CA1319323C - Medicaments for the treatment of emesis - Google Patents
Medicaments for the treatment of emesisInfo
- Publication number
- CA1319323C CA1319323C CA000592765A CA592765A CA1319323C CA 1319323 C CA1319323 C CA 1319323C CA 000592765 A CA000592765 A CA 000592765A CA 592765 A CA592765 A CA 592765A CA 1319323 C CA1319323 C CA 1319323C
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- carbazol
- tetrahydro
- imidazol
- pharmaceutical composition
- 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.)
- Expired - Lifetime
Links
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
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
ABSTRACT
MEDICAMENTS
The invention relates to the co-administration in human or veterinary medicine of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one or a physiologically acceptable salt or solvate thereof and dexamethasone or a physiologically acceptable salt or ester thereof.
The two active ingredients, which may be administered separately either simultaneously or sequentially, or may be combined in a single pharmaceutical preparation, are useful in the relief and/or prevention of nausea and vomiting.
MEDICAMENTS
The invention relates to the co-administration in human or veterinary medicine of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one or a physiologically acceptable salt or solvate thereof and dexamethasone or a physiologically acceptable salt or ester thereof.
The two active ingredients, which may be administered separately either simultaneously or sequentially, or may be combined in a single pharmaceutical preparation, are useful in the relief and/or prevention of nausea and vomiting.
Description
MEDICAMENTS
This invention relates to improvements in the treatment of gastrointestinal disorders. More particu]arly it rslates to the use of a compound having antagonist activity at 5Hr3 receptors and dexamethasone in the treatment of emesis, and to pharmaceutical compositions containing the two compounds.
In our UK Patent Specification No. 2153821A we disclose inter alia 1,2,3,9-tetrahydro-9-methyl-3-~(2-methyl-lH-imidazol-l-yi) methyl]-4H-carbazol-4-one which may be represented by the formula (I) !~ '. / \./ \N
!I ll ! ~./~ (I) \\ / \ / \ / I ' ^ N Me Me and physiologically acceptable salts, solvates and physiologically acceptable equivalents thereof.
In the aforementioned specification the compounds are described as potent and selective antagonists of 5- hydroxytryptamine (5HT) at 'neuronal' 5HT receptors of the type located on terminals of primary afferent nerves, and which are also present in the central nervous system. Receptors of this type are now designated 5HT3 receptors.
The compounds are described as being of use in the treatment of a human or animal subject suffering from a condition caused by a disturbance of neuronal 5HT function, for example in the treatment of migraine pain or a psychotic disorder such as schizophrenia. The compounds may also be useful in the treatment of conditions such as anxiety, obesity and mania.
We have found, as described in our published European Pat~nt Specification No. 226266, that the compounds disclosed in UK Patent Specification No. 2153821A addit~iqnally promote gastric emptying, and are thus useful in the treatment of conditions which may be relieved by the promotion of gastric emptying. Such conditions include gastric - 2 _ l 31 9323 stasis and symptoms of gastrointestinal dysfunction such as dyspepsia, reflex oesophagitis, peptic ulcer and flatulence.
According to published European Patent Specification No. 226266, thP compounds have also been found to be anti-emetics, and may be used in the treatment or prevention ofnausea and vomiting. The use of these compounds for the treatment of emesis is also described in published European Patent Specification No. 201165, which specification additionally refers to the use of the compounds for the treatment of irritable bowel syndrome.
Studies have shown that the anti-emetic properties o~
the compound of formula (I) are enhanced by administering the compound in conjunction with dexamethasone.
Dexamethasone is a systemic anti-inflammatory corticosteroid, which is known to have anti-emetic properties and to be useful in the treatment of emesis resulting from chemotherapy, especially cancer chemotherapy involving the use of, for example, cisplatin.
The present invention thus provides a method of treating and/or preventing nausea and vomiting, which comprises administering to a human or animal subject the compound of formula (I) or a physiologically acceptable salt or solvate thereof, and dexamethasone or a physiologically acceptable salt or estex the.reof.
According to another aspect the invention provides for the use of the compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for administration in conjunction with dexamethasone or a physiologically acceptable salt or ester thereof, for the treatment and/or prevention of nausea and vomiting.
