GB2212724A - Gastrointestinal medicaments - Google Patents
Gastrointestinal medicaments Download PDFInfo
- Publication number
- GB2212724A GB2212724A GB8827641A GB8827641A GB2212724A GB 2212724 A GB2212724 A GB 2212724A GB 8827641 A GB8827641 A GB 8827641A GB 8827641 A GB8827641 A GB 8827641A GB 2212724 A GB2212724 A GB 2212724A
- Authority
- GB
- United Kingdom
- Prior art keywords
- methyl
- physiologically acceptable
- acceptable salt
- phenoxy
- propyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- 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
Description
0 MEDICAMENTS 2212724 This invention relates to improvements in the
treatment of gastrointestinal disorders. More particularly it relates to the use of a compound having antagonist activity at 5HT3 receptors in conjunction with a compound having antagonist activity at H2-receptors in the treatment of such conditions, 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-1-yl) methyll-4H-carbazol4-one which may be represented by the formula (I)
0 M-1 ---11 1 11 H 1 N 1 Me N \ 0 / 1 Me (I) 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 5HT, 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 Patent Specification No. 226266, that the compounds disclosed in UK Patent Specification No. 2153821A additionally 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 stasis and symptoms of gastrointestinal dysfunction such as dyspepsia, reflux oesophagitis, peptic ulcer and flatulence.
According to published European Patent Specification No. 226266, the compounds have also been found to be anti-emetics, and may be used in the treatment or prevention of nausea 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. -
British Patent Specification No. 2047238B describes and claims a class of triazole derivatives and physiologically acceptable salts thereof including inter alia 1-methyl-5-[[3-[3(lpiperidinylmethyl)phenoxylpropyllaminol-lH-1,2,4-triazol e-3-methanol which may be represented by the formula (II)
NCH 0 (CH 2 4 0 Me N-N 2) SNH-e, '/I ---C H 20 H (11) The compound of formula (II) is a potent histamine H2-antagonist which may be used in the treatment of conditions where there is an advantage in lowering gastric acidity. Such conditions include duodenal, gastric and peptic ulceration, reflux oesophagitis and Zollinger-Ellison syndrome. The compound of formula (II) may also be used prophylactically in surgical procedures, and in the treatment of allergic and inflammatory conditions where histamine is a known mediator.
The combination of a 5HT3 receptor antagonist, particularly the compound of formula (I), with the H,-receptor antagonist of formula (II), provides a useful and advantageous combination for the treatment of gastrointestinal disorders. Combination therapy of this type is particularly useful for the treatment of conditions such as reflux oesophagitis where the promotion of gastric emptying by the 5HT, antagonist serves to alleviate the reflux, thereby encouraging the healing effect resulting from the reduction in gastric acidity induced 9 - 3 by the H2-peceptor antagonist. Such co-administration. may also be useful in general anaesthesia. More particularly, when the two compounds are given before or during anaesthesia, the promotion of gastric emptying by the 5HT, antagonist and the reduction of gastric acid production by the compound of formula (II) prevent both acid inhalation during anaesthesia and post-anaesthetic nausea and vomiting. Combination therapy_ of this type may also be useful for the treatment of irritable bowel syndrome.
The present invention thus provides for the use of the 5HTj receptor antagonist of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for administration in conjunction with the compound of formula (11) or a physiologically acceptable salt thereof., for the treatment of a condition which may be relieved by the promotion of gastric emptying and/or the relief of nausea and vomiting.
The compound of formula (I) or a physiologically acceptable salt or solvate thereof, and the compound of formula (II) or a physiologically acceptable salt thereof, may be administered as a single pharmaceutical compos-Ition comprising effective amounts of the two active ingredients. Alternatively the two active ingredients may be co- administered in the form of two separate pharmaceutical compositions for simultaneous or sequential use.
Suitable physiologically acceptable salts of the carbazolone of formula (I) for use according to the invention include acid addition salts formed with organic or inorganic acids for example, hydrochlorides, hydrobromides, sulphates, phosphates, citrates, fumarates and maleates. The solvates may, for example, be hydrates. A preferred form of the compound of formula (1) for use according to the invention is the hydrochloride, particularly in hydrated form, e.g. the dihydrate.
