EP0259360A1 - Xanthine compounds - Google Patents

Xanthine compounds

Info

Publication number
EP0259360A1
EP0259360A1 EP19870900851 EP87900851A EP0259360A1 EP 0259360 A1 EP0259360 A1 EP 0259360A1 EP 19870900851 EP19870900851 EP 19870900851 EP 87900851 A EP87900851 A EP 87900851A EP 0259360 A1 EP0259360 A1 EP 0259360A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
butyl
compounds
xanthine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19870900851
Other languages
German (de)
French (fr)
Inventor
Joachim Goring
Jonathan R. S. Beecham Pharmaceuticals ARCH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Wuelfing GmbH and Co KG
Beecham Group PLC
Original Assignee
Beecham Wuelfing GmbH and Co KG
Beecham Group PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beecham Wuelfing GmbH and Co KG, Beecham Group PLC filed Critical Beecham Wuelfing GmbH and Co KG
Publication of EP0259360A1 publication Critical patent/EP0259360A1/en
Withdrawn legal-status Critical Current

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

Definitions

  • This invention relates to a group of 8-substituted xanthines, to compositions containing such compounds and to their use in medicine.
  • European Patent Application, publication number 0,195,496 discloses certain xanthines and their use in the treatment of proliferate skin disease.
  • R 1 and R 2 each independently represent a C 2-6 alkyl group
  • R 3 represents a moiety -(CH 2 ) m CHOHCH 3 ; or a carboxyl group or a salt ester or amide thereof; and n and m each independently represent an integer 1, 2 or 3.
  • R 1 represents a butyl group, preferably n-butyl.
  • R 2 represents a butyl group, preferably n-butyl.
  • n 1 or 2.
  • R 3 represents. a moiety -(CH 2 ) m -CHOHCH 3
  • m represents 1.
  • R 3 represents a C 1-6 alkyl ester of a carboxyl group, for example an ethyl ester.
  • the present invention also provides a process for the preparation of the hereinbefore defined compound of formula (I), which process comprises reacting a compound of formula (II):
  • R 1 , R 2 and R 3 are as defined in relation to formula (I), with:
  • n is as defined in relation to formula (I) and X represents a leaving group preferably a chlorine atom, or
  • the compound of formula (II) is provided in the form of a metallic salt, preferably a sodium salt.
  • the compounds of formula (II) are novel intermediates and as such form a further aspect of the present invention.
  • the compounds of formula (I) may be isolated and purified by any conventional method,
  • the compounds of formula (II) may be prepared by reacting a compound of formula (V):
  • R 1 , R 2 and R 3 are as defined in relation to formula (I); with a source of nitrite anions, for example sodium nitrite.
  • a source of nitrite anions for example sodium nitrite.
  • the uracils of formula (V) are either known compounds or may be prepared by methods analogous to those used to prepare known compounds.
  • (III) may be carried out under any convenient conditions, for example by reaction of the sodium salt of the compound of formula (II) with a compound of formula (III) in ethanol under reflux.
  • (IV) may be carried out in any convenient solvent, for example methanol, at ambient to elevated temperatures, for example 45°C, preferably in the presence of triethylamine.
  • the present invention provides a compound of formula (I) for use as an active therapeutic substance.
  • the present invention provides a compound of formula (I) for use in the treatment of proliferate skin disease.
  • a pharmaceutical composition which comprises a compound of formula (I) and a pharmaceutically acceptable carrier therefor.
  • the present invention also provides the use of a compound of formula (I) for the manufacture of a medicament for treating proliferative skin disease in human or non-human mammals.
  • proliferative skin diseases means benign and malignant proliferative skin diseases which are characterized by accelerated cell division in the epidermis, dermis or appendages thereto, associated with incomplete tissue differentiation.
  • Such diseases include: psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinomas of the skin, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant sun induced keratosis, non-malignant keratosis, acne, and seborrheic dermatitis in humans and atopic dermatitis and mange in domesticated animals.
  • the compounds of formula (I) are also effective in increasing oxygen tension and contractility in ischaemic skeletal muscle and are therefore of potential use in the treatment of peripheral vascular disease, such as intermittant claudication.
  • the compounds of formula (I) also have a protective effect against the consequences of cerebral metabolic inhibition and/or enhance cognition in animals and are therefore of potential use in the treatment of cerebrovascular disorders and disorders associated with cerebral senility in humans and non-human mammals.
  • the present invention provides a compound of formula (I), for use in the treatment and/or prophylaxis of peripheral vascular disease, such as intermittant claudication and/or cerebrovascular disorders and/or disorders associated with cerebral senility.
  • peripheral vascular disease such as intermittant claudication and/or cerebrovascular disorders and/or disorders associated with cerebral senility.
  • the present invention also provides a method for the treatment and/or prophylaxis of, peripheral vascular disease, such as intermittant clavdication and/or cerebrovascular disorders and/or disorders associated with cerebral senility in humans or non-human mammals, which treatment comprises the administration to the human or non-human mammal in need of such treatment an effective and/or prophylactic amount of a compound of formula (I).
