CA2376886A1 - Therapeutic agents - Google Patents
Therapeutic agents Download PDFInfo
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- CA2376886A1 CA2376886A1 CA002376886A CA2376886A CA2376886A1 CA 2376886 A1 CA2376886 A1 CA 2376886A1 CA 002376886 A CA002376886 A CA 002376886A CA 2376886 A CA2376886 A CA 2376886A CA 2376886 A1 CA2376886 A1 CA 2376886A1
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- triazolo
- ethyl
- pyrimidine
- chlorophenoxy
- compound
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
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- 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
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- 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
- A61P3/04—Anorexiants; Antiobesity agents
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- 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
- A61P3/06—Antihyperlipidemics
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- 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
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- 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
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Abstract
A method of treating obesity and related conditions comprising the administration of a therapeutically effective amount of a compound of formul a (I) including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof in which: R1 represents H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C1-6alkyl, C1-6alkoxy or C1-6alkanoyl; R2 an d R3 independently represent H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C1-6alkyl, C 1- 6alkoxy, C1-6alkanoyl, C1-6alkylthio, C1-6alkylsulphinyl, C1-6alkylsulphonyl or hydroxy; R4 and R5 independently represent H, C1-6alkyl or R4 and R5 combined together with the carbon atom to which they are attached represent C3- 6cycloalkylidene (each alkyl or cycloalkylidene being optionally substituted with one or more of halo, cyano, hydroxy, amino or C1-6alkyl); and R6, R7 an d R8 independently represent H, halo, hydroxy, mercapto, nitro, cyano or one o f the following groups (optionally substituted with one or more of halo, cyano , hydroxy or amino; and any nitrogen atom being optionally substituted with on e or more C1-6alkyl): C1-6alkyl, C1-6alkanoyl, C1-6alkoxy, C2-6alkoxycarbonyl, carboxy, C1-6alkanoyloxy, C1-6alkylthio, C1-6alkylsulphinyl, C1- 6alkylsulphonyl, C1-6alkylsulphonylamino, sulphamoyl, carbamoyl, C2- 6alkylcarbamoyl or C1-6alkanoylamino; to a mammal in need thereof.
Description
Therapeutic Agents The present invention relates to 1,2,4-triazolo[1,5-a]pyrimidines which are useful in the treatment and/or prophylaxis of obesity and related conditions including eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
Compounds of formula A
Rs R~
O
Ra RQ C-RS A
'N~ \
w ~ N~ R, R N
z in which R~ represents H or optionally substituted alkyl, alkoxy or alkanoyl;
R2 and R3 independently represent H or optionally substituted alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl or sulphonyl; R4 and R5 independently represent H, alkyl or together with the carbon atom to which they are attached represent optionally substituted cycloalkylidene; and R6, R~ and R8 independently represent H, halo hydroxy, mercapto, cyano or optionally substituted alkyl, alkanoyl, alkoxy, alkoxycarbonyl, carboxy, alkanoyloxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, sulphamoyl, carbamoyl, alkylcarbamoyl or alkanoylamino; processes for their preparation, and their use in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, head injuries and haemorrhage are described in W095/10521 (Knoll AG). A process for preparing these compounds is disclosed in W098/07724 (Knoll AG).
The present invention provides a method of treating obesity comprising the administration of a therapeutically effective amount of a compound of formula I
Compounds of formula A
Rs R~
O
Ra RQ C-RS A
'N~ \
w ~ N~ R, R N
z in which R~ represents H or optionally substituted alkyl, alkoxy or alkanoyl;
R2 and R3 independently represent H or optionally substituted alkyl, alkoxy, alkanoyl, alkylthio, alkylsulphinyl or sulphonyl; R4 and R5 independently represent H, alkyl or together with the carbon atom to which they are attached represent optionally substituted cycloalkylidene; and R6, R~ and R8 independently represent H, halo hydroxy, mercapto, cyano or optionally substituted alkyl, alkanoyl, alkoxy, alkoxycarbonyl, carboxy, alkanoyloxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, sulphamoyl, carbamoyl, alkylcarbamoyl or alkanoylamino; processes for their preparation, and their use in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, head injuries and haemorrhage are described in W095/10521 (Knoll AG). A process for preparing these compounds is disclosed in W098/07724 (Knoll AG).
The present invention provides a method of treating obesity comprising the administration of a therapeutically effective amount of a compound of formula I
Rs O ~ R~
R
Ra C-Rs a I
N~N
~~- R
~N ~ N i including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof in which:
R~ represents H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C~_salkyl, Ci_salkoxy or C~_salkanoyl;
R2 and R3 independently represent H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C~_salkyl, C~_salkoxy, C~_salkanoyl, C1_salkylthio, C~_salkylsulphinyl, C~_salkylsulphonyl or hydroxy;
R4 and R5 independently represent H, C~_salkyl or R4 and R5 combined together with the carbon atom to which they are attached represent C3_6cycloalkylidene (each alkyl or cycloalkylidene being optionally substituted with one or more of halo, cyano, hydroxy, amino or C~_salkyl); and R6, R~ and R$ independently represent H, halo, hydroxy, mercapto, nitro, cyano or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino; and any nitrogen atom being optionally substituted with one or more C~_6 alkyl): C~_6alkyl, C~_salkanoyl, C~_salkoxy, C2_salkoxycarbonyl, carboxy, C~_salkanoyloxy, C~_salkylthio, C~_salkylsulphinyl, C~_salkylsulphonyl, C~_salkyl-sulphonylamino, sulphamoyl, carbamoyl, C2_salkylcarbamoyl or C~_salkanoylamino;
to a mammal in need thereof.
