EP0651642A1 - Use of 1,3-dicyclopropymethyl-8-amino-xanthine for the treatment and prevention of type ii diabetes mellitus and obesity - Google Patents

Use of 1,3-dicyclopropymethyl-8-amino-xanthine for the treatment and prevention of type ii diabetes mellitus and obesity

Info

Publication number
EP0651642A1
EP0651642A1 EP93917883A EP93917883A EP0651642A1 EP 0651642 A1 EP0651642 A1 EP 0651642A1 EP 93917883 A EP93917883 A EP 93917883A EP 93917883 A EP93917883 A EP 93917883A EP 0651642 A1 EP0651642 A1 EP 0651642A1
Authority
EP
European Patent Office
Prior art keywords
treatment
compound
obesity
day
type
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Withdrawn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
EP93917883A
Other languages
German (de)
French (fr)
Inventor
Barbara Anne Smithkline Beecham Pharm. Spicer
Kathryn Gay Smithkline Beecham Pharm. Ellis
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.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
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 SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0651642A1 publication Critical patent/EP0651642A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a method for the treatment and/or prophylaxis of obesity or for the treatment of Type II diabetes and a compound for use in such method.
  • R* and R ⁇ each independendy represent alkyl or a moiety of formula (a):
  • A represents a substituted or unsubstituted cyclic hydrocarbon radical, providing that when R- represents methyl then R is not methyl;
  • R3a represents a halogen atom, a nitro group, or a group -NR4R5 wherein R4 and R ⁇ each independently represent hydrogen, alkyl or alkylcarbonyl or R ⁇ and R5 together with the nitrogen to which they are attached form an optionally substituted heterocyclic group.
  • Example 9 of EP 903030930.0 is 1,3-di-cyclopropymethyl- 8-amino xanthine (hereinafter preferred to as Compound 1).
  • the compounds in European application No. 90303093.0 are described inter alia as having activity in the treatment of cerebral vascular and neuronal degenerative disease and to act as phosphodiesterase inhibitors elevating cyclic AMP levels.
  • Compound 1 increases energy expenditure and also decreases food intake and is therefore of potential use in the treatment of obesity in mammals, including humans.
  • Compound I is also indicated to be effective in improving insulin sensitivity and hence to be effective in the treatment of Type II diabetes.
  • the present invention provides a method for the treatment and/or prophylaxis of obesity or for the treatment of Type II diabetes in mammals, such as humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective and/or prophylactic, non-toxic amount of Compound 1.
  • the present invention also provides Compound 1 for use in the treatment and/or prophylaxis of obesity or for the treatment of Type II diabetes.
  • a pharmaceutical composition for use in the treatment and/or prophylaxis of obesity or for the treatment of Type II diabetes which comprises Compound 1 and a pharmaceutically acceptable carrier.
  • the present invention provides the use of Compound 1 for the manufacture of a medicament for the treatment and/or prophylaxis of obesity or for the treatment of Type II diabetes.
  • the administration to the mammal may be by way of oral administration or parenteral administration.
  • a unit dose will normally contain 0.1 to 200 mg for example 5 to 50 mg or 1 to 20 mg, of Compound 1.
  • Unit doses will normally be administered once or more than once a day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.5 to 500 mg, for example 50 to 250 mg or 10 to 150 mg, that is in the range of approximately 0.001 to 10 mg kg day, more usually 1 to 3 mg/kg day or 0.2 to 2.5 mg/kg/day, for example 0.7 to 2 mg/kg/day.
  • Compound 1 is administered in the form of a unit-dose composition, such as a unit dose oral or parenteral composition.
  • 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.
  • 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 j>-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • 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 monoole
  • Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
  • fluid unit dose forms are prepared containing Compound 1 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 and filter 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.
  • test animals were 12 male and 12 female, Sprague-Dawley rats (body weights 200-270g, approximately 8-10 weeks of age).
  • the rats were fed on SQC rat and mouse maintenance diet No. 1; diet and drinking water were freely available.
  • test compound was administered orally to the treatment group by oesophageal gavage as a suspension in 1% aqueous methylcellulose at a dose level of 1 mg/kg/day. Animals were dosed at a constant dose volume of lml/lOOg of bodyweight.
  • mice Female CFLP mice (29-37g) were fed ad libitium on a pelleted diet and housed in pairs on a light cycle in which lights were off from 6pm to 6am. Compound 1 or vehicle was given at 2pm and food intake and body weight changes were measured over the following 20 hours. Results are means ⁇ SEM of 5 (food intake) or 10 (body weight) values.

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  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A method for the treatment and/or prophylaxis of obesity or for the treatment of Type II diabetes in mammals, such as humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective and/or prophylactic, non-toxic amount of Compound 1 (1,3-dicyclopropymethyl-8-amino-xanthine).