  • the present invention also provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment and/or prophylaxis of; peripheral vascular disease, such as intermittant claudication and/or cerebrovascular disorders and/or disorders associated with cerebral senility.
  • peripheral vascular disease such as intermittant claudication and/or cerebrovascular disorders and/or disorders associated with cerebral senility.
  • the administration to the human or non-human mammal may be by way of oral administration, parenteral administration or, in the case of proliferate skin disease, topical administration.
  • a unit dose will normally contain 5 to 500 mg for example 20 to 200 mg, of compound (I).
  • Unit doses will normally be administered once or more than once a day, for example 2, 3, 4, 5 or 6 times a day, more usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 5 to 1000 mg, for example 50 to 600 mg, that is in the range of approximately 0.07 to 15 mg/kg/day, more usually 1 to 10 mg/kg/day, for example 2 to 5 mg/kg/day.
  • peripheral vascular disease such as intermittant claudication, and/or cerebrovascular disorders and/or disorders associated with cerebral senility depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the human or non-human mammal.
  • a unit dose will normally contain 1 to 100 mg for example 2 to 50 mg, of the compound of the invention.
  • Unit doses will normally be administered once or more than once a day, for example 2, 3, 4, 5 or 6 times a day, more usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 250 mg, for example 50 to 150 mg, that is in the range of approximately 0.002 to 3.5 mg/kg/day, more usually 1 to 3 mg/kg/day, for example 0.7 to 2 mg/kg/day.
  • a compound of formula (I) is administered in the form of a unit-dose composition, such as a unit dose oral or parenteral composition.
  • compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions.
  • Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
  • fluid unit dose forms are prepared containing a compound of formula (I) and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle andfilter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • the compounds of formula (I) may also be administered as a topical formulation in combination with conventional topical excipients.
  • Topical formulations may be presented as, for instance, ointments, creams or lotions, impregnated dressings gels, gel sticks, spray and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Suitable cream, lotion, gel, stick, ointment, spray, or aerosol formulations that may be used for compounds of formula (I) are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics and cosmetics, such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences, and the British and US Pharmacopoeias.
  • the compound of formula (I) will comprise from about 0.5 to 20% by weight of the formulation, favourably from about 1 to 10% for example 2 to 5%.
  • 1,3-di-n-butyl-8-(2-hydroxypropyl)xanthine(2.4g), methylvinyl ketone (0.6g) and triethylamine (0.3ml) were dissolved in methanol (8ml) and the mixture was slowly heated with stirring at 45°C for seven hours, then cooled to room temperature and continued stirring overnight to complete tne reaction.
  • 1,3-di-n-butyl-8-carbethoxy-xathine (1.7g) was treated witn sodium (0.12g) in absolute ethanol (5ml) to give the 1,3 di-n-butyl-8-carbethoxy sodium salt by heating under reflux for one hour.
  • 1-chloropropan-2-one (0.92g) dissolved in ethanol (10ml) was added dropwise and the reaction mixture heated under reflux for a further 6 hours. The reaction was then complete (as inidcated by thin layer of chromatography (tlc)).
  • the filtrate was diluted with water and the precipitated 1,3-di-n-butyl-7-(2'-oxopropyl)-8- carbethoxy-xanthine raw material filtered off under suction, washed with water, dried and recrystallised several times from acetone/water (80%:20%)diethylether and finally methanol/water (90%: 10%) to give a white powder.
  • reaction was completed, as indicated by tlc, by stirring for a further 30 minutes.
  • the reaction mixture was poured into ice-water and extracted with chloroform several times, the chloroform washed with water.
  • the chloroform phase was dried with sodium-sulphate, filtered and the chloroform removed in vacuo to yield an oil which was dissolved in toluene (200ml) and heated to reflux for 3 hours to remove the reaction water with a water separator.
  • the activity of cyclic AMP phosphodiererase in homogenates of rat gastocnemius muscle was measured in the presence of various concentrations of compounds of formulae (I) using 0.31 ⁇ M cyclic AMP as substration.
  • the reciprocal of the reaction rate was plotted on the y axis against the concentration of each compound on the x axis (Dixon plot).
  • the apparent Ki value was estimated by extrapolating the steeper linear portion of the Dixon plot to the x axis and obtaining the negative intercept on the x axis.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés de formule (I) où R1 et R2 représentent chacun indépendamment un groupe C2-6 alkyle, R3 représente une moitié -(CH2)mCHOHCH3; ou un groupe carboxyle ou un sel, un ester ou un amide de ce dernier, et n et m représentent chacun indépendamment un nombre entier égal à 1, 2 ou 3; sont également décrits un procédé de préparation d'un tel composé, une composition pharmaceutique contenant ledit composé et leur utilisation en médecine.Compounds of formula (I) where R1 and R2 each independently represent a C2-6 alkyl group, R3 represents a half - (CH2) mCHOHCH3; or a carboxyl group or a salt, an ester or an amide thereof, and n and m each independently represent an integer of 1, 2 or 3; also described are a process for preparing such a compound, a pharmaceutical composition containing said compound and their use in medicine.

