WO1987004435A2 - Composes de xanthine - Google Patents

Composes de xanthine Download PDF

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Publication number
WO1987004435A2
WO1987004435A2 PCT/GB1987/000033 GB8700033W WO8704435A2 WO 1987004435 A2 WO1987004435 A2 WO 1987004435A2 GB 8700033 W GB8700033 W GB 8700033W WO 8704435 A2 WO8704435 A2 WO 8704435A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
butyl
xanthine
compounds
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.)
Ceased
Application number
PCT/GB1987/000033
Other languages
English (en)
Other versions
WO1987004435A3 (fr
Inventor
Joachim Goring
Jonathan Robert Sanders 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 WO1987004435A2 publication Critical patent/WO1987004435A2/fr
Publication of WO1987004435A3 publication Critical patent/WO1987004435A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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.

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  • 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.
PCT/GB1987/000033 1986-01-21 1987-01-20 Composes de xanthine Ceased WO1987004435A2 (fr)

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 (2)

Publication Number Publication Date
WO1987004435A2 true WO1987004435A2 (fr) 1987-07-30
WO1987004435A3 WO1987004435A3 (fr) 1988-03-24

Family

ID=10591686

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1987/000033 Ceased WO1987004435A2 (fr) 1986-01-21 1987-01-20 Composes de xanthine

Country Status (3)

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

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0523513A1 (fr) 1991-07-05 1993-01-20 Byk Gulden Lomberg Chemische Fabrik GmbH Utilisation de pyridazines substituées dans le traitement des dermatoses
EP0570831A3 (fr) * 1992-05-20 1994-03-16 Hoechst Ag
EP1370562A1 (fr) 2001-02-14 2003-12-17 Warner-Lambert Company LLC Derives de thieno'2,3-d pyrimidinone utilises comme inhibiteurs de metalloproteinases matricielles
CN104892610A (zh) * 2015-05-27 2015-09-09 福建师范大学 一种8-酯基咖啡因衍生物的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1245969B (de) * 1967-08-03 VEB Arzneimittelwerk Dresden, Radebeul Verfahren zur Herstellung von Xanthinderivaten
DE213711C (fr) *
GB982079A (en) * 1962-05-01 1965-02-03 Dresden Arzneimittel Process for the production of xanthine derivatives
DE2462367A1 (de) * 1974-01-22 1976-11-11 Wuelfing J A Fa 7-(oxoalkyl)-1,3-dialkylxanthine enthaltende arzneimittelzubereitungen

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0523513A1 (fr) 1991-07-05 1993-01-20 Byk Gulden Lomberg Chemische Fabrik GmbH Utilisation de pyridazines substituées dans le traitement des dermatoses
EP0570831A3 (fr) * 1992-05-20 1994-03-16 Hoechst Ag
EP1370562A1 (fr) 2001-02-14 2003-12-17 Warner-Lambert Company LLC Derives de thieno'2,3-d pyrimidinone utilises comme inhibiteurs de metalloproteinases matricielles
CN104892610A (zh) * 2015-05-27 2015-09-09 福建师范大学 一种8-酯基咖啡因衍生物的制备方法

Also Published As

Publication number Publication date
WO1987004435A3 (fr) 1988-03-24
GB8601371D0 (en) 1986-02-26
EP0259360A1 (fr) 1988-03-16

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