Description

USE OF 1 -3-DICYCL0PR0PYMETHYL-8-AMIN0-XANTHINE FOR THE TREATMENT AND PREVENTION OF TYPE II DIABETES MELLITUS AND OBESITY
The present invention relates to a method for the treatment and/or prophylaxis of obesity or for the treatment of Type II diabetes and a compound for use in such method.
European patent application, Publication No. 0389282 describes compounds of formula (A):
or if appropriate a pharmaceutically acceptable salt thereof, wherein R* and R^ each independendy represent alkyl or a moiety of formula (a):
-(CH2)m-A (a)
wherein m represents zero or an integer 1, 2 or 3, A represents a substituted or unsubstituted cyclic hydrocarbon radical, providing that when R- represents methyl then R is not methyl; and
R3a represents a halogen atom, a nitro group, or a group -NR4R5 wherein R4 and R^ each independently represent hydrogen, alkyl or alkylcarbonyl or R^ and R5 together with the nitrogen to which they are attached form an optionally substituted heterocyclic group.
Example 9 of EP 903030930.0 is 1,3-di-cyclopropymethyl- 8-amino xanthine (hereinafter preferred to as Compound 1). The compounds in European application No. 90303093.0 are described inter alia as having activity in the treatment of cerebral vascular and neuronal degenerative disease and to act as phosphodiesterase inhibitors elevating cyclic AMP levels.
It has now surprisingly been discovered that Compound 1 increases energy expenditure and also decreases food intake and is therefore of potential use in the treatment of obesity in mammals, including humans.
Compound I is also indicated to be effective in improving insulin sensitivity and hence to be effective in the treatment of Type II diabetes.
Accordingly, the present invention provides a method for the treatment and/or prophylaxis of obesity or for the treatment of Type II diabetes in mammals, such as humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective and/or prophylactic, non-toxic amount of Compound 1.
The present invention also provides Compound 1 for use in the treatment and/or prophylaxis of obesity or for the treatment of Type II diabetes. In a further aspect of the present invention there is provided a pharmaceutical composition for use in the treatment and/or prophylaxis of obesity or for the treatment of Type II diabetes which comprises Compound 1 and a pharmaceutically acceptable carrier.
In yet a further aspect, the present invention provides the use of Compound 1 for the manufacture of a medicament for the treatment and/or prophylaxis of obesity or for the treatment of Type II diabetes.
The administration to the mammal may be by way of oral administration or parenteral administration.
An amount effective to treat obesity or of Type II diabetes depends on the usual factors such as the nature and severity of the problem and the weight of the mammal. However, a unit dose will normally contain 0.1 to 200 mg for example 5 to 50 mg or 1 to 20 mg, of Compound 1. Unit doses will normally be administered once or more than once a day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 0.5 to 500 mg, for example 50 to 250 mg or 10 to 150 mg, that is in the range of approximately 0.001 to 10 mg kg day, more usually 1 to 3 mg/kg day or 0.2 to 2.5 mg/kg/day, for example 0.7 to 2 mg/kg/day.
Preferably, Compound 1 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 j>-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 Compound 1 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 and filter 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.
The following pharmacological data illustrate the activity of Compound 1. PHARMACOLOGICAL DATA
Experimental Procedure
The test animals were 12 male and 12 female, Sprague-Dawley rats (body weights 200-270g, approximately 8-10 weeks of age).
The rats were fed on SQC rat and mouse maintenance diet No. 1; diet and drinking water were freely available.
Temperature and relative humidity were maintained at 21 ± 2°C and 55 ± 10% respectively, lighting was controlled to give 12 hours light per 24 hours. After 6 days acclimatisation the animals were grouped into two groups (control group and treatment group) by stratified random allocation to give approximately equal group mean bodyweights. Each group consisted of 6 males and 6 females. The rats were housed in groups of 3. Dosing of all animals commenced on the same day after a 4 day baseline observation period. All animals were dosed once a day, for 10 days.
The test compound was administered orally to the treatment group by oesophageal gavage as a suspension in 1% aqueous methylcellulose at a dose level of 1 mg/kg/day. Animals were dosed at a constant dose volume of lml/lOOg of bodyweight.
Control animals received the vehicle alone at the same dose volume. Food intake and water intake were recorded daily.
Results
INTER-GROUP COMPARISON OF BODY WEIGHTS (g)
Control Treatment Group Group
Days
Males
266.8NS -1 4.1 (6)
11 268.5** -16 12.0 (6)
Females
-2 3.0 (6)
11 211.2* -7 8.5 (6)
% differences calculated on unrounded data Significance levels for Student 't' -test (2-tailed): * P < 0.05 ** P < 0.01 NS not significant NT not tested 2. INTER-GROUP COMPARISON OF BODY WEIGHT GAINS (g)
% differences calculated on unrounded data Significance levels for Student 't' -test (2-tailed): *P<0.05 **P<0.01
3. INTER-GROUP COMPARISON OF FOOD CONSUMPTION
(g/animal/day)
% differences calculated on unrounded data 4. INTER-GROUP COMPARISON OF WATER CONSUMPTION
(g/animal/day)
% differences calculated on unrounded data
1. 19 HOUR FOOD INTAKE IN RATS
Male Sprague-Dawley rats (420-550g) were fed ad libitium on a pelleted diet and housed singly on a light cycle in which lights were off from 6pm to 6am. Compound 1 or vehicle was given at 2.30 pm and food intake and body weight change were measured from this time to 10 am the following day. Results are mean ± SEM (n=6).
Dose of 0 1 Compound 1 (mg kg p.o.)
Food intake (g) 25.0 ± 2.3 11.0 1 3.51 3.8 ± 2.8 - Weight loss (g) 1.0 ± 1.9 27.0 ± 1.21 32.0 ± 3.4l
lp<0.001 compared to control value. 2. 20 HOUR FOOD INTAKE IN MICE
Female CFLP mice (29-37g) were fed ad libitium on a pelleted diet and housed in pairs on a light cycle in which lights were off from 6pm to 6am. Compound 1 or vehicle was given at 2pm and food intake and body weight changes were measured over the following 20 hours. Results are means ± SEM of 5 (food intake) or 10 (body weight) values.
Dose of 0 0.3 1 3 5 Compound 1 (mg/kg p.o.)
*P<0.05; **P<0.01, ***P<0.001 compared to control values.
3. 4HOURFOODINTAKEINMICE
Female CFLP mice (22-34g) were housed in pairs and fed on a pelleted diet. They were adapted over a period of a week to a light cycle in which lights were off from 12 noon to 12 midnight. Compound 1 or vehicle was dosed between 11.30am and 12.15pm and food intake was assessed 4 hours later (3.30pm to 4.15 pm). Results are means ± SEM (n=5).
Toxicology
No adverse toxicological effects were established in die abovementioned tests. The physical condition of the test animals revealed no indication of any adverse responsle to treatment.