Co-administration of the compound of formula (I) with dexamethasone is particularly useful for the treatment and/or prevention of nausea and vomiting associated with chemotherapy, especially cancer chemotherapy involving the use of, for example, cisplatin. Such co-administration may '~;., `-` 1 3 1 9323 - 2a -also reduce delayed nausea and vomiting associated with this type of chemotherapy.
The compound of formula (I) or a physiologically acceptable salt or solvate thereof, and dexamethasone or a physiologically acceptable ~alt or ester thereof, may be administered as a single pharmaceutical composition comprising effective amounts of the two active ....
~,~
ingredisnts. Alternatively the two active ingrsdi~nts may bs co-administ~red in ths form of two separate pharmaceutical composi~ions for simultaneous or sequential use.
Suitable physiologically acceptable salts of ths carbazolons of formula (I) for use according to the invention include acid addition salts formed with organic or inorganic acids for sxample, hydrochlorides, hydrobromides, sulphatss, phosphatss, citratss, fumarates and maleates. The solvates may, for sxample, bs hydratss.
A prsferred form of the compound of formula (I) for use according to the invention is the hydrochloride) particularly in hydratsd form, 9.9. the dihydrats.
Dexamethasone may be administered according to the invention as dsxamsthasons alcohol or in the form of a physiologically accsptabls salt or sster. Suitabls salts and ssters includs ths acetate, isonicotinoate, phenylpropionate, pivalate, t-butyl acetate, trioxaundecanoats, disodium mstasulphobsnzoats and disodium phosphate.
A proposed dosage of -the compound of formula ~I) for uss according to the invention for administration to man (of approximately 70kg body wsight), is 0.05 to 25mg, more preferably 0.05 to 20mg, and most preferably 0.1 to lOmg per unit dose, expressed as the weight of free base. A preferred dose of dexamethasone for use according to the invention is in the range of 0.5 to 20mg per dosage unit, expressed as the weight of the alcohol.
The unit doses may be administered, for example, 1 to 4 times per day. The exact dose will depend on the route of administration and the condition being treated, and it will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and wsight of the patisnt as w911 as the severity of the condition to be-treated.
When the two activs ingredients ars administsred as separate preparations, they are preferably given orally or parenterally (D.9.
intramuscularly or, mors particularly, intravsnously).
According to a further aspect the invention provides a pharmaceutical composition, for use in human or veterinary medicine, comprising the compound of formula (I) or a physiologically acceptable salt or solvate thereof, and dexarnethasone or a physiologically acceptable sal~ or ester thereof.
Compositions according to the invention may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients. Thus ths compositions may, for example, be formulated for oral, buccal, parenteral or rectal administration.
Compositions for administration by the oral route, in the form of for example tablets or capsules, are preferred.
Compositions for oral use such as tablets and capsules rnay be prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.
lactose, microcrystalline cellulose or calcium hydrogen phosphate);
lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivativss or llydrogenated edible fats); emulsifying agents (e.g.
lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxyben~oates or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of one or both active ingredients.
For parenteral administration the compositions may be presented in a form suitable for bolus injection or continuous infusion.
Formulations for injection may be presented in unit dosage form e.g.
in ampoules or in multi-dose containers, with an added preservative.
The compositions rnay take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
Alternatively, the active ingredients may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
For rectal administration the compositions may bs formulated as suppositories or retention enemas, e.g containing conventional suppository bases such as cocoa butter or other glycsrides.
The pharrnaceutical compositions of the invention may be prepared according to conventional techniques well known in the pharmaceutical industry. Thus, for example, the compound of formula (I) or a salt or solvate thereof and the dexamethasone or dexamethasone salt or ester may be admixed together, if desired, with suitable excipients.
Tablets may be prepared, for example, by direct compression of such a mixturs. Capsules may be prepared by filling the blend along with suitable excipients into gelatin capsules, using a suitable filling machine. Controlled release forms for oral or rectal administration may be formulated in a conventional manner associated with controlled release forms.