The use of physiologically acceptable equivalents of the compound of formula (I), i.e. a physiologically acceptable compound which is converted in vivo into the parent compound of formula (I), is also included within the scope of the invention.
The triazole of formula (II) may be administered according to the invention in the form of either its free base or a physiologically 1 acceptable salt. Suitable salts include salts of inorganic or organic acids such as the hydrochloride, hydrobromide, sulphate, methanesulphonate, acetate, maleate, succinate, citrate, tartrate, benzoate and fumarate salts.
The compound of formula (II) in the form of a succinate salt (e.g. the hemisuccinate 2:1 salt with succinic acid) represents a preferred form for administration.
A proposed dosage of the compound of formula (I) for use according to the invention for administration to man (of approximately 70kg body weight), is 0.05 to 25mg, more preferably 0.05 to 20mg, and most preferably 0.1 to 10mg per unit dose, expressed as the weight of free base.
A preferred dose of the compound of formula (II) for use according to the invention is in the range of 5-2QOmg, more preferably 5-150mg, and for example 5-80mg, per dosage unit, expressed as the weight of free base.
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 weight of the patient as well as the severity of the condition to be treated.
According to a further aspect the invention provides a method of treating a condition which may be relieved by the promotion of gastric emptying and/or relieving 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 the compound of formula (II) or a physiologically acceptable salt thereof.
According to yet another 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 the compound of formula (II) or a physiologically acceptable salt thereof.
k, I Compositions containing the compound of formula (I) in the form of a physiologically acceptable equivalent, as defined above, are also included within this aspect of the invention.
Compositions according to the invention may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients. Thus the compositions may, for example, be formulated for oral, buccal, parenteral or rectal administration.
Particularly useful pharmaceutical compositions for use according to the invention are those in a form suitable for oral or rectal administration.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules 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). The 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 derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or frectionatedvegetable oils); and preservatives (e.g. methyl or propyl-รบ7hydroxybenzoates 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 buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
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 may 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 be formulated as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described previously, the compositions according to the invention may also take the form of depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the active ingredients may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
The pharmaceutical 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 compound of formula (II) or a salt thereof may be admixed together, if desired, with suitable excipients. Tablets may be prepared, for example, by direct compression of such a mixture. 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 f orms - 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 V 1 1 7 pack 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 compounds of formulae (I) and (II) are intended for administration as two separate is 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 OC.
Example 1 [(2-methyl-1H-imidazol-l-yl)methyll-4H1,2,3,9-Tetrehydro-9-methyl-3carbazol-4-one A solution of 3[(dimethylamino)methyll-1,2,3,9-tetrahydro-9-methyl -4H-carbazol-4-one hydrochloride (1.7g) in water (17m1) was treated with 2-methylimidazole (1.4g) and then heated under reflux for 20h. The cooled mixture was filtered and the residue washed with water (3x15m1) to give a product (1. 7g) m.p. 221-221.50. This material was recrystallised from methanol to give the title compound (1.4g) m.p. 231-2320.
Example 2
1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-l-yl)methyll-4Hcarbazol-4-one hydrochloride dihydrate 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-IH-imidazol-l-yl)methyl]-4Hcarbazol-4-one (18.3g) in a hot mixture of isopropenol (90m1) and water (18.3m1) was treated with concentrated hydrochloric acid (6.25m1). The hot mixture was filtered and the filtrate diluted with isopropanol (90m1) and stirred at room temperature for 17h, cooled to and the solid filtered off (21.6g). A sample (69) was recrystallised from a mixture of water (6m1) and isopropanol (10m1) to give the title compound as a white crystalline solid (69) m.p.
178.5-179.50.
Analysis Found: C59.45;H6.45;N,11.5.
C,,H,,N,MC1.2H20 requires C,59.1;H,6.6;N711.5%.
Water assay Found: 10.23% C,8H,9N3O.HCI.2H20 requires 9.85% The following examples illustrate pharmaceutical compositions according to the invention, containing 1,2,3,9-tetrahydro-9-methyl-3[(2methyl-IH-imidazol-1-yl)methyll-4H-carbazol -4-one hydrochloride dihydrate (Compound A) and 1-methyl-5-[[3-[3-(l-piperidinylmethyl) phenoxylpropyllamino-lH-1,2,4-triazole-3-methenol succinate (2:1) (Compound B) as the active ingredients. Other physiologically acceptable salts and/or solvates of the compound of formu ' la (I), and the compound of formula (II) or physiologically acceptable salts thereof, may be formulated in a similar manner.