Description

XANTHINE COMPOUNDS
This invention relates to a group of 8-substituted xanthines, to compositions containing such compounds and to their use in medicine.
European Patent Application, publication number 0,195,496 discloses certain xanthines and their use in the treatment of proliferate skin disease.
It has now surprisingly been discovered that certain 8-substituted xanthines are active as phosphodiesterase inhibitors and that they also elevate cyclic AMP levels; they are therefore potentially useful in the treatment of proliferate skin disease. These compounds are also potentially useful in the treatment and/or prophylaxis of peripheral vascular disease, such as intermittant claudication and/or cerebrovascular disorders and/or disorders associated with cerebral senility.
Accordingly, the present invention provides a compound of formula (I):
wherein, R1 and R2 each independently represent a C2-6 alkyl group,
R3 represents a moiety -(CH2 )mCHOHCH3; or a carboxyl group or a salt ester or amide thereof; and n and m each independently represent an integer 1, 2 or 3.
Suitably, R1 represents a butyl group, preferably n-butyl.
Suitably, R2 represents a butyl group, preferably n-butyl.
Suitably, n represents 1 or 2.
Suitably, when R3 represents. a moiety -(CH2)m-CHOHCH3, m represents 1.
Suitably, R3 represents a C1-6 alkyl ester of a carboxyl group, for example an ethyl ester.
The present invention also provides a process for the preparation of the hereinbefore defined compound of formula (I), which process comprises reacting a compound of formula (II):
wherein R1, R2 and R3 are as defined in relation to formula (I), with:
(a) a compound of formula (III):
X-(CH2)n-CO.CH3 (III) wherein n is as defined in relation to formula (I) and X represents a leaving group preferably a chlorine atom, or
(b) for compounds of formula (I) wherein n represents 2 or 3, a compound of formula (IV):
CH2=CH-(CH2)p-CO-CH3 (IV)
wherein p represents zero or 1.
Suitably, in the reaction between the compounds of formula (II) and (III), the compound of formula (II) is provided in the form of a metallic salt, preferably a sodium salt.
The compounds of formula (II) are novel intermediates and as such form a further aspect of the present invention.
The compounds of formula (I) may be isolated and purified by any conventional method,
The compounds of formula (II) may be prepared by reacting a compound of formula (V):
wherein R1, R2 and R3 are as defined in relation to formula (I); with a source of nitrite anions, for example sodium nitrite. The uracils of formula (V) are either known compounds or may be prepared by methods analogous to those used to prepare known compounds.
The reaction between the compounds of formulae (II) and
(III) may be carried out under any convenient conditions, for example by reaction of the sodium salt of the compound of formula (II) with a compound of formula (III) in ethanol under reflux.
The reaction between the compounds of formulae (II) and
(IV) may be carried out in any convenient solvent, for example methanol, at ambient to elevated temperatures, for example 45°C, preferably in the presence of triethylamine.
As indicated above the compounds of formula (I) have useful pharmaceutical properties.
Accordingly, the present invention provides a compound of formula (I) for use as an active therapeutic substance.
In one aspect the present invention provides a compound of formula (I) for use in the treatment of proliferate skin disease.
In a further aspect of the present invention there is provided a pharmaceutical composition which comprises a compound of formula (I) and a pharmaceutically acceptable carrier therefor.
The present invention also provides the use of a compound of formula (I) for the manufacture of a medicament for treating proliferative skin disease in human or non-human mammals. As used herein the expression 'proliferative skin diseases' means benign and malignant proliferative skin diseases which are characterized by accelerated cell division in the epidermis, dermis or appendages thereto, associated with incomplete tissue differentiation. Such diseases include: psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinomas of the skin, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant sun induced keratosis, non-malignant keratosis, acne, and seborrheic dermatitis in humans and atopic dermatitis and mange in domesticated animals.
The compounds of formula (I) are also effective in increasing oxygen tension and contractility in ischaemic skeletal muscle and are therefore of potential use in the treatment of peripheral vascular disease, such as intermittant claudication.
The compounds of formula (I) also have a protective effect against the consequences of cerebral metabolic inhibition and/or enhance cognition in animals and are therefore of potential use in the treatment of cerebrovascular disorders and disorders associated with cerebral senility in humans and non-human mammals.
Accordingly, the present invention provides a compound of formula (I), for use in the treatment and/or prophylaxis of peripheral vascular disease, such as intermittant claudication and/or cerebrovascular disorders and/or disorders associated with cerebral senility. The present invention also provides a method for the treatment and/or prophylaxis of, peripheral vascular disease, such as intermittant clavdication and/or cerebrovascular disorders and/or disorders associated with cerebral senility in humans or non-human mammals, which treatment comprises the administration to the human or non-human mammal in need of such treatment an effective and/or prophylactic amount of a compound of formula (I).
The present invention also provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment and/or prophylaxis of; peripheral vascular disease, such as intermittant claudication and/or cerebrovascular disorders and/or disorders associated with cerebral senility.
The administration to the human or non-human mammal may be by way of oral administration, parenteral administration or, in the case of proliferate skin disease, topical administration.
An amount effective to treat proliferative skin disease depends on the usual factors such as the nature and severity of the problem and the weight of the human or non-human mammal. However, a unit dose will normally contain 5 to 500 mg for example 20 to 200 mg, of compound (I). Unit doses will normally be administered once or more than once a day, for example 2, 3, 4, 5 or 6 times a day, more usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 5 to 1000 mg, for example 50 to 600 mg, that is in the range of approximately 0.07 to 15 mg/kg/day, more usually 1 to 10 mg/kg/day, for example 2 to 5 mg/kg/day. An amount effective to treat peripheral vascular disease, such as intermittant claudication, and/or cerebrovascular disorders and/or disorders associated with cerebral senility depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the human or non-human mammal. However, a unit dose will normally contain 1 to 100 mg for example 2 to 50 mg, of the compound of the invention. Unit doses will normally be administered once or more than once a day, for example 2, 3, 4, 5 or 6 times a day, more usually 2 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.1 to 250 mg, for example 50 to 150 mg, that is in the range of approximately 0.002 to 3.5 mg/kg/day, more usually 1 to 3 mg/kg/day, for example 0.7 to 2 mg/kg/day.
Suitably, a compound of formula (I) is administered in the form of a unit-dose composition, such as a unit dose oral or parenteral composition.
Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.
Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. These solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
For parenteral administration, fluid unit dose forms are prepared containing a compound of formula (I) and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle andfilter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
In the treatment of proliferate skin disease, the compounds of formula (I) may also be administered as a topical formulation in combination with conventional topical excipients.
Topical formulations may be presented as, for instance, ointments, creams or lotions, impregnated dressings gels, gel sticks, spray and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. The formulations may contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
Suitable cream, lotion, gel, stick, ointment, spray, or aerosol formulations that may be used for compounds of formula (I) are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics and cosmetics, such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences, and the British and US Pharmacopoeias.
Suitably, the compound of formula (I) will comprise from about 0.5 to 20% by weight of the formulation, favourably from about 1 to 10% for example 2 to 5%.
No adverse toxicological effects are indicated in any of the above mentioned dosage ranges.
The invention will now be illustrated by reference to the following Examples which do not limit it in any way.