The compositions for use according to the invention may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients. The pacl< may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Where the compound of formula (I) and the dexarnethasone are intended for administration as two separate compositions these may be presented in the form of, for example, a twin pack.
The following examples illustrate the preparation of the compound of formula (I). Temperatures are in ~C.
Example 1 1,2j3,9-Tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-l-yl)methyl]-4H-carbazol-4-one A solution of 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-mèthyl -4H-carbazol-4-one hydrochloride (1.79) in water (17ml) was treatPd with 2-me'chylirnidazole (1.4~) and then heated under reflux for 2ûh.
The cooled mixture was Filtered and the residue ~ashed with ~later (3xl5ml) to give a product (1.79) m.p. 221-221.5. This material ,las recrystallised from methanol to give the titl~ compound ~1.4g) m.p.
231-232.
_xampls 2 9-Tetrahydro-9-me~hyl-3-[(2-methyl-lH-imiclazol-l-yl)methyl]-4H-carbazol-4-ons hydrochloride dihydrate 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-l-yl)methyl]-4H-carbazol-4-one (18.39) in a hot mixture of isopropanol (9Oml) and water (18.3ml) was treated with concentrated hydrochloric acid (6.25ml). The hot mixture was filtered and the filtrats diluted with isopropanol (9Oml) and stirred at room temperature for 17h, cooled to 2 and the solid filtered off (21.69). A sample (69) ~las recrystallised from a mixture of water (6ml) and isopropanol (lOml) to give the title compound as a white crystalline solid (6g) m.p.
178.5-179.5.
Analysis Found: C,59.45;H,6.45;N,11.5.
C18HlgN30.HCl.2H20 requires C,59.1;H,6.6;N,11.5~.
Water assay Founcl: 10.23 Cl8HlgN30.HCl.2H20 re4uires 9.85~
The following examples illustrate pharmaceutical compositions according to the invention, containing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-l-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate (Compound A) and dexamethasone as the active ingredients.
Other physiologically acceptable salts and/or solvates of the compound of formula (I)~ and dexamethasone or physiologically acceptable salts or esters thereof, may be formulated in a similar manner.
TABLETS FOR ORAL ADMINISTRATION
Tablets may be prepared by the normal methods such as direct compression or wet granulation.
`` 1 31 9323 The tablets may be filrn coated with suitable film forming materials, such as hydroxypropyl methylcellulose, using standard ~echnique~s.
Direct Compression Tablets mq/tablet Compound A 5.û * 10.0**
Dexamethasone BP 4-0 4.0 Anhydrous lactose USNF 76.05 71.05 Pregelatinised starch USNF 4.5 4.50 Magnesium stearate BP 0.45 0.45 Compression weight 90.00 90.00 * Equivalent to 4.Omg free base.
** Equivalent to 8.Omg free base.
Compound A and the dexamethasone are sieved through a suitable sieve and blsnded with the lactose, pregelatinised starch and magnesium stearate. The resultant mix is compressed into tablets using a suitable tablet press fitted with 6.5mm normal concave punches.
Tablets of other strengths and/or combination of doses may be prepared by appropriate alterations in the amounts of the activs ingredients and the excipients and using punches to suit.
CAPSULES
mq/capsule Compound A 10 00 Dexamethasone BP 4.00 Pregelatinised Starch USNF 7Q.625 Magnesium stearate BP 0.375 Fill weight 85.00 Compound A and the dexamethasone are sieved through a 250~rn sieve and blended with the pregelatinised starch and magnesium stearate~ The resultant mix is filled into size 3 hard gelatin capsules using a suitable filling machine.
.
This invention relates to improvements in the treatment of gastrointestinal disorders. More particu]arly it rslates to the use of a compound having antagonist activity at 5Hr3 receptors and dexamethasone in the treatment of emesis, and to pharmaceutical compositions containing the two compounds.
In our UK Patent Specification No. 2153821A we disclose inter alia 1,2,3,9-tetrahydro-9-methyl-3-~(2-methyl-lH-imidazol-l-yi) methyl]-4H-carbazol-4-one which may be represented by the formula (I) !~ '. / \./ \N
!I ll ! ~./~ (I) \\ / \ / \ / I ' ^ N Me Me and physiologically acceptable salts, solvates and physiologically acceptable equivalents thereof.
In the aforementioned specification the compounds are described as potent and selective antagonists of 5- hydroxytryptamine (5HT) at 'neuronal' 5HT receptors of the type located on terminals of primary afferent nerves, and which are also present in the central nervous system. Receptors of this type are now designated 5HT3 receptors.
The compounds are described as being of use in the treatment of a human or animal subject suffering from a condition caused by a disturbance of neuronal 5HT function, for example in the treatment of migraine pain or a psychotic disorder such as schizophrenia. The compounds may also be useful in the treatment of conditions such as anxiety, obesity and mania.
We have found, as described in our published European Pat~nt Specification No. 226266, that the compounds disclosed in UK Patent Specification No. 2153821A addit~iqnally promote gastric emptying, and are thus useful in the treatment of conditions which may be relieved by the promotion of gastric emptying. Such conditions include gastric - 2 _ l 31 9323 stasis and symptoms of gastrointestinal dysfunction such as dyspepsia, reflex oesophagitis, peptic ulcer and flatulence.
According to published European Patent Specification No. 226266, thP compounds have also been found to be anti-emetics, and may be used in the treatment or prevention ofnausea and vomiting. The use of these compounds for the treatment of emesis is also described in published European Patent Specification No. 201165, which specification additionally refers to the use of the compounds for the treatment of irritable bowel syndrome.
Studies have shown that the anti-emetic properties o~
the compound of formula (I) are enhanced by administering the compound in conjunction with dexamethasone.
Dexamethasone is a systemic anti-inflammatory corticosteroid, which is known to have anti-emetic properties and to be useful in the treatment of emesis resulting from chemotherapy, especially cancer chemotherapy involving the use of, for example, cisplatin.
The present invention thus provides a method of treating and/or preventing nausea and vomiting, which comprises administering to a human or animal subject the compound of formula (I) or a physiologically acceptable salt or solvate thereof, and dexamethasone or a physiologically acceptable salt or estex the.reof.
According to another aspect the invention provides for the use of the compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for administration in conjunction with dexamethasone or a physiologically acceptable salt or ester thereof, for the treatment and/or prevention of nausea and vomiting.
Co-administration of the compound of formula (I) with dexamethasone is particularly useful for the treatment and/or prevention of nausea and vomiting associated with chemotherapy, especially cancer chemotherapy involving the use of, for example, cisplatin. Such co-administration may '~;., `-` 1 3 1 9323 - 2a -also reduce delayed nausea and vomiting associated with this type of chemotherapy.
The compound of formula (I) or a physiologically acceptable salt or solvate thereof, and dexamethasone or a physiologically acceptable ~alt or ester thereof, may be administered as a single pharmaceutical composition comprising effective amounts of the two active ....
~,~
ingredisnts. Alternatively the two active ingrsdi~nts may bs co-administ~red in ths form of two separate pharmaceutical composi~ions for simultaneous or sequential use.
Suitable physiologically acceptable salts of ths carbazolons of formula (I) for use according to the invention include acid addition salts formed with organic or inorganic acids for sxample, hydrochlorides, hydrobromides, sulphatss, phosphatss, citratss, fumarates and maleates. The solvates may, for sxample, bs hydratss.
A prsferred form of the compound of formula (I) for use according to the invention is the hydrochloride) particularly in hydratsd form, 9.9. the dihydrats.
Dexamethasone may be administered according to the invention as dsxamsthasons alcohol or in the form of a physiologically accsptabls salt or sster. Suitabls salts and ssters includs ths acetate, isonicotinoate, phenylpropionate, pivalate, t-butyl acetate, trioxaundecanoats, disodium mstasulphobsnzoats and disodium phosphate.
A proposed dosage of -the compound of formula ~I) for uss according to the invention for administration to man (of approximately 70kg body wsight), is 0.05 to 25mg, more preferably 0.05 to 20mg, and most preferably 0.1 to lOmg per unit dose, expressed as the weight of free base. A preferred dose of dexamethasone for use according to the invention is in the range of 0.5 to 20mg per dosage unit, expressed as the weight of the alcohol.
The unit doses may be administered, for example, 1 to 4 times per day. The exact dose will depend on the route of administration and the condition being treated, and it will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and wsight of the patisnt as w911 as the severity of the condition to be-treated.
When the two activs ingredients ars administsred as separate preparations, they are preferably given orally or parenterally (D.9.
intramuscularly or, mors particularly, intravsnously).
According to a further aspect the invention provides a pharmaceutical composition, for use in human or veterinary medicine, comprising the compound of formula (I) or a physiologically acceptable salt or solvate thereof, and dexarnethasone or a physiologically acceptable sal~ or ester thereof.
Compositions according to the invention may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients. Thus ths compositions may, for example, be formulated for oral, buccal, parenteral or rectal administration.
Compositions for administration by the oral route, in the form of for example tablets or capsules, are preferred.
Compositions for oral use such as tablets and capsules rnay be prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g.
lactose, microcrystalline cellulose or calcium hydrogen phosphate);
lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivativss or llydrogenated edible fats); emulsifying agents (e.g.
lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxyben~oates or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of one or both active ingredients.
For parenteral administration the compositions may be presented in a form suitable for bolus injection or continuous infusion.
Formulations for injection may be presented in unit dosage form e.g.
in ampoules or in multi-dose containers, with an added preservative.
The compositions rnay take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
Alternatively, the active ingredients may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
For rectal administration the compositions may bs formulated as suppositories or retention enemas, e.g containing conventional suppository bases such as cocoa butter or other glycsrides.
The pharrnaceutical compositions of the invention may be prepared according to conventional techniques well known in the pharmaceutical industry. Thus, for example, the compound of formula (I) or a salt or solvate thereof and the dexamethasone or dexamethasone salt or ester may be admixed together, if desired, with suitable excipients.
Tablets may be prepared, for example, by direct compression of such a mixturs. Capsules may be prepared by filling the blend along with suitable excipients into gelatin capsules, using a suitable filling machine. Controlled release forms for oral or rectal administration may be formulated in a conventional manner associated with controlled release forms.
The compositions for use according to the invention may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients. The pacl< may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Where the compound of formula (I) and the dexarnethasone are intended for administration as two separate compositions these may be presented in the form of, for example, a twin pack.
The following examples illustrate the preparation of the compound of formula (I). Temperatures are in ~C.
Example 1 1,2j3,9-Tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-l-yl)methyl]-4H-carbazol-4-one A solution of 3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-mèthyl -4H-carbazol-4-one hydrochloride (1.79) in water (17ml) was treatPd with 2-me'chylirnidazole (1.4~) and then heated under reflux for 2ûh.
The cooled mixture was Filtered and the residue ~ashed with ~later (3xl5ml) to give a product (1.79) m.p. 221-221.5. This material ,las recrystallised from methanol to give the titl~ compound ~1.4g) m.p.
231-232.
_xampls 2 9-Tetrahydro-9-me~hyl-3-[(2-methyl-lH-imiclazol-l-yl)methyl]-4H-carbazol-4-ons hydrochloride dihydrate 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-l-yl)methyl]-4H-carbazol-4-one (18.39) in a hot mixture of isopropanol (9Oml) and water (18.3ml) was treated with concentrated hydrochloric acid (6.25ml). The hot mixture was filtered and the filtrats diluted with isopropanol (9Oml) and stirred at room temperature for 17h, cooled to 2 and the solid filtered off (21.69). A sample (69) ~las recrystallised from a mixture of water (6ml) and isopropanol (lOml) to give the title compound as a white crystalline solid (6g) m.p.
178.5-179.5.
Analysis Found: C,59.45;H,6.45;N,11.5.
C18HlgN30.HCl.2H20 requires C,59.1;H,6.6;N,11.5~.
Water assay Founcl: 10.23 Cl8HlgN30.HCl.2H20 re4uires 9.85~
The following examples illustrate pharmaceutical compositions according to the invention, containing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-l-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate (Compound A) and dexamethasone as the active ingredients.
Other physiologically acceptable salts and/or solvates of the compound of formula (I)~ and dexamethasone or physiologically acceptable salts or esters thereof, may be formulated in a similar manner.
TABLETS FOR ORAL ADMINISTRATION
Tablets may be prepared by the normal methods such as direct compression or wet granulation.
`` 1 31 9323 The tablets may be filrn coated with suitable film forming materials, such as hydroxypropyl methylcellulose, using standard ~echnique~s.
Direct Compression Tablets mq/tablet Compound A 5.û * 10.0**
Dexamethasone BP 4-0 4.0 Anhydrous lactose USNF 76.05 71.05 Pregelatinised starch USNF 4.5 4.50 Magnesium stearate BP 0.45 0.45 Compression weight 90.00 90.00 * Equivalent to 4.Omg free base.
** Equivalent to 8.Omg free base.
Compound A and the dexamethasone are sieved through a suitable sieve and blsnded with the lactose, pregelatinised starch and magnesium stearate. The resultant mix is compressed into tablets using a suitable tablet press fitted with 6.5mm normal concave punches.
Tablets of other strengths and/or combination of doses may be prepared by appropriate alterations in the amounts of the activs ingredients and the excipients and using punches to suit.
CAPSULES
mq/capsule Compound A 10 00 Dexamethasone BP 4.00 Pregelatinised Starch USNF 7Q.625 Magnesium stearate BP 0.375 Fill weight 85.00 Compound A and the dexamethasone are sieved through a 250~rn sieve and blended with the pregelatinised starch and magnesium stearate~ The resultant mix is filled into size 3 hard gelatin capsules using a suitable filling machine.
.
Claims (22)
1. A pharmaceutical composition for use in human or veterinary medicine comprising 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one or a physiologically acceptable salt or solvate thereof and dexamethasone or a physiologically acceptable salt or ester thereof.
2. A pharmaceutical composition as claimed in claim 1 wherein the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one is used in the form of a hydrochloride salt.
3. A pharmaceutical composition as claimed in claim 2 wherein the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one is used in the form of the hydrochloride dihydrate.
4. A pharmaceutical composition as claimed in claim 1 in unit dose form containing 0.05 to 25mg per unit dose of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one expressed as the weight of free base and 0.5 to 20mg per unit dose of dexamethasone expressed as the weight of the alcohol.
5. A pharmaceutical composition as claimed in claim 4 in which the unit dose of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one is 0.1 to 10mg.
6. A pharmaceutical composition as claimed in claim 1 in a form adapted for oral, buccal, parenteral or rectal administration.
7. A pharmaceutical composition as claimed in claim 6 for oral administration in the form of tablets.
8. A pharmaceutical composition as claimed in claim 6 for parenteral administration in a form suitable for injection or infusion.
9. A pharmaceutical composition as claimed in claim 1 containing at least one physiologically acceptable carrier or excipient.
10. A method for the manufacture of a pharmaceutical composition as claimed in claim 1 which comprises processing the components by conventional techniques to form a pharmaceutical composition.
11. The use of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for administration in conjunction with dexamethasone or a physiologically acceptable salt or ester thereof in the treatment and/or prevention of nausea and vomiting.
12. The use as claimed in claim 11 wherein the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one is used in the form of a hydrochloride salt.
13. The use as claimed in claim 12 wherein the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one is used in the form of the hydrochloride dihydrate.
14. The use as claimed in claim 11 wherein the medicament is in unit dose form containing 0.05 to 25mg per unit dose of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one expressed as the weight of free base for administration in conjunction with dexamethasone in a unit dose of 0.5 to 20mg expressed as the weight of the alcohol.
15. The use as claimed in claim 14 in which the unit dose of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one is 0.1 to 10mg.
16. The use as claimed in claim 11 wherein the medicament is in a form adapted for oral, buccal, parenteral or rectal administration.
17. The use as claimed in claim 16 wherein the medicament is for oral administration in the form of tablets.
18. The use as claimed in claim 16 wherein the medicament is for parenteral administration in a form suitable for injection or infusion.
19. The use as claimed in claim 16 wherein the medicament is for administration in conjunction with dexamethasone but separately therefrom.
20. The use as claimed in claim 19 wherein the medicament and the dexamethasone are for parenteral administration in the form of a preparation adapted to be given intravenously.
21. The use as claimed in claim 11 wherein the medicament contains at least one physiologically acceptable carrier or excipient.
22. A twin pack comprising separate unit dose forms of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one or a physiologically acceptable salt or solvate thereof and dexamethasone or a physiologically acceptable salt or ester thereof in association for separate administration.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB888805269A GB8805269D0 (en) | 1988-03-04 | 1988-03-04 | Medicaments |
| GB8805269 | 1988-03-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1319323C true CA1319323C (en) | 1993-06-22 |
Family
ID=10632894
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000592765A Expired - Lifetime CA1319323C (en) | 1988-03-04 | 1989-03-03 | Medicaments for the treatment of emesis |
Country Status (23)
| Country | Link |
|---|---|
| US (2) | US6544550B1 (en) |
| JP (1) | JPH0296525A (en) |
| KR (1) | KR890014109A (en) |
| AT (1) | AT400301B (en) |
| AU (1) | AU626010B2 (en) |
| BE (1) | BE1002255A5 (en) |
| CA (1) | CA1319323C (en) |
| CH (1) | CH678149A5 (en) |
| CY (1) | CY1634A (en) |
| CZ (1) | CZ402391A3 (en) |
| DE (1) | DE3906883C2 (en) |
| DK (1) | DK175428B1 (en) |
| FR (1) | FR2627986B1 (en) |
| GB (2) | GB8805269D0 (en) |
| HK (1) | HK41792A (en) |
| IE (1) | IE61516B1 (en) |
| IT (1) | IT1232662B (en) |
| NL (1) | NL194463C (en) |
| NZ (1) | NZ228214A (en) |
| SE (1) | SE508342C2 (en) |
| SG (1) | SG9092G (en) |
| SK (1) | SK402391A3 (en) |
| ZA (1) | ZA891639B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9101221D0 (en) * | 1991-01-19 | 1991-02-27 | Smithkline Beecham Plc | Pharmaceuticals |
| US5929059A (en) * | 1991-01-19 | 1999-07-27 | Smithkline Beecham P.L.C. | Pharmaceutical compositions containing granisetron and dexamethasone |
| ATE195867T1 (en) * | 1991-09-20 | 2000-09-15 | Glaxo Group Ltd | NEW MEDICAL INDICATION FOR TACHYKININ ANTAGONISTS |
| CA2157671A1 (en) * | 1993-03-08 | 1994-09-15 | Kiyotaka Katsuta | Medicament for treating or preventing cerebrovascular diseases |
| US5661142A (en) * | 1996-04-17 | 1997-08-26 | Naeger; David M. | Anti-emetic composition |
| CA2565854A1 (en) * | 2004-05-07 | 2005-11-17 | Taro Pharmaceutical Industries Ltd. | Process for preparing ondansetron hydrochloride dihydrate having a defined particle size |
| US20050277624A1 (en) * | 2004-06-09 | 2005-12-15 | Nigel Cook | Use of corticosteroids alone or in conjunction with nutritional therapy to reduce stress in animals |
| US20060263421A1 (en) * | 2005-05-18 | 2006-11-23 | Abeille Pharmaceuticals Inc | Transdermal Method and Patch for Nausea |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES8609309A1 (en) * | 1984-01-25 | 1986-07-16 | Glaxo Group Ltd | 3-Imidazolylmethyl-1,2,3,9-tetrahydro-4H-carbazol-4-one derivatives |
| AU583343B2 (en) * | 1985-01-23 | 1989-04-27 | Glaxo Group Limited | Heterocyclic compounds |
| DE201165T1 (en) * | 1985-03-14 | 1989-04-20 | Beecham Group P.L.C., Brentford, Gb | MEDICINES FOR TREATING EMESIS, ANXIETAS AND "IRRITABLE BOWEL SYNDROME". |
| GB8516083D0 (en) * | 1985-06-25 | 1985-07-31 | Glaxo Group Ltd | Heterocyclic compounds |
| GB8628475D0 (en) * | 1986-11-28 | 1987-01-07 | Glaxo Group Ltd | Medicaments |
| IE60991B1 (en) * | 1986-12-17 | 1994-09-07 | Glaxo Group Ltd | Use of ketone derivatives in the treatment of cognitive disorders |
| US4920219A (en) * | 1988-11-29 | 1990-04-24 | Rorer Pharmaceutical Corp. | Substituted saturated and unsaturated indole quinoline and benzazepine carboxamides and their use as pharmacological agents |
| US5166145A (en) * | 1990-09-10 | 1992-11-24 | Alza Corporation | Antiemetic therapy |
| US5246709A (en) * | 1990-09-10 | 1993-09-21 | Alza Corporation | Antiemetic therapy |
-
1988
- 1988-03-04 GB GB888805269A patent/GB8805269D0/en active Pending
-
1989
- 1989-03-03 BE BE8900221A patent/BE1002255A5/en not_active IP Right Cessation
- 1989-03-03 CA CA000592765A patent/CA1319323C/en not_active Expired - Lifetime
- 1989-03-03 FR FR898902779A patent/FR2627986B1/en not_active Expired - Lifetime
- 1989-03-03 NL NL8900526A patent/NL194463C/en not_active IP Right Cessation
- 1989-03-03 NZ NZ228214A patent/NZ228214A/en unknown
- 1989-03-03 IT IT8947713A patent/IT1232662B/en active
- 1989-03-03 CH CH805/89A patent/CH678149A5/fr not_active IP Right Cessation
- 1989-03-03 IE IE69789A patent/IE61516B1/en not_active IP Right Cessation
- 1989-03-03 DK DK198901043A patent/DK175428B1/en not_active IP Right Cessation
- 1989-03-03 KR KR1019890002613A patent/KR890014109A/en not_active Application Discontinuation
- 1989-03-03 JP JP1051814A patent/JPH0296525A/en active Pending
- 1989-03-03 GB GB8904881A patent/GB2216414B/en not_active Expired - Lifetime
- 1989-03-03 ZA ZA891639A patent/ZA891639B/en unknown
- 1989-03-03 DE DE3906883A patent/DE3906883C2/en not_active Expired - Lifetime
- 1989-03-03 AT AT0048389A patent/AT400301B/en not_active IP Right Cessation
- 1989-03-03 AU AU30976/89A patent/AU626010B2/en not_active Expired
- 1989-03-03 SE SE8900751A patent/SE508342C2/en unknown
-
1991
- 1991-12-23 CZ CS914023A patent/CZ402391A3/en unknown
- 1991-12-23 SK SK4023-91A patent/SK402391A3/en unknown
-
1992
- 1992-01-30 SG SG90/92A patent/SG9092G/en unknown
- 1992-06-11 HK HK417/92A patent/HK41792A/en not_active IP Right Cessation
- 1992-11-06 CY CY1634A patent/CY1634A/en unknown
-
1993
- 1993-11-24 US US08/156,727 patent/US6544550B1/en not_active Expired - Fee Related
-
1994
- 1994-05-27 US US08/250,960 patent/US5482716A/en not_active Expired - Lifetime
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1296637C (en) | Pharmaceutical composition for the treatment of gastrointestinal disorders | |
| JP2608079B2 (en) | Medicine | |
| US5578628A (en) | Medicaments for the treatment of nausea and vomiting | |
| US4835173A (en) | Method of medical treatment | |
| CA1319323C (en) | Medicaments for the treatment of emesis | |
| US5330982A (en) | Pharmaceutical composition containing a 5-HT receptor antagonist and an H+ K+ Atpase inhibitor and a method of treating gastrointestingal disorders therewith | |
| US4983621A (en) | Medicaments | |
| JP2834175B2 (en) | Medicine | |
| US5240954A (en) | Medicaments | |
| EP0269452A2 (en) | Use of ketone derivatives for the manufacture of medicaments | |
| EP0567498A1 (en) | Pharmaceutical composition containing granisetron and dexamethasone | |
| IE902769A1 (en) | Medicaments | |
| EP0433043A1 (en) | Medicaments | |
| GB2212724A (en) | Gastrointestinal medicaments |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |
Effective date: 20100622 |