It will be understood that any group mentioned herein which contains a chain of three or more carbon atoms signifies a group in which the chain may be straight or branched. For example, an alkyl group may comprise propyl which includes n-propyl and isopropyl and butyl which includes n-butyl, sec-butyl, isobutyl and tert-butyl. The total number of carbon atoms is specified herein for certain substituents, for example C,_6 signifies an alkyl group having from 1 to 6 carbon atoms. The term 'halo' as used herein signifies fluoro, chloro, bromo and iodo. The term 'optionally substituted' as used herein, unless immediately followed by a list of substituent groups, means optionally substituted with one or more group or groups selected from halo, cyano, hydroxy and amino. When the phenyl ring substituents R6, R, and Ra are other than H, the substituent may replace any H attached to a carbon atom in the ring and may be located at any such position of the ring, ie up to three of positions 2, 3, 4 and/or 5.
Specific compounds of formula I are:-7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
7-[1-(4-bromophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(4-cyanophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(4-trifluoromethylphenoxy)ethyl]-1,2,4-triazolo [1,5-a]pyrimidine;
7-[1-(4-methoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
7-{1-(4-trifluoromethoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-acetylphenoxy)ethyl]-1,2,4-triazolo[1,5-aJ-pyrimidine;
7-{1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(4-methylsulphinylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methylsulphonylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-{1-[4-(ethylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(3-chlorophenoxy)ethyl]-1,2,4-triazolo [1,5-a]pyrimidine;
7-[1-(2,4-difluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(2,4-dichlorophenoxy)ethyl]-1,2,4-triazolo [1,5-a]pyrimidine;
7-[1-(3,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(2-chloro-4-fluorophenoxy)ethyl]-1,2,4-triazolo[1, 5-a]pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-2-methyl-1,2,4-triazolo [1,5-a]pyrimidine;
7-(4-chlorophenoxymethyl)-1,2,4-triazolo[1,5-a] pyrimidine;
7-[1-(4-chlorophenoxy)-1-methylethyl]-1,2,4-triazolo [1,5-a]pyrimidine;
7-(1-(4-chlorophenoxy)propyl]-1,2,4-triazolo[1,5-a]-pyrimidine; and 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of their stereoisomers; and pharmaceutically acceptable salts thereof.
Specific examples of the stereoisomers of compounds of formula I are:-(+)-7-(1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine; and (-)-7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine (+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
(-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
(+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol; and (-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of and pharmaceutically acceptable salts thereof.
Preferred compound of formula I are 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidin-5-of including the racemates, enantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof. More preferred compounds of formula I
are (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and (S)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and pharmaceutically acceptable salts thereof. A most preferred compound of formula I is (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and pharmaceutically acceptable salts thereof.
The compounds of formula I may be prepared as described in W095/10521 (Knoll AG) and W098/07724 (Knoll AG).
The compound of formula I may be administered in any of the known pharmaceutical dosage forms. The amount of the compound to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound to be administered will be in the range 0.1 to 1000 mg preferably 1 to 500 mg per day given in one or more doses.
Oral dosage forms are the preferred compositions for use in the present invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oil suspensions.
The 5 excipients used in the preparation of these compositions are the excipients known in the pharmacist's art. Tablets may be prepared from a mixture of the active compound with fillers, for example calcium phosphate; disintegrating agents, for example maize starch; lubricating agents, for example magnesium stearate;
binders, for example microcrystalline cellulose or polyvinylpyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods.
The tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethylcellulose phthalate.
The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner. The contents of the capsule may be formulated using known methods so as to give sustained release of the active compound. The tablets and capsules may conveniently each contain 1 to 500 mg of the active compound.
Preferably the tablets and capsules each contain 5, 10, 15, 20, 25, 30, 50,100 ,250 or 500mg.
Other dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxy-methylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil. The active compound may be formulated into granules with or without additional excipients. The granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example, water) before ingestion. The granules may contain disintegrants, eg an effervescent couple formed from an acid and a carbonate or bicarbonate salt to facilitate dispersion in the liquid medium.