Example 1
Preparation of 1,3-dibutyl-7-(-3'-oxobutyl)-8-(2- hydroxypropyl)-xanthine
1,3-di-n-butyl-8-(2-hydroxypropyl)xanthine(2.4g), methylvinyl ketone (0.6g) and triethylamine (0.3ml) were dissolved in methanol (8ml) and the mixture was slowly heated with stirring at 45°C for seven hours, then cooled to room temperature and continued stirring overnight to complete tne reaction.
The reaction mixture was treated with water and then extracted with chloroform several times, the chloroform phase washed with IN NaOH and water, dried with sodium sulphate, filtered and the chloroform remained in vacuo to yield a solid which, on crystallisation in petroether (40°/80°C), gave 1,3 di-butyl-7- (3'-oxobutyl)-8-(2-hydroxypropyl)xanthine as a white powder.
Melting point: 82°C Yield: 1.3g
Example 2
Preparation of 1,3-di-n-butyl-7-(2'-oxopropyl)-8- carbethoxy-xanthine
1,3-di-n-butyl-8-carbethoxy-xathine (1.7g) was treated witn sodium (0.12g) in absolute ethanol (5ml) to give the 1,3 di-n-butyl-8-carbethoxy sodium salt by heating under reflux for one hour. 1-chloropropan-2-one (0.92g) dissolved in ethanol (10ml) was added dropwise and the reaction mixture heated under reflux for a further 6 hours. The reaction was then complete (as inidcated by thin layer of chromatography (tlc)).
After standing overnight, the precipitated sodium chloride was filtered off under suction.
The filtrate was diluted with water and the precipitated 1,3-di-n-butyl-7-(2'-oxopropyl)-8- carbethoxy-xanthine raw material filtered off under suction, washed with water, dried and recrystallised several times from acetone/water (80%:20%)diethylether and finally methanol/water (90%: 10%) to give a white powder.
Melting point: 108°C. Yield: 0.3g
Preparation 1
Preparation of 1,3-dibutyl-8-(2-hydroxypropyl)xanthine
To a suspension of sodium nitrite (2.4g) in methanol (36ml) 1,3-di-n-butyl-4-(-3-hydroxybutyl)aminouracil (9.6g) was added at about -5°C. At this temperature concentrated hydrochloric acid (3.5ml) was slowly added to give a pH of 3.
The reaction was completed, as indicated by tlc, by stirring for a further 30 minutes. The reaction mixture was poured into ice-water and extracted with chloroform several times, the chloroform washed with water.
The chloroform phase was dried with sodium-sulphate, filtered and the chloroform removed in vacuo to yield an oil which was dissolved in toluene (200ml) and heated to reflux for 3 hours to remove the reaction water with a water separator.
Then the reaction mixture was cooled to room temperature. After several hours a pale solid precipitated which was first recrystallised from methanol/water (80% : 20%) and then twice more from ethylacetate to yield 1,3-di-n-butyl-8-(2-hydroxypropyl)-xanthine. Melting point: 171ºC. Yield: 3,9g.
Preparation 2
Preparation of 1,3-di-n-butyl-8-carbethoxy-xanthine
To a suspension of sodium nitrite (1.45g) in methanol (22ml) 1,3-di-n-butyl-4-(carbethoxymethyl)-aminouracil (5.9g) was added at about -5°C. At this temperature concentrated hydrochloric acid (2.7ml) was dropwise added with stirring, then stirring continued until the reaction is complete (as indicated by tlc). The reaction mixture was then poured into water, extracted with chloroform several times and the chloroform phase washed with water. Then the chloroform phase was dried with sodium sulphate, filtered and the chloroform removed in vacuo to yield an oil and a solid, which was dissolved in toluene and heater to reflux for several hours with a water separator.
Then the toluene was removed in vacuo, the residue dissolved in methanol and treated with charcoal to remove the colour of the solution. The precipitated compound was recrystallised twice from methanol/water (90% : 10%) to yield the
1,3-d-n-butyl-8-carbethoxy-xanthine as a white powder. Melting point: 184°C Yield: 1,3g
Pharmacological Data
The activity of cyclic AMP phosphodierterase in homogenates of rat gastocnemius muscle was measured in the presence of various concentrations of compounds of formulae (I) using 0.31 μM cyclic AMP as substration. The reciprocal of the reaction rate was plotted on the y axis against the concentration of each compound on the x axis (Dixon plot). The apparent Ki value was estimated by extrapolating the steeper linear portion of the Dixon plot to the x axis and obtaining the negative intercept on the x axis.
Compounds of formula (I)
Apparent Ki value,
R1 R2 R3 n (μ Molar)
C4H9 C4H9 CH2CHOHCH3 2 18
C4H9 C4H9 COOC2H5 1 28.8

Claims

Claims
1. A compound of formula (I):
wherein,
R1 and R2 each independently represent a C2-6 alkyl group;
R3 represents a moiety -(CH2)mCHOHCH3; or a carboxyl group or a salt ester or amide thereof; and n and m each independently represent an integer 1, 2 or 3.
2. A compound according to claim 1, wherein R1 represents a butyl group.
3. A compound according to claim 1 or claim 2, wherein R2 represents a butyl group.
4. A compound according to any one of claims 1 to 3, wherein R3 represents a C1-6 alkyl ester of a carboxyl group.
5. A compound according to any one of claims 1 to 4, wherein when R3 represents a moiety -(CH2)m-CHOHCH3, m represents 1.
6. A compound according to any one of claims 1 to 5, wherein when n represents 1 or 2.
7. A compound according to claims 1, selected from:
1,3-dibutyl-7-(-3'-oxobutyl)-8-(2-hydroxypropyl)-xanthine; and
1,3-di-n-butyl-7-(2'-oxopropyl)-8-carbethoxy- xanthine.
8. A process for the preparation of a compound of formula (I) as claimed in claim 1, which process comprises reacting a compound of formula (II):
wherein R1, R2 and R3 are as defined in relation to formula (I), with:
(a) a compound of formula (III):
X-(CH2)n-CO.CH3 (III)
wherein n is as defined in relation to formula (I) and X represents a leaving group preferably a chlorine atom; or
(b) for compounds of formula (I) wherein n represents 2 or 3, a compound of formula (IV): CH2=CH- ( CH2 )p-CO-CH3 ( IV )
wherein p represents zero or 1.
9. A process according to claim 8, wherein the compound of formula (II) is provided in the form of a metallic salt.
10. A pharmaceutical composition which comprises a compound of formula (I), according to claim, and a pharmaceutically acceptable carrier therefor.
11. A compound of formula (I), according to claim 1, for use as an active therapeutic substance.
12. A compound of formula (I), according to claim 1, for use in the treatment and/or prophylaxis of; peripheral vascular disease, such as intermittant claudication and/or cerebrovascular disorders and/or disorders associated with cerebral senility.
13. The use of a compound of formula (I), according to claim 1, for the manufacture of a medicament for treating proliferative skin disease in human or non-human mammals.
14 A compound of formula (I),
wherein R1, R2 and R3 are as defined in relation to formula (I), useful as an intermediate.
EP19870900851 1986-01-21 1987-01-20 Xanthine compounds Withdrawn EP0259360A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8601371 1986-01-21
GB868601371A GB8601371D0 (en) 1986-01-21 1986-01-21 Compounds

Publications (1)

Publication Number Publication Date
EP0259360A1 true EP0259360A1 (en) 1988-03-16

Family

ID=10591686

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19870900851 Withdrawn EP0259360A1 (en) 1986-01-21 1987-01-20 Xanthine compounds

Country Status (3)

Country Link
EP (1) EP0259360A1 (en)
GB (1) GB8601371D0 (en)
WO (1) WO1987004435A2 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06508842A (en) 1991-07-05 1994-10-06 ビイク　グルデン　ロンベルク　ヒエーミツシエ　フアブリーク　ゲゼルシヤフト　ミツト　ベシユレンクテル　ハフツング Use of substituted pyridazines against skin diseases
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
MXPA03004926A (en) 2001-02-14 2005-02-14 Warner Lambert Co Thieno 2,3-d pyrimidindione derivatives as matrix metalloproteinase inhibitors.
CN104892610B (en) * 2015-05-27 2016-08-24 福建师范大学 A kind of preparation method of 8-ester group caffeine derivative

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE213711C (en) *
DE1245969B (en) * 1967-08-03 VEB Arzneimittelwerk Dresden, Radebeul Process for the production of xanthine derivatives
GB982079A (en) * 1962-05-01 1965-02-03 Dresden Arzneimittel Process for the production of xanthine derivatives
DE2462367A1 (en) * 1974-01-22 1976-11-11 Wuelfing J A Fa 7-(Oxo-alkyl)-1,3-dialkyl-xanthines - as agents for increasing blood flow in skeletal muscles

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8704435A2 *

Also Published As

Publication number Publication date
WO1987004435A2 (en) 1987-07-30
WO1987004435A3 (en) 1988-03-24
GB8601371D0 (en) 1986-02-26

Similar Documents

Publication Publication Date Title
KR0160768B1 (en) Pharmaceutical compositions containing 8-substituted xantrines
AU717913B2 (en) Xanthines and their therapeutic use
EP0682027B1 (en) Pyrrolopyrimidine derivatives with antiproliferative action
US5821366A (en) Xanthines and their therapeutic use
US5972936A (en) Benzofuran carboxamides and their therapeutic use
EP0946541B1 (en) Quinolines and their therapeutic use
DE69132291T2 (en) XANTINE DERIVATIVES
EP0873331B1 (en) Benzofuran carboxamides and sulphonamides
EP0369744B1 (en) Xanthine derivatives, process for their preparation and pharmaceutical compositions
JPS59101484A (en) Novel arylphenyl ether derivative and manufacture
EP0641344A1 (en) 8-substituted anthines as phosphodiesterase inhibitors
KR930001835B1 (en) Hypoglycemic hydantion derivatives
US4861789A (en) Dihydro-indene-amine-dihydrooxazoles
EP0089028B1 (en) Theophyllin derivatives, and process for their preparation
CN110088108B (en) Substituted pyrazoloazepin-4-ones and their use as phosphodiesterase inhibitors
EP0259360A1 (en) Xanthine compounds
EP0195496A2 (en) Use of xanthines in the treatment of proliferative skin disease
EP0260127A2 (en) Xanthine derivatives, their preparation and pharmaceutical compositions containing them
CN110167944B (en) Substituted pyrazoloazepin-4-ones and their use as phosphodiesterase inhibitors
FR2596051A1 (en) NOVEL DERIVATIVES OF PURINE, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS
US4696941A (en) 1,8-diacyloxy-10-acylanthrones
JPH0352465B2 (en)
DE69222818T2 (en) Condensed naphthyridine derivatives
IE44708B1 (en) Esters of hydroxyalkoxylkyl purines, their preparation, and pharmaceutical compositions containing them
KR20010005492A (en) Method of Making Arylamino Triazolopyridines

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): BE CH DE FR GB IT LI NL

D17D Deferred search report published (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19871222

RIN1 Information on inventor provided before grant (corrected)

Inventor name: ARCH, JONATHAN, R., S.BEECHAM PHARMACEUTICALS

Inventor name: GORING, JOACHIM