Claims

Claims
1. A method for the treatment and/or prophylaxis of obesity or for the treatment of Type π diabetes in mammals, such as humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective and/or prophylactic, non-toxic amount of 1,3-di-cyclopropymethyl- 8-amino xanthine (Compound 1).
2. A method according to claim 1, wherein the administration of Compound 1 is by way of oral administration or parenteral administration.
3. A method according to claim 1, wherein Compound 1 is administered in the form of a unit-dose composition.
4. A method according to claim 3, wherein the unit dose contains from 0.1 to 200 mg of Compound 1.
5. A method according to claim 3, wherein the unit dose contains from 5 to 50 mg or from 1 to 20 mg of Compound 1.
6. A method according to claim 1, wherein Compound 1 is administered in the range of approximately 0.001 to 10 mg/kg day.
7. A method according to claim 1, wherein Compound 1 is administered in the range of 1 to 3 mg/kg/day, 0.2 to 2.5 mg/kg/day or 0.7 to 2 mg/kg/day.
8. The use of 1,3-di-cyclopropymethyl- 8-amino xanthine (Compound 1) for the manufacture of a medicament for the treatment and/or prophylaxis of obesity or for the treatment of Type II diabetes.
9. A pharmaceutical composition for use in the treatment and/or prophylaxis of obesity or for the treatment of Type II diabetes which comprises 1,3-di-cyclopropymethyl- 8-amino xanthine (Compound 1) and a pharmaceutically acceptable carrier.
EP93917883A 1992-07-23 1993-07-21 Use of 1,3-dicyclopropymethyl-8-amino-xanthine for the treatment and prevention of type ii diabetes mellitus and obesity Withdrawn EP0651642A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9215633 1992-07-23
GB929215633A GB9215633D0 (en) 1992-07-23 1992-07-23 Novel treatment
PCT/GB1993/001539 WO1994002150A1 (en) 1992-07-23 1993-07-21 Use of 1,3-dicyclopropymethyl-8-amino-xanthine for the treatment and prevention of type ii diabetes mellitus and obesity

Publications (1)

Publication Number Publication Date
EP0651642A1 true EP0651642A1 (en) 1995-05-10

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Country Link
EP (1) EP0651642A1 (en)
JP (1) JPH07509456A (en)
CN (1) CN1043610C (en)
AU (1) AU4714393A (en)
GB (1) GB9215633D0 (en)
MX (1) MX9304435A (en)
TW (1) TW258663B (en)
WO (1) WO1994002150A1 (en)
ZA (1) ZA935339B (en)

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CN1043610C (en) 1999-06-16
JPH07509456A (en) 1995-10-19
AU4714393A (en) 1994-02-14
WO1994002150A1 (en) 1994-02-03
ZA935339B (en) 1995-01-18
CN1114880A (en) 1996-01-17
TW258663B (en) 1995-10-01
MX9304435A (en) 1994-04-29
GB9215633D0 (en) 1992-09-09

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