissolved in an alkali hydroxide solution and the resulting solution heated to reflux temperature.
B) In a variant of this process, the uracil(II) is alkylated with agent containing a function which may be converted into a hydroxyl group, for example a -COO-R 4 function, I S1 in accordance with the following reaction scheme: 0 0
II
H NH-C-R 8
N
O N NH
X-(CH
2 yCOO-R 4
NH
2
R
3 0 0
R
4 -OOC- (CH 2 y NH- -R 1'Nk (IV) 0 I NH 2
R
3 in which R 3
R
8 and X are as defined above, y is a number of from 1 to 4 and R 4 is an alkyl group. This alkylation reaction is carried out in the same way as for A) in a solvent suitable for all the reactants, such as DMF, DMSO or HMPT, at a temperature of from 20 to 40 0 C and in the presence of an alkali metal hydroxide in solid form. The alkylation step is followed by cyclization and simultaneous hydrolysis of the ester (IV) at 20 to l00C in an alkali metal hydroxide solution in accordance with the following reaction scheme: &0 R4-00 C- (H NH-C-R 8 °0 *t ()N2 y N
SNH
R
3 fiOoC- (CH 2 yN N R 8
N
z N (V)
R
3 Although the acid may be directly rnduc-d to 1lcohol, Ii IU~__~1L 6 1 it is preferred to re-esterify the acid with an alcohol, such as methanol, ethanol or propanol, under reflux to obtain the corresponding ester which is then reduced in known manner, for example in the presence of LiAlH4 in THF, to obtain the following product according to the invention:
HO-CH
2
(CH
2 Accordingly, it can be seen that w-hydroxyalkyl xanthines are always obtained in this second embodiment of the process according to the invention.
C) In a final embodiment of the process according to the invention, (w-1)-hydroxyalkyl xanthines are prepared by alkylation of the uracil (II) 0 NH-6-R
(II)
NH
2 with an alkylating agent of the formula R 5 X, where R 3
R
8 and X are as defined above and R 5 is a C 3
-C
5 (u-l)-alkenyl group. The alkylation reaction is carried out under the same conditions as for A) and namely in a solvent suitable for all the reactants, such as DMF, DMSO or HMPT, at a temperature in the range from 20 to 40 0 C and in the presence of an alkali metal hydroxide in solid form. The intermediate product obtained is then cyclized at 20 to 100°C in an alkali metal hydroxide solution in accordance with the following reaction scheme: i 7 Rs NH-C-R 8
R
5 N -N SN
(VI)
R
3
R
3 3 The final step comprises hydration of the double bond of
R
5 by an addition reaction of the Markownikoff type. This addition may be carried out in two ways: Method A: using dilute sulfuric acid at a temperature of approximately 100 0 C over a period of several days.
Method B: by the reductive oxymercuration-demercuration method in the presence of mercury acetate and then NaBH 4 (Larock, Solvomercuration/Demercuration Reactions in Organic Synthesis, Springer Verlag, Berlin, 1986, Chap. 2).
The present invention also relates to a pharmaceutical composition containing a compound of general formula (I) in combination with an inert, pharmaceutically acceptable support.
The medicament according to the invention may be made up in various pharmaceutical forms containing the usual excipients or vehicles, such as tablets, capsules, suppositories, solutions, suspensions, and may be administered orally, sublingually, rectally, subcutaneously, intramuscularly, intraveneously or by inhalation.
Before actual examples of the synthesis of the compounds according to the invention are given, Table I below shows the method of preparation and the alkylating agent to be used for 27 compounds according to the invention. Table II shows the melting point and recrystallization solvent for these same 27 compounds and Table III the 13 R values.
C NMR values.
Table I xanthine no.