I i TABLETS FOR ORAL ADMINISTRATION Tablets may be prepared by the normal methods such as direct compression or wet granulation. The tablets may be film coated with suitable film forming materials, such as hydroxypropyl methylcellulose, using standard techniques.
Direct Compression Tablet Compound A Compound B Microcrystalline cellulose NF Anhydrous lactose NF Magnesium stearate BP mg/tablet
10. 0 23.3 125.7 40.0 1.0 10.0 46.6 110.4 32.0 1.0 Compression weight Equivalent to 8.Omg free base.
Equivalent to 20.Omg free base.
Equivalent to 40.Omg free base 200.00 200.0 Compound A and Compound B are blended with the excipients. The resultant mix is compressed into tablets using a suitable tablet press fitted with 8mm normal concave punches.
t.
1 Wet Granulation Tablet Compound A Compound B Lactose BP Starch BP Pregelatinised Maize Starch BP Magnesium Stearate BP Compression Weight mg/tablet 1 0.0 23.3 13 4. 7 20.0 10.0 2.0 200.0 The active ingredients are sieved through a suitable sieve and blended with lactose, starch and pregelatinised maize starch. Suitable volumes of purified water are added and the powders are granulated. After drying, the granules are screened and blended with the magnesium stearate. The granules are then compressed into tablets using 8mm diameter punches.
Tablets of other strengths and/or combination of doses may be prepared by appropriate alterations in the amounts of the active ingredients and the excipients and using punches to suit.
SYRUP This may be either a sucrose or sucrose free presentation.
A. Sucrose Syrup Compound A Compound B Sucrose BP Glycerine BP Buffer Flavour Colour Preservative) Purified Water BP mg/5mi dose 10.0 23.3 2750.0 500.0 as required to 5. Om The active ingredients, buffer, flavour, colour and preservativ are dissolved in some of the water and the glycerine is added. The remainder of the water is heated to dissolve the sucrose and is then 0 cooled. The two solutions are combined, adjusted to volume and mixed. The syrup is clarified by filtration.
B. Sucrose-Free mg/5mt dose Compound A 10.0 Compound B 23.3 Hydroxypropylmethyleellulose USP (viscosity type 4000) 22.5 Buffer Flavour Colour As required Preservative) Sweetener Purified Water BP to 5.0mI The h ydroxy prop yImeth ylcellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredients and the other components of the formulation. The resultant.solution is adjusted to volume and mixed. The syrup is clarified by filtration.
i v 1 -F
Claims (10)
- A pharmaceutical composition for use in human or veterinary medicine comprising 1, 2, 3, 9 -tetrahydro-9 -methyl -3 - [ (2 -methyl- 1Himida z ol - 1 -yl) methyl] -4-H-carbazol-4 -one or a physiologically acceptable salt or solvate thereof and 1-methyl-5-[[3-[3(1piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazol e-3methanol or a physiologically acceptable salt thereof.
- 2. A pharmaceutical composition as claimed in claim 1 wherein the 1,2,3,9tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-lyl) methyl] -4H-carbazol-4one is used in the form of the hydrochloride dihydrate salt.
- 3. A pharmaceutical composition as claimed in claim 1 or 2 wherein the 1methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4triazole-3-methanol is used in the form of a succinate salt.
- 4. A pharmaceutical composition as claimed in any of claims 1 to 3 in unit dose form containing from 0.05 to 25mg per unit dose of 1, 2, 3, 9 - t etrahydro-9 -methyl- 3 - [ (2 -methyl -1H-imidaz ol -1yl)nethyl]-4Hcarbazol-4-one or a physiologically acceptable salt or solvate thereof and from 5 to 200mg per unit dose of 1-methyl5- [ 3- [3- (1piperidinylmethyl) phenoxy] propyl]amino] -1H-1,2,4triazole-3-methanol or a physiologically acceptable salt thereof, both amounts being expressed as the weight of free base.