R
Ra C-Rs a I
N~N
~~- R
~N ~ N i including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof in which:
R~ represents H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C~_salkyl, Ci_salkoxy or C~_salkanoyl;
R2 and R3 independently represent H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C~_salkyl, C~_salkoxy, C~_salkanoyl, C1_salkylthio, C~_salkylsulphinyl, C~_salkylsulphonyl or hydroxy;
R4 and R5 independently represent H, C~_salkyl or R4 and R5 combined together with the carbon atom to which they are attached represent C3_6cycloalkylidene (each alkyl or cycloalkylidene being optionally substituted with one or more of halo, cyano, hydroxy, amino or C~_salkyl); and R6, R~ and R$ independently represent H, halo, hydroxy, mercapto, nitro, cyano or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino; and any nitrogen atom being optionally substituted with one or more C~_6 alkyl): C~_6alkyl, C~_salkanoyl, C~_salkoxy, C2_salkoxycarbonyl, carboxy, C~_salkanoyloxy, C~_salkylthio, C~_salkylsulphinyl, C~_salkylsulphonyl, C~_salkyl-sulphonylamino, sulphamoyl, carbamoyl, C2_salkylcarbamoyl or C~_salkanoylamino;
to a mammal in need thereof.
It will be understood that any group mentioned herein which contains a chain of three or more carbon atoms signifies a group in which the chain may be straight or branched. For example, an alkyl group may comprise propyl which includes n-propyl and isopropyl and butyl which includes n-butyl, sec-butyl, isobutyl and tert-butyl. The total number of carbon atoms is specified herein for certain substituents, for example C,_6 signifies an alkyl group having from 1 to 6 carbon atoms. The term 'halo' as used herein signifies fluoro, chloro, bromo and iodo. The term 'optionally substituted' as used herein, unless immediately followed by a list of substituent groups, means optionally substituted with one or more group or groups selected from halo, cyano, hydroxy and amino. When the phenyl ring substituents R6, R, and Ra are other than H, the substituent may replace any H attached to a carbon atom in the ring and may be located at any such position of the ring, ie up to three of positions 2, 3, 4 and/or 5.
Specific compounds of formula I are:-7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
7-[1-(4-bromophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(4-cyanophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(4-trifluoromethylphenoxy)ethyl]-1,2,4-triazolo [1,5-a]pyrimidine;
7-[1-(4-methoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
7-{1-(4-trifluoromethoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-acetylphenoxy)ethyl]-1,2,4-triazolo[1,5-aJ-pyrimidine;
7-{1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(4-methylsulphinylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methylsulphonylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-{1-[4-(ethylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(3-chlorophenoxy)ethyl]-1,2,4-triazolo [1,5-a]pyrimidine;
7-[1-(2,4-difluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(2,4-dichlorophenoxy)ethyl]-1,2,4-triazolo [1,5-a]pyrimidine;
7-[1-(3,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(2-chloro-4-fluorophenoxy)ethyl]-1,2,4-triazolo[1, 5-a]pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-2-methyl-1,2,4-triazolo [1,5-a]pyrimidine;
7-(4-chlorophenoxymethyl)-1,2,4-triazolo[1,5-a] pyrimidine;
7-[1-(4-chlorophenoxy)-1-methylethyl]-1,2,4-triazolo [1,5-a]pyrimidine;
7-(1-(4-chlorophenoxy)propyl]-1,2,4-triazolo[1,5-a]-pyrimidine; and 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of their stereoisomers; and pharmaceutically acceptable salts thereof.
Specific examples of the stereoisomers of compounds of formula I are:-(+)-7-(1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine; and (-)-7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine (+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
(-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
(+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol; and (-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of and pharmaceutically acceptable salts thereof.
Preferred compound of formula I are 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidin-5-of including the racemates, enantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof. More preferred compounds of formula I
are (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and (S)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and pharmaceutically acceptable salts thereof. A most preferred compound of formula I is (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and pharmaceutically acceptable salts thereof.
The compounds of formula I may be prepared as described in W095/10521 (Knoll AG) and W098/07724 (Knoll AG).
The compound of formula I may be administered in any of the known pharmaceutical dosage forms. The amount of the compound to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound to be administered will be in the range 0.1 to 1000 mg preferably 1 to 500 mg per day given in one or more doses.
Oral dosage forms are the preferred compositions for use in the present invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oil suspensions.
The 5 excipients used in the preparation of these compositions are the excipients known in the pharmacist's art. Tablets may be prepared from a mixture of the active compound with fillers, for example calcium phosphate; disintegrating agents, for example maize starch; lubricating agents, for example magnesium stearate;
binders, for example microcrystalline cellulose or polyvinylpyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods.
The tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethylcellulose phthalate.
The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner. The contents of the capsule may be formulated using known methods so as to give sustained release of the active compound. The tablets and capsules may conveniently each contain 1 to 500 mg of the active compound.
Preferably the tablets and capsules each contain 5, 10, 15, 20, 25, 30, 50,100 ,250 or 500mg.
Other dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxy-methylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil. The active compound may be formulated into granules with or without additional excipients. The granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example, water) before ingestion. The granules may contain disintegrants, eg an effervescent couple formed from an acid and a carbonate or bicarbonate salt to facilitate dispersion in the liquid medium.
The therapeutically active compounds of formula I may be formulated into a composition which the patient retains in his mouth so that the active compound is administered through the mucosa of the mouth.
Dosage forms suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.
Dosage forms suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.
Dosage forms for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. A suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, e.g. paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol.
Alternatively the active compounds may be dispersed in a pharmaceutically acceptable cream, gel or ointment base. The amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin.
The therapeutically active compound of formula I may be formulated into a composition which is dispersed as an aerosol into the patients oral or nasal cavity.
Such aerosols may be administered from a pump pack or from a pressurised pack containing a volatile propellant.
The therapeutically active compounds of formula I used in the method of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body. Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as an oily suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or a lipophilic ester or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused. The support may be a single body containing all of the compound or a series of several bodies each containing part of the compound to be delivered. The amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.
In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
The following in vivo test supports the finding that compounds of formula I
have efficacy in the treatment of obesity.
There is evidence from preclinical studies that (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine given to rodents as a suspension in 0.4%
Cellosize in purified water BP caused dose-related reductions in food intake from 5-50mg/kg po.
In marmosets, animals lost bodyweight in response to (R)-7-(1-(4 chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine (100-300 mg/kg po given in the same suspension as above) without altering the animals' food intake.
The present invention also comprises a compound of Formula I for use as a medicament.
The pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I may be used to treat obesity, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress in mammals particularly humans, and as an aid to smoking cessation in human beings.
Whilst the precise amount of active compound administered in such treatment will depend on a number of factors, for example the age of the patient, the severity of the condition and the past medical history, and always lies within the sound discretion of the administering physician, the amount of active compound administered per day is in the range 1 to 1000 mg preferably 5 to 500 mg given in single or divided doses at one or more times during the day.
In yet another aspect, the present invention provides the use of a compound of Formula I in the manufacture of a medicament for use in the treatment of obesity, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
The present invention also provides a method of treating obesity, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia and stress which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
The present invention also provides a method of reducing the craving to smoke in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof. The present invention also provides a method of reducing weight gain after smoking cessation in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
In addition the compounds of the present invention may be useful in the treatment or prevention of metabolic diseases and conditions arising therefrom, for example non exercise activity thermogenesis and increased metabolic rate.
The compounds of the present invention may be useful in preventing cardio-vascular disease, and in reducing platelet adhesiveness, in aiding weight loss after pregnancy and in aiding weight loss after smoking cessation.
Dosage forms suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.
Dosage forms suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.
Dosage forms for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. A suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, e.g. paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol.
Alternatively the active compounds may be dispersed in a pharmaceutically acceptable cream, gel or ointment base. The amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin.
The therapeutically active compound of formula I may be formulated into a composition which is dispersed as an aerosol into the patients oral or nasal cavity.
Such aerosols may be administered from a pump pack or from a pressurised pack containing a volatile propellant.
The therapeutically active compounds of formula I used in the method of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body. Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as an oily suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or a lipophilic ester or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused. The support may be a single body containing all of the compound or a series of several bodies each containing part of the compound to be delivered. The amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.
In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
The following in vivo test supports the finding that compounds of formula I
have efficacy in the treatment of obesity.
There is evidence from preclinical studies that (R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine given to rodents as a suspension in 0.4%
Cellosize in purified water BP caused dose-related reductions in food intake from 5-50mg/kg po.
In marmosets, animals lost bodyweight in response to (R)-7-(1-(4 chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine (100-300 mg/kg po given in the same suspension as above) without altering the animals' food intake.
The present invention also comprises a compound of Formula I for use as a medicament.
The pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I may be used to treat obesity, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress in mammals particularly humans, and as an aid to smoking cessation in human beings.
Whilst the precise amount of active compound administered in such treatment will depend on a number of factors, for example the age of the patient, the severity of the condition and the past medical history, and always lies within the sound discretion of the administering physician, the amount of active compound administered per day is in the range 1 to 1000 mg preferably 5 to 500 mg given in single or divided doses at one or more times during the day.
In yet another aspect, the present invention provides the use of a compound of Formula I in the manufacture of a medicament for use in the treatment of obesity, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress, and as an aid to smoking cessation.
The present invention also provides a method of treating obesity, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia and stress which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
The present invention also provides a method of reducing the craving to smoke in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof. The present invention also provides a method of reducing weight gain after smoking cessation in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
In addition the compounds of the present invention may be useful in the treatment or prevention of metabolic diseases and conditions arising therefrom, for example non exercise activity thermogenesis and increased metabolic rate.
The compounds of the present invention may be useful in preventing cardio-vascular disease, and in reducing platelet adhesiveness, in aiding weight loss after pregnancy and in aiding weight loss after smoking cessation.
Accordingly the present invention further provides a method for, and the use of a compound of formula I in the manufacture of the medicament for, thetreament of obesity. The present invention also provides a method for, and the use of a compound of formula I in the manufacture of a medicament for, the prophylaxis of obesity.
In an alternative embodiment the present invention provides a pharmaceutical composition for the treatment and/or the prevention of obesity comprising a therapeutically effective amount of a compound of formula I including enantiomers and pharmaceutically acceptable salts thereof in conjunction with a pharmaceutically acceptable diluent or carrier.
In an alternative embodiment the present invention provides a method for the prophylaxis of obesity comprising the administration of a compound of formula I
including enantiomers and pharmaceutically acceptable salts thereof in conjunction with a pharmaceutically acceptable diluent or carrier to a mammal in need thereof.
The invention is illustrated by the following Examples which are given by way of example only. The final product of each of these Examples was characterised by one or more of the following procedures: gas-liquid chromatography; high performance liquid chromatography; elemental analysis; nuclear magnetic resonance spectroscopy and infrared spectroscopy.
The compounds of the present invention are prepared as described in W095/10521 (Knoll AG) and W098/07724 (Knoll AG) which are incorporated herein by reference.
Example 1 1 a) A mixture of 2-(4-chlorophenoxy)propionic acid (30.0 g) in toluene (300 ml) was added to a solution of thionyl chloride (22.0 ml) and dimethylformamide (2 ml) in toluene (150 ml) at 60-70°C with stirring. The mixture was stirred for 18 hours at 70-80°C and then evaporated under reduced pressure to give the acid chloride. A solution of Meldrum's acid (23.5 g) in dichloromethane (90 ml) was cooled to 0-5°C under nitrogen and pyridine (33 ml) was added at 0-5°C. To this mixture was added a solution of the acid chloride prepared above in dichloromethane (90 ml) dropwise keeping the temperature below 5 5°C. The mixture was stirred for 1 hour at 0-5°C and then at ambient temperature for 18 hours. The mixture was diluted with dichloromethane (150 ml) and washed with 2M hydrochloric acid and then with saturated sodium bicarbonate solution and then water. The bicarbonate washes were acidified with 5M hydrochloric acid and extracted into dichloromethane.
In an alternative embodiment the present invention provides a pharmaceutical composition for the treatment and/or the prevention of obesity comprising a therapeutically effective amount of a compound of formula I including enantiomers and pharmaceutically acceptable salts thereof in conjunction with a pharmaceutically acceptable diluent or carrier.
In an alternative embodiment the present invention provides a method for the prophylaxis of obesity comprising the administration of a compound of formula I
including enantiomers and pharmaceutically acceptable salts thereof in conjunction with a pharmaceutically acceptable diluent or carrier to a mammal in need thereof.
The invention is illustrated by the following Examples which are given by way of example only. The final product of each of these Examples was characterised by one or more of the following procedures: gas-liquid chromatography; high performance liquid chromatography; elemental analysis; nuclear magnetic resonance spectroscopy and infrared spectroscopy.
The compounds of the present invention are prepared as described in W095/10521 (Knoll AG) and W098/07724 (Knoll AG) which are incorporated herein by reference.
Example 1 1 a) A mixture of 2-(4-chlorophenoxy)propionic acid (30.0 g) in toluene (300 ml) was added to a solution of thionyl chloride (22.0 ml) and dimethylformamide (2 ml) in toluene (150 ml) at 60-70°C with stirring. The mixture was stirred for 18 hours at 70-80°C and then evaporated under reduced pressure to give the acid chloride. A solution of Meldrum's acid (23.5 g) in dichloromethane (90 ml) was cooled to 0-5°C under nitrogen and pyridine (33 ml) was added at 0-5°C. To this mixture was added a solution of the acid chloride prepared above in dichloromethane (90 ml) dropwise keeping the temperature below 5 5°C. The mixture was stirred for 1 hour at 0-5°C and then at ambient temperature for 18 hours. The mixture was diluted with dichloromethane (150 ml) and washed with 2M hydrochloric acid and then with saturated sodium bicarbonate solution and then water. The bicarbonate washes were acidified with 5M hydrochloric acid and extracted into dichloromethane.
10 These dichloromethane extracts were combined with the original dichloromethane solution and dried and evaporated to give the crude intermediate Meldrum's acid derivative. This derivative was boiled under reflux with methanol (400 ml) for 6 hours and then left to stand at ambient temperature for 66 hours with methanolic hydrogen chloride solution (10 ml).
The mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated off, washed with saturated sodium bicarbonate solution, brine and then dried and evaporated under reduced pressure to give an oil which was distilled under high vacuum. The distillate was purified by flash column chromatography on silica using petroleum ether, b.p. 60-80°C / ethyl acetate 20:1 as the mobile phase to give methyl 4-(4-chlorophenoxy)-3-oxopentanoate as an oil.
b) Guanidine hydrochloride (1.87 g) was added with stirring to a solution of sodium (0.41 g) in ethanol (15 ml). The mixture was stirred for 15 minutes and then to this mixture was added a solution of methyl 4-(4-chlorophenoxy)-3-oxopentanoate (5.0 g) in ethanol (15 ml). The mixture was stirred and boiled under reflux for 16 hours. The mixture was cooled and then evaporated to dryness under reduced pressure to give a solid. The solid was triturated with water (10 ml) containing glacial acetic acid (2 ml) and dichloromethane (20 ml) for 1 hour and then filtered. The residue obtained was washed with water and then with dichloromethane to give 2-amino-4-[1-(4-chlorophenoxy)ethyl-6-hydroxypyrimidine, m.p. 125°C.
The mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated off, washed with saturated sodium bicarbonate solution, brine and then dried and evaporated under reduced pressure to give an oil which was distilled under high vacuum. The distillate was purified by flash column chromatography on silica using petroleum ether, b.p. 60-80°C / ethyl acetate 20:1 as the mobile phase to give methyl 4-(4-chlorophenoxy)-3-oxopentanoate as an oil.
b) Guanidine hydrochloride (1.87 g) was added with stirring to a solution of sodium (0.41 g) in ethanol (15 ml). The mixture was stirred for 15 minutes and then to this mixture was added a solution of methyl 4-(4-chlorophenoxy)-3-oxopentanoate (5.0 g) in ethanol (15 ml). The mixture was stirred and boiled under reflux for 16 hours. The mixture was cooled and then evaporated to dryness under reduced pressure to give a solid. The solid was triturated with water (10 ml) containing glacial acetic acid (2 ml) and dichloromethane (20 ml) for 1 hour and then filtered. The residue obtained was washed with water and then with dichloromethane to give 2-amino-4-[1-(4-chlorophenoxy)ethyl-6-hydroxypyrimidine, m.p. 125°C.
c) A mixture of 2-amino-4-[1-(4-chlorophenoxy)ethyl-6-hydroxypyrimidine (0.5 g), dimethylformamide dimethyl acetal (0.5 ml) and toluene (5 ml) was stirred and boiled under reflux for 8 hours. The mixture was evaporated for 8 hours. The mixture was allowed to stand at ambient temperature for 24 hours and then evaporated to dryness under reduced pressure to give a solid which was triturated with ether and filtered to give the amidine as a solid.
d) Sodium hydride (62 mg of a 60% dispersion in mineral oil from which the mineral oil had been removed by washing with petrol) was dissolved in methanol (10 ml) and hydroxylamine hydrochloride (0.12 g) was added. The mixture was stirred for 5 minutes and then added to the amidinopyrimidine (0.5 g) obtained in c). The mixture was stirred at ambient temperature for 72 hours and then evaporated to dryness under reduced pressure to give a residue which was washed with water and dried to give the formamidoxine.
e) The product from d) (5.0 g) and polyphosphoric acid (100 g) were stirred and heated on a steam bath for 4 hours. The mixture was allowed to cool to ambient temperature and then ice (100 g) and ethyl acetate (100 ml) were added. A solution of potassium carbonate (110 g) in water (total volume 100 ml) was added dropwise over 15 minutes to neutralise the mixture. The mixture was separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were dried and evaporated to give a solid which was purified by flash column chromatography on silica using dichloromethane / methanol (75:3) as the mobile phase to give 7-[1-(4 chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol, m.p. 190°C.
Example A
The use of compounds of the present invention in the manufacture of pharmaceutical compositions is illustrated by the following description. In this description the term "active compound" denotes any compound of the invention but particularly any compound which is the final product of one of the preceding Examples.
d) Sodium hydride (62 mg of a 60% dispersion in mineral oil from which the mineral oil had been removed by washing with petrol) was dissolved in methanol (10 ml) and hydroxylamine hydrochloride (0.12 g) was added. The mixture was stirred for 5 minutes and then added to the amidinopyrimidine (0.5 g) obtained in c). The mixture was stirred at ambient temperature for 72 hours and then evaporated to dryness under reduced pressure to give a residue which was washed with water and dried to give the formamidoxine.
e) The product from d) (5.0 g) and polyphosphoric acid (100 g) were stirred and heated on a steam bath for 4 hours. The mixture was allowed to cool to ambient temperature and then ice (100 g) and ethyl acetate (100 ml) were added. A solution of potassium carbonate (110 g) in water (total volume 100 ml) was added dropwise over 15 minutes to neutralise the mixture. The mixture was separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were dried and evaporated to give a solid which was purified by flash column chromatography on silica using dichloromethane / methanol (75:3) as the mobile phase to give 7-[1-(4 chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol, m.p. 190°C.
Example A
The use of compounds of the present invention in the manufacture of pharmaceutical compositions is illustrated by the following description. In this description the term "active compound" denotes any compound of the invention but particularly any compound which is the final product of one of the preceding Examples.
a) Capsules In the preparation of capsules, 10 parts by weight of active compound and 240 parts by weight of lactose are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of active compound.
b) Tablets Tablets are prepared from the following ingredients.
Parts by weiaht Active compound 10 Lactose 190 Maize starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3 The active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture is granulated with a solution of the polyvinyl-pyrrolidone in ethanol. The dry granulate is blended with the magnesium stearate and the rest of the starch. The mixture is then compressed in a tabletting machine to give tablets each containing a unit dose or a part of a unit dose of active compound.
c) Enteric coated tablets Tablets are prepared by the method described in (b) above. The tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol:dichloromethane (1:1 ).
d) Suppositories In the preparation of suppositories, 100 parts by weight of active compound is incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient.
b) Tablets Tablets are prepared from the following ingredients.
Parts by weiaht Active compound 10 Lactose 190 Maize starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3 The active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture is granulated with a solution of the polyvinyl-pyrrolidone in ethanol. The dry granulate is blended with the magnesium stearate and the rest of the starch. The mixture is then compressed in a tabletting machine to give tablets each containing a unit dose or a part of a unit dose of active compound.
c) Enteric coated tablets Tablets are prepared by the method described in (b) above. The tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol:dichloromethane (1:1 ).
d) Suppositories In the preparation of suppositories, 100 parts by weight of active compound is incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient.
Claims (8)
1. A method of treating obesity and related conditions comprising the administration of a therapeutically effective amount of a compound of formula I
including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof in which:
R1 represents H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C1-6alkyl, C1-6alkoxy or C1-6alkanoyl;
R2 and R3 independently represent H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C1-6alkyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkylthio, C1-6alkylsulphinyl, C1-6alkylsulphonyl or hydroxy;
R4 and R5 independently represent H, C1-6alkyl or R4 and R5 combined together with the carbon atom to which they are attached represent C3-6cycloalkylidene (each alkyl or cycloalkylidene being optionally substituted with one or more of halo, cyano, hydroxy, amino or C1-6alkyl); and R6, R7 and R8 independently represent H, halo, hydroxy, mercapto, nitro, cyano or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino; and any nitrogen atom being optionally substituted with one or more C1-6 alkyl): C1-6alkyl, C1-6alkanoyl, C1-6alkoxy, C2-6alkoxycarbonyl, carboxy, C1-6alkanoyloxy, C1-6alkylthio, C1-6alkylsulphinyl, C1-6alkylsulphonyl, C1-6alkyl-sulphonylamino, sulphamoyl, carbamoyl, C2-6alkylcarbamoyl or C1-6alkanoylamino;
to a mammal in need thereof.
including pharmaceutically acceptable salts, solvates, racemates, enantiomers, diastereoisomers and mixtures thereof in which:
R1 represents H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C1-6alkyl, C1-6alkoxy or C1-6alkanoyl;
R2 and R3 independently represent H or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino): C1-6alkyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkylthio, C1-6alkylsulphinyl, C1-6alkylsulphonyl or hydroxy;
R4 and R5 independently represent H, C1-6alkyl or R4 and R5 combined together with the carbon atom to which they are attached represent C3-6cycloalkylidene (each alkyl or cycloalkylidene being optionally substituted with one or more of halo, cyano, hydroxy, amino or C1-6alkyl); and R6, R7 and R8 independently represent H, halo, hydroxy, mercapto, nitro, cyano or one of the following groups (optionally substituted with one or more of halo, cyano, hydroxy or amino; and any nitrogen atom being optionally substituted with one or more C1-6 alkyl): C1-6alkyl, C1-6alkanoyl, C1-6alkoxy, C2-6alkoxycarbonyl, carboxy, C1-6alkanoyloxy, C1-6alkylthio, C1-6alkylsulphinyl, C1-6alkylsulphonyl, C1-6alkyl-sulphonylamino, sulphamoyl, carbamoyl, C2-6alkylcarbamoyl or C1-6alkanoylamino;
to a mammal in need thereof.
2. The use of a compound of formula I as described in claim 1 in the manufacture of the medicament for the prevention or the treament of obesity or related conditions.
3 A pharmaceutical composition for the treatment and/or the prevention of obesity or related conditions comprising a therapeutically effective amount of a compound of formula I as described in claim 1 in conjunction with a pharmaceutically acceptable diluent or carrier.
4. A method according to claim 1, a use according to claim 2 or a composition according to claim 3, wherein the compound is selected from:
7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
7-[1-(4-bromophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(4-cyanophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(4-trifluoromethylphenoxy)ethyl]-1,2,4-triazolo [1,5-a]pyrimidine;
7-[1-(4-methoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
7-[1-(4-trifluoromethoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-acetylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-(1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(4-methylsulphinylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methylsulphonylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-[4-(ethylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(3-chlorophenoxy)ethyl]-1,2,4-triazolo [1,5-a]pyrimidine;
7-[1-(2,4-difluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(2,4-dichlorophenoxy)ethyl]-1,2,4-triazolo [1,5-a]pyrimidine;
7-(1-(3,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(2-chloro-4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-2-methyl-1,2,4-triazolo[1,5-a]pyrimidine;
7-(4-chlorophenoxymethyl)-1,2,4-triazolo[1,5-a] pyrimidine;
7-[1-(4-chlorophenoxy)-1-methylethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)propyl]-1,2,4-triazolo[1,5-a]-pyrimidine; and 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of
7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
7-[1-(4-bromophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(4-cyanophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(4-trifluoromethylphenoxy)ethyl]-1,2,4-triazolo [1,5-a]pyrimidine;
7-[1-(4-methoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
7-[1-(4-trifluoromethoxyphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-acetylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-(1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(4-methylsulphinylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-methylsulphonylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-[4-(ethylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(3-chlorophenoxy)ethyl]-1,2,4-triazolo [1,5-a]pyrimidine;
7-[1-(2,4-difluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(2,4-dichlorophenoxy)ethyl]-1,2,4-triazolo [1,5-a]pyrimidine;
7-(1-(3,4-dichlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
7-[1-(2-chloro-4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)ethyl]-2-methyl-1,2,4-triazolo[1,5-a]pyrimidine;
7-(4-chlorophenoxymethyl)-1,2,4-triazolo[1,5-a] pyrimidine;
7-[1-(4-chlorophenoxy)-1-methylethyl]-1,2,4-triazolo[1,5-a]pyrimidine;
7-[1-(4-chlorophenoxy)propyl]-1,2,4-triazolo[1,5-a]-pyrimidine; and 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of
5. A method according to claim 1, a use according to claim 2 or a composition according to claim 3, wherein the compound is selected from:
(+)-7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
(-)-7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
(+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
(-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
(+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidin-5-ol; and (-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidin-5-ol
(+)-7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
(-)-7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine;
(+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
(-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine;
(+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidin-5-ol; and (-)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidin-5-ol
6. A method according to claim 1, a use according to claim 2 or a composition according to claim 3, wherein the compound is selected from:
7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and 7-[1-(4-chloro-phenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol including the racemates, enantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof.
7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine and 7-[1-(4-chloro-phenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol including the racemates, enantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof.
7. A method according to claim 1, a use according to claim 2 or a composition according to claim 3, wherein the compound is selected from:
(R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine and pharmaceutically acceptable salts thereof.
(R)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a] pyrimidine and pharmaceutically acceptable salts thereof.
8. A method according to any one of claims 1, 4, 5, 6 or 7 wherein the related condition is selected from eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, and stress,
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9914743.1A GB9914743D0 (en) | 1999-06-24 | 1999-06-24 | Therapeutic agents |
| GB9914743.1 | 1999-06-24 | ||
| PCT/EP2000/005543 WO2001000186A2 (en) | 1999-06-24 | 2000-06-16 | New use of 1,2,4-triazolo'1,5-a! pyrimidines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2376886A1 true CA2376886A1 (en) | 2001-01-04 |
Family
ID=10855954
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002376886A Abandoned CA2376886A1 (en) | 1999-06-24 | 2000-06-16 | Therapeutic agents |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1218008A2 (en) |
| JP (1) | JP2003503343A (en) |
| AU (1) | AU6150200A (en) |
| CA (1) | CA2376886A1 (en) |
| GB (1) | GB9914743D0 (en) |
| MX (1) | MXPA01013421A (en) |
| WO (1) | WO2001000186A2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2743299A1 (en) | 2008-11-12 | 2010-05-20 | Schering Corporation | Inhibitors of fatty acid binding protein (fabp) |
| US8759357B2 (en) | 2009-10-08 | 2014-06-24 | Merck Sharp & Dohme Corp. | Inhibitors of fatty acid binding protein (FABP) |
| KR101775682B1 (en) * | 2015-11-30 | 2017-09-06 | 주식회사 대웅 | Methods for Preparing Botulinum Toxin |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9321162D0 (en) * | 1993-10-13 | 1993-12-01 | Boots Co Plc | Therapeutic agents |
| GB9906124D0 (en) * | 1999-03-18 | 1999-05-12 | Knoll Ag | Therapeutic agent |
| GB9906126D0 (en) * | 1999-03-18 | 1999-05-12 | Knoll Ag | Pharmaceutical formulations |
| GB9906130D0 (en) * | 1999-03-18 | 1999-05-12 | Knoll Ag | Compounds for use in therapy |
-
1999
- 1999-06-24 GB GBGB9914743.1A patent/GB9914743D0/en not_active Ceased
-
2000
- 2000-06-16 AU AU61502/00A patent/AU6150200A/en not_active Abandoned
- 2000-06-16 JP JP2001505896A patent/JP2003503343A/en not_active Withdrawn
- 2000-06-16 CA CA002376886A patent/CA2376886A1/en not_active Abandoned
- 2000-06-16 WO PCT/EP2000/005543 patent/WO2001000186A2/en not_active Application Discontinuation
- 2000-06-16 EP EP00947848A patent/EP1218008A2/en not_active Withdrawn
- 2000-06-16 MX MXPA01013421A patent/MXPA01013421A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP1218008A2 (en) | 2002-07-03 |
| GB9914743D0 (en) | 1999-08-25 |
| AU6150200A (en) | 2001-01-31 |
| MXPA01013421A (en) | 2002-07-30 |
| WO2001000186A3 (en) | 2002-05-10 |
| WO2001000186A2 (en) | 2001-01-04 |
| JP2003503343A (en) | 2003-01-28 |
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