Compoxund according to the invention Preparation Alkylating agent 1- (2-Hydroxyethyl) -3-propyl xanthi-ne 1- (2-Hydroxyethyl) -3-isobutyl xanthine 1- (2-Hydroxyethyl) -3-isobutyl-8-nethyl xanthine 1- (2-Hydroxypropyl) -3-propyl xanthine 1- (2-Hydroxypropyl) -3-propyl-8-methyl xanthine 1- (2-Hydroxypropyl) -3--butyl xanthine 1- (3-Hydro>Eypropyl) -3-propyl xanthine 1- (3-Hydroxypropyl) -3-propyl-8-methyl xanthine, 1- (3-Hydroxypropyl) -3-propyl--8-ethyl xantine 1- (3-Hydroxypropyl) -3-butyl xanthlne 1- (3-Hydroxypropyl) -3-isobutyl xanthine 1- (3-Hydroxypr.opyl) -3-isobutyl-8-nethyl xanthine 1- (3-Hydroxybutyl)-3-methyl xanthine 1- (3-Hydroxybutyl)-3-ethyl xanthine 1- (3-Hydroxybutyl) -3-ethyl-8-methyl xanthi-ne 1-Q(-Hydroxybutyl) -3-propyl xanthine 1- (3-Hydroxybutyl)-3-isobutyl xanthine 1- (4-Hydroxybutyl)-3-ethyl xanthine 1- (4-Hydroxybutyl)-3-propyl xanthine 1- (4-Hydroxybutyl) -3-propyl-8-methyl xanthine 1- (4-Hydroxybutyl) -3-butyl xanthine 1- (4-Hydroxybutyl) -3-isobutyl-8-methyl xanthine 1- (4-Hydroxypentyl) -3-methyl xanthine 1- (4-Hydroxypentyl) -3-propyl xanthine 1- (5-Hydroxypentyl) -3-methyl xanthine 1- (5-Hydroxypentyl) -3-propyl xanthine 1- (5-Hydroxypentyl) -3-propyl-8-methyl xanthine Method A Method A Method A 2-Bromoethanol 2-Brcmoethanol 2-Braioethanol Allyl bromide Allyl bromide Ailyl bromnide Method C/Variant B Method C/Variant A Method C/Variant B Method A Method A Method A Method A Method A Method A Method C/Variant A.
Method C/Variant. A Method C/Variant A Method C/Variant A Method C/Variant A Method B Method B Method B Method B method B Method C%/Variant A Method C/Variant B 3-BrCfno-1-prOpanOI 3-Brcrno-1-propanol 3-Brciro-1-propanol 3-Brawo-1-propanol, 3-Braro-l-propanol, 3-Branx>-1-propanoI 4-Brom-I-butene 4-Brano-1-butene 4-Brcrno-I-butene 4-Brcrno-l-butene 4-Brano-1-butene Ethyl 4-brcnobutyrate, Ethyl 4-bromobutyrate Ethyl 4-brczinbutyrate Ethlyl 4-bromobutyrate Ethyl 4-brcmobutyrate 5-Brcino-1-pentene 5-Brcino-1-pentene 5-Brcuio-1-pentanol method A Method A Method A.
0 0 0 0 0 0 000 0 00 000 6. 4 -9- Table II Xanthine No. Mp. (OC) Recrystallization solvent 1 178-179 Acetone 2 200-202 Acetone 3 227-229 Chloroform 4 150-1452 Chloroform 196-197 Methanol 6 157-158 Water 7 145-146 Methanol 8 221-222 Methanol 9 196-19$ Water 111-112 Water 11 159-160 Acetone 12 248-250 Ethanol 13 200-201 Acetone 14 217-218 Water 212-213 Water 16 163-164 Acetone 17 142 -142 Acetone 18 207-2Q8 Water 19 173-174 Acetone 192-193 Water 21 122-123 Acetone 22 211-212 Methanol 23 180-181 Acetone 24 153-154 Acetone 25190-191 water 26 151-152 Water 27 184-185 Dioxane Table 111: 13C-NMR values (6ppm;, solvent:DMSO-d&; temperature: ambient, except 80 0 c) Xanthine no. Purine ring C-2 C -4 C-5 C-6 C-8 Substituents R-1 150.8 151.0 151 .0 147.7 147-.9 148.2 147-7 147.9 147.6 106.5 106.5 106-1 106-6 106.2 106-6 154.4 154.4 153-8 154-6 154-0 154.5 151.0 151.0 151.0 150.6 150.7 150.7 150.7 150.8 150.8 150.9 150.4 150.4 150.7 150 .8 150.3 150.6 150.5 150.6 150.8 147.6 147.9 147.8 147.6 147.7 148.0 147.8 147.3 147 .6 147.6 147.9 106.5 106.2 106.2 106.6 106.3 106.0 106.5 106.6 106.3 106.3 106.4 154.2 153.8 153.9 154.3 154-1 153.6 154.3 154.3 153.7 154.3 154.2 15 4. 0 154.3 153.8 154.3 153. .6 140.4 140.3 150.3 140.5 150.4 140.4 140.5 150.5 155.4 140.5 139.9 150.0 140.4 140.6 150.5 140.5 140.3 140.0 140.5 150.5 140.5 150.0 42-6 42-7 42.5 47.5 47.3 47-5 38.4 38.3 38.3 38.4 38.1 37.9 38.4 38.3 38-4 38.3 38.4 40.5 40.5 40.5 40-6 40.2 31-0 31.1 31.1 31.1 3C1.9 30-9 37-2 37-2 37.2 37.2 37.2 24.2 24.4 24.5 24.5 24.2 58.8B 58.9 SR. 9 58.9 58.7 5B .6 57.9 57.9 57.9 63-7 63-6 20.9 20.9 20.9 44.4 49.9 49.8 44.4 44.4 42.6 44.4 44-.4 44.3 42.6 49.7 49.5 29.6 38.0 38.0 44.4 49.8 20.8 26.9 ,26.8 20.9 20.9 29.6 20.8 20.9 20.8 29.6 26.6 26.5 10.9 19.-8 (24~ 19.7 (2x) 10.9 10.9 19.3 13-5 10.9 10.9 10.9 19.4 13.5 19.4 (2x) 19.3 (2x) 14.2 14.2 14.2 ,21.7 12.2 14.2 64.3 23.5 64.3 23.5 64.3 23.4 64.4 23.4 64.3 23.4 13.1 13.1 20.8 10.9 26.8 19.7 (2x) 147.1 106-4 147.6 '06.5 147.9 106.2 147.7 106.6 148.0 106.0 29.7 30.0 30.0 30.0 29.7 60.4 60.6 60.6 60-7 60.5 37.7 44.4 44.3 42.6, 49.6 12.7 20.8 20.9 29.7 26.5 10.9 10. 9 19.4 13.5 19.4 (2x) 14.2 13.8 150.9 147.9 106.4 154.2 140.4 150.6 147.6 106.5 154.2 140.4 40.8 24.2 36.2 A5.7 23.5 29.6 40-6 24.1 36.2 6'rA- 23.5 44->4 20.8 10.9 150.9 147.8 106.5 154.2 150.6 147.6 106.3 154.2 150.5 147.9 106.1 153.7 140.3 140.4 1-50-5 40.6 4.-6 40.5 27.4 22.9 32.2 60-6 27.4 22.9 32.1 60.5 27-4 22.9 32.2 60.5 29.6 44.4 20.8 10A9 44-3 20.8 10-9 14.2 11 The invention is illustrated by the following Examples in which the quantities are by weight, unless otherwise indicated.
EXAMPLE 1 1- (5-hydroxypentyl)-3.propyl-8-methyl1 xanthine (Method xanthine no. 27) 22.6 g (0.1 mole) of 1-propyl-5--acetylamino-6-aminouracil (II) (R 3 methyl, R 8 methyl) are suspended unier nitrogen in 200 ml of anhydrous dimethylformamide (DMF), 21.7 g (0.13 mole) of 5-bromo-l--pentanol are then added, after which 6 g (0.15 mole) of powder-form solid NaOH are added with stirrin9 in portions of I. g at a time at intervals of 1 hour. After the third addition, the suspension is completely dissolvad. The solution is left standing overnight to complete the reaction, The solvent is evaporated in a rotary evaporator at 40'C/0.,l mm, Hg, The oily residue, which is the tracil (III) (R 1 R =propyl, R, methyl) which is not purified, is diosolved in 100 ml of 10%t NP.OH and the solution heated under ref lux for 2 hours The liolution is thon cooled in a ice bath and neutralized to PT 5 with acetiO 4cidk The Prod, precipitated is filtered, washed with Cold wa-ter n dried in a vacuum~ oven*~ The dried product is dissolvck..
500 ml of ethanol and the solution. is docolourod Ovrm'ight.
with active carbon. The product is precipitated by addition of I litre of Water, filtered andl the treatment with active carbon repeated, Th0re pouti recrystallized twice with 120 ml of dioxftne, Yieldt 23 5 q colourless crystals,' Mp. 1$4 185"C,
EXAMIPLE
(Mtthod B, Nyinthine no. 21) 11,,3 q (0.05 mole) of -fTu -s 12 1 uracil (II) (R 1 butyl, R 8 H) are dissolved under nitrogen in 200 ml of DMF. 10.6 ml (0.075 mole) of ethyl 4-bromobutyrate are added, after which 2 g (0.05 mole) of solid powder-form NaOH is added with thorough stirring in portions of 0.5 g at intervals of 1 hour. On completion of the addition, the mixture is left to react overnight.
The solvent is then evaporated and the oily residue of (IV) (substituent in the 1-position (CH 2 3 COOt) is dissolved in 100 ml of 10% NaOH, This solution is then heated under reflux for 0.5 hour and then cooled, neutralized to pH 5 with acetic acid and filtered. The precipitate formed is dried. Yield: 9.2 g ot c-ude xanthine (V) (substituent in the 1-position (CH 2 3 COOH, R 3 butyl,
R
8
H)
Without purification, the p-roduct is esterified under reflux for 5 hours with 200 ml of methanol containing 1 ml of concentrated sulfuric acid. The solution is concentrated to a small volume and 50 ml of water are added. The ester precipitate formed (substituent in the 1-position
(CH
2 3 COOMe) is filtered, washed and dried. Yield: 9 g Without purification, this product is dissolved in 200 ml of anhydrous tetrahydrofuran (THF), cooled to between 0 and -10°C and added dropwise to a solution containing 2.13 g (0.056 mole) of LiAlH 4 in 150 ml of anhydrous THF.
On completion of the addition, the mixture is left to react for another 2 hours at O'C, after which the excess LiAH 4 is destroyed by addition of 50 ml of water, The mixture is acidified to pH 2 with concentrated HC1, after which the THF is evaporated. The residual aqueous solution is continuously extracted overnight with dichloromethane.
The organic extract is dried and the solvent evaporated.
The slightly coloured solid residue (6.1 g) is recrystallized twice from acetone. Yield: 4.6 g (33% from II); colourless crystals; Mp. 122 123°C.
13 1 EXAMPLE 3 1-(3-hydroxybutyl)-3-isobutyl xanthine (Method C/Variant A, xanthine no. 17) 11.3 g (0.05 mole) of 1-isobutyl-5-formylamino-6-aminouracil (II) (R 3 isobutyl, R 8 H) are dissolved in 220 ml of DMF. 8.8 g (0.065 mole) of 4-bromo-l-butene are added, after which 3 g (0.075 mole) of powder-form NaOH are added with stirring in portions of 0.5 g at intervals of 1 hour.
The mixture is left standing overnight, after which the solvent is evaporated in vacuo. The crude residue (R 3-butenyl) is taken up in 100 ml of 10% NaOH and heated under reflux for 0.5 hour. The solution is then cooled and neutralized to pH 5 with acetic acid, after which the precipitate formed is filtered and dried. 8.5 g of crude solid product (VI) (R 5 3-butenyl, R 3 isobutyl, Rg H) are obtained. This product i, purified by passage through a column of silica (85 g) using chloroform as eluent: g of colourless product.
A mixture containing 6 g of the above compound in 100 ml of 20% sulfuric acid is heated at 100 0 C for 4 days, cooled and neutralized to pH 5 with 50% KOH. The solution is evaporated to dryness, the residue is taken up in 100 ml of boiling absolute ethanol and the insoluble fraction is filtered. The filtrate is freed from the solvent, leaving a coloured solid residue (6.4 g) which is passed through a column of silica (650 g) eluted with a gradient of chloroform/methanol methanol). The xanthine is recrystallized twice from acetone. Yield: 4.5 g (33% based on II); Mp. 141 142CC.
EXAMPLE 4 1- (2-hydroxypropyl)-3-butyl xanthine (Method C:Variant B, xanthine no. 6) 16 g (0.050 mole) of mercury (II) acetate are dissolved in 250 ml water. 12.4 g (0.05 mole) of l-allyl-3-butyl C UIP~t- 14 1 xanthine (prepared as described above from amino-6-aminouracil and allyl bromide) dissolved in 250 ml of THF are added dropwise with stirring over a period of minutes. After a few minutes, a preci'pitate is formed.
Stirring is continued for 30 minutes, after which the mixture is cooled in an ice bath. 68 ml of 3 N NaOH are added, followed by the dropwise addition of 60 ml of a freshly prepared 0.5 M solution of NaBH 4 in 3 N NaOH. On completion of the addition, stirring is continued for another 15 minutes. The solution is neutralized to pH with 6 N HCI (approximately 60 mi), saturated with NaCI and the xanthine extracted with dich,.oromethane (3 x 200 ml), The organic extract is dried and the solvent is evaporated: 12.9 g of crude product containing 20% of starting product.
The products are separated by passing the mixture through a column of silica using chloroform as eluent for the starting product and chloroform/methanol (95/5) for the hydroxylated xanthine (9.5 The xanthine is recrystallized twice from water: 8.5 g Mp. 157 158 0
C.
EXAMPLE The compounds according to the invention have been found to show low toxicity and have little or no effect on the central nervous system. By contrast, they were found to be active in the in vitro tests for inotropic (cardiotonic) activity. Table IV shows the results of these tests.
15 Table (IV) Xanthine No.
1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 Cardiotonic activity 1 (minimum effective concentration in vjig/ml producing a significant response) 1 2 3.3 0.6 4.2 1.3 4.2 2 0.4 0.7 0.8 0.6 0.1 1.3 3.3 0.4 0.7 2 33.3 0.7 6.7 0.2 0.3 16 References Theophylline 2) Amrinone 2 100 Milrinone 2
IBMX
3 1) Measurement of the force of contraction of the isolated and electrically stimulated left auricle of a guinea pig in accordance with Erjavek, F. and Adamic, Arch.
Int. Pharmacodyn. 155: 251, 1965. A response is considered to be significant when the basic contraction force is increased by more than 2) Prior art cardio stimulant medicament.
3) l-methyl-3-isobutylxanthine.
Claims (3)
1. A compound corresponding to the following formula 0H R N N R 3 in which Ris a C 2 C, w-hydroxy-n-alkyl group or a R 1 arnd R 3 is between 4 and 9, or a physiologically acceptable salt of this comnpound. A compound as claimed in Claim 1, characterized in that it is selected from the group comprising; 1- (2-Hydroxyethyl) -3-propyl xanthine, 1- (2-lydroxyethyl) -3-isobutyl xanthine 1- (2-Hydroxyethyl)-3-isobutyl-8-nethyl xanthine, 1- (2-Hydroxypropyl)-3-propyl xanthine, 1- (2-H-ydroxypropyl) -3-propyl-8-methyl xanthine, 1-(2-Hydroxcypropyl)-3-butyl xanthine, 1- (3-Hydroxypropyl) -3-propyl xanthine, 1- (3-Hydroxypropyl) -3-propyl-8-methyl xanthine, 1- (3-Hydroxypropyl) -3-propyl-8-ethyl xanthine, 1- (3-Hydroxypropyl) -3-butyl xanthine, 1- (3-hydroxypropyl) -3-isobutyl xanthine, (3-Hydroxypropyl) -3-isobutyl-8-methyl xanthine, 1- (3-Hydroxybutyl) -3-methyl xanthine, 1- (3-Hydroxybutyl) -3-ethyl xanthine, 1- (3-Hydroxybutyl)',-3-ethyl-8-rnethyl xanthine, -18 1- (3-Hydroxybutyl) -3-propyl xanthine, 1- (3-Hydlroxybutyl)-3-isobutyl xanthine, 1- (4-Hydroxybutyl) -3-ethyl xanthine, 1- (4-Hydroxybutyl)--3-propyl xanthine, 1- (4-Hydroxyb'utyl)-3-propyl-8-m~ethYl xanthine, 1- Hydroxybutyl) -3-butyl xanthine, 1- (4-Hydroxybutyl)-3-isobutyl-8-mfethyI xanthine, 1- (4-Hydroxypentyl) -3-methyl xanthine, 1,-(4-Hydroxypeityl) -3-propyl xanthine, 1- (5-Hydroxypentyl) -3-methyl xanthine, 1- (5-Hydroxypentyl) -3-propyl xanthine, 1- (5-Hydroxypentyl)-3-propyl-8-fethyl xanthine.
3. A process for the preparation of a compound corresponding to the followi~ng formula 0 H N R 3 in which Ris a C-C 5 w-hydroxy-n-alkyl group or a C (w-l)-hydroxy-n-alkyl group, R 3 is a C-C 4 alkyl group, P,is H, methyl or ethyl and the sum of the carbon atoms in Rand R 3 is between 4 and 9, Aa compound corresponding to the following formula
19- o H _NH-C-R 8 I l I I 0 N NH 1 2 R 3 is reacted with an alkylating agent of the formula R1-X, where R1, R 3 and R 8 are as defined above, except that R 1 is not W-hydroxybutyl, and X is a halogen atom, monosulfate or disulfate or p-toluenesulfonate, and the compound obtained is cyclized, or B) a compound corresponding to the following formula 0 0 1 NH-C-R "N (II) NH 2 1 2 R 3 is reacted with an alkylating agent of the formula X-(CH) COO-R 4 where R 3 R 8 and X are as defined above, y is a number of from 1 to 4 and R 4 is an alkyl group, the compound obtained is cyclized in aqueous alkaline medium to form the following compound 0 H HOOC-(CH 2 N SN N R 3 the compound thus obtained is esterified and the ester obtained is reduced to form the compound in which R is the group -(CH 2 -CH2-OH or 20 C) a compound corresponding to the following formula 0 0 H N /NH--R 8 N 2(II) 0 N NH R 3 is reacted with an alkylating a ent of the formula R 5 X, where R R 8 and X are as defined above and R 5 is a C3- C alkenyl group, the compound obtained is cyclized, the double bond of R is ther hydrated by an addition reaction of the Markownikoff type to form in which R1 is a C 3 -C 5 (w-l)-hydroxy-n-alkyl group. 4. A pharmaceutical comnosition, characterized in that it contains a compound corresponding to the following formula 0 H R N I 8 (I) O <N I R 3 in which R 1 is a C: -C 5 w-hydroxy-n-alkyl group or a C3-C (-1)-hydroxy-n-alkyl group, R 3 is a C 1 -C 4 alkyl group, R 8 is H, methyl or ethyl and the sum of the carbon atoms in R and R 3 is between 4 and 9, or a physiologically acceptable salt of this compound in conjunction with a pharmaceutically acceptable excipient. A pharmaceutical composition as claimed in Claim characterized in that it contains a compound of the type claimed in Claim 2 or 3. 21 6. A compound of formula as defined by claim 1, substantially as herein described with reference to any one of the examples. 7. A process for preparing a compound of formula as defined by claim 1, substantially as herein described with reference to any one of the examples. DATED this 21st day of October, 1987 SOCIETE DES PRODUITS NESTLE S.A. Attorney: WILLIAM S. LLOYD Fellow Institute of Patent Attorneys of Australia of SHELSTON WATERS
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH4253/86 | 1986-10-27 | ||
| CH4253/86A CH670090A5 (en) | 1986-10-27 | 1986-10-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU7998087A AU7998087A (en) | 1988-04-28 |
| AU604767B2 true AU604767B2 (en) | 1991-01-03 |
Family
ID=4272668
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU79980/87A Ceased AU604767B2 (en) | 1986-10-27 | 1987-10-21 | 1-hydroxyalkylxanthines, processes for their preparation and medicaments containing them |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0269841B1 (en) |
| JP (1) | JP2527769B2 (en) |
| KR (1) | KR930010559B1 (en) |
| AT (1) | ATE82289T1 (en) |
| AU (1) | AU604767B2 (en) |
| CA (1) | CA1296001C (en) |
| CH (1) | CH670090A5 (en) |
| DE (1) | DE3782619T2 (en) |
| DK (1) | DK169336B1 (en) |
| ES (1) | ES2043631T3 (en) |
| GR (1) | GR3006223T3 (en) |
| IL (1) | IL84266A (en) |
| ZA (1) | ZA877851B (en) |
Families Citing this family (2)
| 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 |
| DE4316576A1 (en) * | 1993-05-18 | 1994-11-24 | Boehringer Ingelheim Kg | Improved process for the preparation of 1,3-dipropyl-8- (3-oxocyclopentyl) xanthine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU569935B2 (en) * | 1983-12-12 | 1988-02-25 | Eugene M. Laska | Analgesic & anti-inflammatory compositions containing xanthines |
| AU574419B2 (en) * | 1983-12-12 | 1988-07-07 | Richardson-Vicks Inc. | Analgesic and anti-inflammatory compositions comprising xanthines and methods of using same |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2517410A (en) * | 1947-08-15 | 1950-08-01 | Searle & Co | Hydroxy alkyl xanthines and the production thereof |
| FR1211333A (en) * | 1955-10-19 | 1960-03-15 | Boehringer Sohn Ingelheim | Improvements in processes for manufacturing oxyalkylxanthines |
-
1986
- 1986-10-27 CH CH4253/86A patent/CH670090A5/fr not_active IP Right Cessation
-
1987
- 1987-10-19 ZA ZA877851A patent/ZA877851B/en unknown
- 1987-10-21 AU AU79980/87A patent/AU604767B2/en not_active Ceased
- 1987-10-21 DK DK551487A patent/DK169336B1/en not_active IP Right Cessation
- 1987-10-23 ES ES87115591T patent/ES2043631T3/en not_active Expired - Lifetime
- 1987-10-23 DE DE8787115591T patent/DE3782619T2/en not_active Expired - Fee Related
- 1987-10-23 EP EP87115591A patent/EP0269841B1/en not_active Expired - Lifetime
- 1987-10-23 AT AT87115591T patent/ATE82289T1/en active
- 1987-10-25 IL IL84266A patent/IL84266A/en not_active IP Right Cessation
- 1987-10-26 CA CA000550244A patent/CA1296001C/en not_active Expired - Fee Related
- 1987-10-26 KR KR1019870011905A patent/KR930010559B1/en not_active IP Right Cessation
- 1987-10-27 JP JP62271591A patent/JP2527769B2/en not_active Expired - Lifetime
-
1992
- 1992-11-12 GR GR920402559T patent/GR3006223T3/el unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU569935B2 (en) * | 1983-12-12 | 1988-02-25 | Eugene M. Laska | Analgesic & anti-inflammatory compositions containing xanthines |
| AU574419B2 (en) * | 1983-12-12 | 1988-07-07 | Richardson-Vicks Inc. | Analgesic and anti-inflammatory compositions comprising xanthines and methods of using same |
Also Published As
| Publication number | Publication date |
|---|---|
| DK169336B1 (en) | 1994-10-10 |
| AU7998087A (en) | 1988-04-28 |
| ES2043631T3 (en) | 1994-01-01 |
| CA1296001C (en) | 1992-02-18 |
| JP2527769B2 (en) | 1996-08-28 |
| CH670090A5 (en) | 1989-05-12 |
| EP0269841B1 (en) | 1992-11-11 |
| DK551487D0 (en) | 1987-10-21 |
| JPS63122683A (en) | 1988-05-26 |
| DE3782619T2 (en) | 1993-04-22 |
| EP0269841A1 (en) | 1988-06-08 |
| KR880005131A (en) | 1988-06-28 |
| ZA877851B (en) | 1988-04-22 |
| DK551487A (en) | 1988-04-28 |
| IL84266A0 (en) | 1988-03-31 |
| GR3006223T3 (en) | 1993-06-21 |
| DE3782619D1 (en) | 1992-12-17 |
| KR930010559B1 (en) | 1993-10-28 |
| ATE82289T1 (en) | 1992-11-15 |
| IL84266A (en) | 1992-02-16 |
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