- 5. A pharmaceutical composition as claimed in any of claims 1 to 4 in a form adapted for oral, buccal, parenteral or rectal administration.
- 6. A pharmaceutical composition as claimed in claim 5 for oral administration in the form of tablets.
- 7. Use of 1,2,3,9-tetrahydrog-methyl-3-[(2-methyl-1Himida z ol - 1 -yl) methyl] -4H-carbazol-4 -one or a physiologically acceptable salt or solvate thereof for the manufacture of a 5539/1 ' IQ-, medicament for administration in conjunction with 1-methyl-5-[[3[3- (1piperidinylmethyl)phenoxy]propyl] amino] -IH-1, 2,4-triazole3-methanol or a physiologically acceptable salt thereof in the treatment of gastrointestinal disorders.
- 8. Use according to claim 7 wherein the 1,2,3,9-tetrahydro-9nethyl-3-[(2inethyl-1H-imidazol-l-yl)methyl]-4H-carbazo l-4-one is used in the form of the hydrochloride dihydrate salt.
- 1,1 g. Use according to claim 7 or 8 wherein the 1-methyl-5-[[3[3-(1piperidinylmethyl)phenoxy]propyl]anino]-1H-1,2,4-triazol e3-methanol is used in the form of a succinate salt.
- 10. A twin pack comprising separate unit dosage forms of 1,2,3,9tetrahydro-9-methyl-3-[(2-Tnethyl-1H-imidazol-lyl)methyl]-4H-carbazo1-4one or a physiologically acceptable salt or solvate thereof and 1-methylS-[[3-[3-(1piperidinylr,ethyl)phenoxy]propyl]artino]-1H-1,2,4-triaz ole3methanol or a physiologically acceptable salt thereof in association for separate administration.5539/1 Published 1989 at The Patent Office. State House, 86.171 High Ho1born, LondonWClR4TP- Further copies MAY be obtainedfroin The PatentOfflee. Sales Branch, St Mary Cray, Orpington. Kent BR5 3RD. Printed by Multiplex techruques ltd, St Mary Cray, Kent, Con. 1/87
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB878727685A GB8727685D0 (en) | 1987-11-26 | 1987-11-26 | Medicaments |
Publications (2)
Publication Number | Publication Date |
---|---|
GB8827641D0 GB8827641D0 (en) | 1988-12-29 |
GB2212724A true GB2212724A (en) | 1989-08-02 |
Family
ID=10627570
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB878727685A Pending GB8727685D0 (en) | 1987-11-26 | 1987-11-26 | Medicaments |
GB8827641A Withdrawn GB2212724A (en) | 1987-11-26 | 1988-11-25 | Gastrointestinal medicaments |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB878727685A Pending GB8727685D0 (en) | 1987-11-26 | 1987-11-26 | Medicaments |
Country Status (6)
Country | Link |
---|---|
JP (1) | JPH01250319A (en) |
DE (1) | DE3839883A1 (en) |
FR (1) | FR2623713A1 (en) |
GB (2) | GB8727685D0 (en) |
IT (1) | IT1235158B (en) |
NL (1) | NL8802906A (en) |
-
1987
- 1987-11-26 GB GB878727685A patent/GB8727685D0/en active Pending
-
1988
- 1988-11-25 GB GB8827641A patent/GB2212724A/en not_active Withdrawn
- 1988-11-25 FR FR8815444A patent/FR2623713A1/en not_active Withdrawn
- 1988-11-25 IT IT8848597A patent/IT1235158B/en active
- 1988-11-25 NL NL8802906A patent/NL8802906A/en not_active Application Discontinuation
- 1988-11-25 JP JP63297987A patent/JPH01250319A/en active Pending
- 1988-11-25 DE DE3839883A patent/DE3839883A1/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
JPH01250319A (en) | 1989-10-05 |
IT8848597A0 (en) | 1988-11-25 |
NL8802906A (en) | 1989-06-16 |
GB8827641D0 (en) | 1988-12-29 |
FR2623713A1 (en) | 1989-06-02 |
DE3839883A1 (en) | 1989-06-08 |
GB8727685D0 (en) | 1987-12-31 |
IT1235158B (en) | 1992-06-22 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |