JPH01316319A - Medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to improvements in the treatment of gastrointestinal disorders. More particularly, the present invention relates to the use of compounds having antagonistic activity at 5HT3 receptors and dexamethasone in the treatment of emesis, and to pharmaceutical compositions containing these two compounds.

In the applicant's UK Patent No. 2153821A, the applicant specifically describes 1, 2.
3. 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl] -.
4H-Carbazol-4-one: and physiologically acceptable salts, solvates and physiologically acceptable equivalents thereof are disclosed.

In the said specification, the present compounds are effective and selective antagonists of 5-hydroxytryptamine (5HT) at "neuronal" 5HT receptors, a type of receptor located at the terminal ends of -order afferent nerves and also present in the central nervous system. listed as an agent.

This type of receptor is currently named the 5HT3 receptor. The compounds are described for use in the treatment of humans or animals with conditions based on impairment of neuronal 5HT function, for example in the treatment of migraine or psychiatric disorders such as schizophrenia. The compounds are also useful in treating conditions such as anxiety, obesity and chronic illness.

We have published British Patent No. 215382 as described in our published European Patent No. 226266.
It has been found that the compounds disclosed in No. 1A further promote gastric emptying and are therefore useful in treating conditions that are alleviated by promoting gastric emptying. Such symptoms include gastric stasis and symptoms of gastrointestinal dysfunction such as dyspepsia, reflux esophagitis, peptic ulcers, and flatulence.

According to published EP 226 266, the compounds are also found to be antiemetics and can also be used in the treatment or prevention of nausea and vomiting.

The use of these compounds for the treatment of emesis is covered by published European patent no.
No. 01165, which further relates to the use of the compounds for the treatment of irritable bowel syndrome.

Studies have revealed that the antiemetic effect of the compound of formula (1) is enhanced by administering the compound with dexamethasone. Dexamethasone is a systemic anti-inflammatory corticoid that has antiemetic properties and is known to be useful in the treatment of emesis caused by chemotherapy, particularly cancer chemotherapy using, for example, cisplatin.

As described above, the present invention provides a method for treating and/or preventing nausea and vomiting, which method comprises administering a compound of formula (1) or a physiologically acceptable salt or solvate thereof to a human or animal subject. and dexamethasone or a physiologically acceptable salt or ester thereof.

In another aspect, the invention provides a compound of formula (I) or a compound thereof for the manufacture of a medicament to be administered together with dexamethasone or a physiologically acceptable salt or ester thereof for the treatment and/or prevention of nausea and vomiting. Use of physiologically acceptable salts or solvates.

The combined administration of a compound of formula (1) and dexamethasone is particularly useful for the treatment and/or prevention of nausea and vomiting associated with chemotherapy, especially cancer chemotherapy using, for example, cisplatin. Such combined administration can also suppress the delayed nausea and vomiting associated with this type of chemotherapy.

The compound of formula (1) or a physiologically acceptable salt or solvate thereof and dexamethasone or a physiologically acceptable salt or ester thereof as a single pharmaceutical composition containing effective amounts of the two active ingredients. can be administered. On the other hand, the two active ingredients can also be co-administered in the form of two separate pharmaceutical compositions for simultaneous or sequential use.

Suitable physiologically acceptable salts of carbazolone of formula (I) for use in the present invention include, for example, hydrochloride, hydrobromide, sulfate, phosphate, citrate, fumarate and maleate. There are acid addition salts formed from organic or inorganic acids such as acid salts. Examples of solvates include hydrates. A preferred form of the compound of formula (T) used in the invention is the hydrochloride salt, especially in the hydrated form, such as the dihydrate.

Dexamethasone is administered according to the invention as dexamethasone alcohol or in the form of a physiologically acceptable salt or ester. Suitable salts or esters include salts or esters of acetic acid, isonicotinic acid, phenylpropionic acid, pivalic acid, t-butylacetic acid, trioxaundecanoic acid, disodium metasulfobenzoate and disodium phosphate.

The suggested dosage for the compound of formula (1) used in the present invention when administered to humans (body weight approximately 70 kg) is:
0.05-25 mg when expressed as free base weight
, more preferably 0.05-20 mg, most preferably 0.1-10 mg/unit dose. Preferred doses of dexamethasone used in the present invention are within the range of 0.5 to 20 mg/dose unit expressed as weight of alcohol.

A unit dose is administered, for example, from 1 to 4 times per day.

The precise dosage will depend on the route of administration and the condition being treated, but it will be apparent that routine modifications to the dosage will be necessary depending on the age and weight of the patient and the severity of the condition being treated.

When the two active ingredients are administered in separate formulations, they are preferably administered orally or parenterally (eg, intramuscularly or more particularly intravenously).

According to yet another aspect, the present invention provides a compound for human or veterinary medicine containing a compound of formula (1) or a physiologically acceptable salt or solvate thereof and dexamethasone or a physiologically acceptable salt or ester thereof. A pharmaceutical composition is provided.

The compositions of the invention are formulated in conventional manner using one or more physiologically acceptable carriers or excipients. For example, the compositions are formulated for oral, buccal, parenteral or rectal administration. Oral compositions, eg in the form of tablets or capsules, are preferred.

Oral compositions such as tablets and capsules can contain binders (such as pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose), fillers (such as lactose, microcrystalline cellulose or calcium hydrogen phosphate), lubricants. (e.g. magnesium stearate, talc or silica), disintegrants (e.g. potato starch or sodium starch glycolate),
or prepared by conventional means with pharmaceutically acceptable excipients such as wetting agents (eg, sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of solutions, syrups or suspensions, for example, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifiers (e.g. lecithin or gum arabic), non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol) or fractionated vegetable oil), and pharmaceutically acceptable additives such as preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid).

The formulations may also contain buffer salts, flavoring agents, youthful agents and sweetening agents, as appropriate.

Preparations for oral administration may be suitably formulated to provide controlled release of one or both active ingredients.

For parenteral administration, the compositions can be presented in a form suitable for porous injection or continuous infusion.

Formulations for injection are presented in unit dosage form, eg, 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 formulating agents such as suspending, stabilizing, and/or dispersing agents. You can.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg sterile pyrogen-free water, before use.

For rectal administration, the compositions are formulated as herbal or retention enemas containing conventional herbal bases such as cocoa butter or other glycerides.

The pharmaceutical compositions of the present invention are manufactured according to conventional techniques well known in the pharmaceutical industry. For example, a compound of formula (1) or a salt or solvate thereof and dexamethasone or a salt or ester of dexamethasone are mixed together, if desired with suitable excipients. Tablets are made, for example, by direct compression of such mixtures. Capsules are manufactured by filling the mixture with suitable excipients into gelatin capsules using a suitable filling machine. Controlled release forms for oral or rectal administration are formulated according to conventional methods for controlled release forms.

The compositions used in accordance with the invention can, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. The bag is, for example, a metal or plastic foil, such as a blister bag. The bag or dispenser device may be accompanied by instructions for administration. If the compound of formula (1) and dexamethasone are administered as two separate compositions, they can be provided, for example, in the form of a twin bag.

The following examples illustrate the preparation of compounds of formula (I). Temperature is in °C.

Example 1 3-[(dimethylamino)methyl) in water (17 ml)
-1,2,3,9-tetrahydro-9-methyl-4H-
A solution of carbazol-4-one hydrochloride (1.7 g) was
-Methylimidazole (1.4 g) and then heated under reflux for 20 hours. Filter the cooled mixture;
The residue was washed with water (3X15ml) and the mp221-2
A product of 21.5° (1.7 g) was obtained. This material was recrystallized from methanol to give the title compound (1.4g) with mp 231-232°.

Example 2 Acid dihydrate isopropanol (90 ml) and water (18.3 ml)
1. in a hot mixture of 2. 3. 9-tetrahydro-
9-Methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (18.3 g) was treated with concentrated hydrochloric acid (6.25 ml). The hot mixture was filtered and the filtrate was treated with isopropanol (90 m
l), stirred at room temperature for 17 hours, cooled to 2°,
The solid was collected by filtration (21.6 g) and the sample (6 g) was recrystallized from a mixture of water (6 ml) and isopropanol (10 ml) to yield mp178.5-179.5@
The title compound (6 g) was obtained as a white crystalline solid.

Analysis actual values: C59.45, H8.45, N 11.
Calculated value as 5C18HI9N30・HCI・2H20: C59,1, He, e; N 11.5% Moisture content analysis actual value: I (1,23% Cl8H19N30・H
Calculated value as CI・2H20=9.85% The example words below have 1. 2. 3. 9-
Tetrahydro-9-methyl-3-[(2-methyl-1H
-imidazol-1-yl)methyl] -4H-carbazol-4-one A pharmaceutical composition of the present invention containing hydrochloric acid dihydrate (compound A) and dexamethasone is described. Other physiologically acceptable salts and/or solvates of compounds of formula (1) and dexamethasone or its physiologically acceptable salt or ester are formulated in a similar manner.

Tablets for oral administration Tablets are manufactured by conventional methods such as direct compression or wet granulation.

Tablets may be film coated with a suitable film forming material such as hydroxypropyl methylcellulose using standard techniques.

Direct compression tablet ff1g/tablet Compound A 5.0"10.0" Dexamethasone BP 4.0 4.0 Anhydrous Lactose USNF 7B, 05 71
．． 05 pre-gelatinized starch USNF 4.5
4.50 Magnesium stearate BP O,4
50.45 Compressed weight 90.00
90.00 equivalents to 4.0 mg of free base** equivalent to 8.0 mg of free base Compound A and dexamethasone are passed through a suitable sieve and mixed with the lactose, pre-gelatinized starch and magnesium stearate. The resulting mixture is compressed into tablets in a suitable tablet press equipped with 6.5 mm normal concave punches.

Tablets of other strengths and/or dose combinations are made by appropriate variation of the amounts of active ingredient and excipients and use of suitable punches.

Capsule mg/capsule compound A
10.00 Dexamethasone BP 4.1) 0 Pregelatinized Starch USNP 70.625 Magnesium Stearate BP Q, 375 Filled Weight i
85.00 Compound A and dexamethasone are passed through a 250 μm sieve and mixed with pregelatinized starch and magnesium stearate. The resulting mixture is filled into No. 3 hard gelatin capsules in a suitable filling machine.

A study of patients receiving cisplatin chemotherapy found that 1.2.3°9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]- as an antiemetic agent. 4H-rubazol-4-
Treatment with OHCl dihydrate resulted in a complete response (ie, no nausea and vomiting) in 26% of the patients studied. However, treatment with Compound A (8 mg orally 3 times daily for 5 days) in combination with dexamethasone (8a+sr administered 3 times daily for 48 hours) resulted in a complete response in 50% of the patients studied.

Applicant's representative: Mr. Sato

Claims (1)

[Claims] 1,1,2,3,9-tetrahydro-9-methyl-3-
Contains [(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 A pharmaceutical composition for human or veterinary medicine. 2,1,2,3,9-tetrahydro-9-methyl-3-
Pharmaceutical composition according to claim 1, wherein [(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one is used in the form of its hydrochloride. 3,1,2,3,9-tetrahydro-9-methyl-3-
Pharmaceutical composition according to claim 2, wherein [(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one is used in the form of hydrochloric acid dihydrate. 4. 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl from 0.05 to 25 mg/unit dose when expressed as free base weight ] -4H-carbazol-4-one and 0.0 when expressed as alcohol weight.
Pharmaceutical composition according to any one of claims 1 to 3, in unit dose form containing 5 to 20 mg/unit dose of dexamethasone. 5,1,2,3,9-tetrahydro-9-methyl-3-
If the unit dose of [(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one is 0.
The pharmaceutical composition according to claim 4, which is 1 to 10 mg. 6. A pharmaceutical composition according to any one of claims 1 to 5, which is in a form adapted for oral, buccal, parenteral or rectal administration. 7. The pharmaceutical composition according to claim 6, which is administered orally in the form of a tablet. 8. Pharmaceutical composition according to any one of claims 1 to 7, containing at least one physiologically acceptable carrier or excipient. 9. Process for manufacturing a pharmaceutical composition according to any one of claims 1 to 8, characterized in that the ingredients are processed to form the pharmaceutical composition by conventional techniques. 10. 1,2,3,9-tetrahydro- as active ingredient
It is characterized by containing 9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one or a physiologically acceptable salt or solvate thereof. treatment of nausea and vomiting and/or
or a therapeutic agent for human or veterinary medicine administered together with dexamethasone or a physiologically acceptable salt or ester thereof in prophylaxis. 11,1,2,3,9-tetrahydro-9-methyl-3
Therapeutic agent according to claim 10, wherein -[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one is used in the form of its hydrochloride. 12,1,2,3,9-tetrahydro-9-methyl-3
The therapeutic agent according to claim 11, wherein -[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one is used in the form of hydrochloric acid dihydrate. 13. 0.05 to 20 mg expressed as free base weight, administered with a unit dose of dexamethasone of 0.5 to 20 mg expressed as alcohol weight.
25 mg/unit dose of 1,2,3,9-tetrahydro-
13. A unit dosage form according to any one of claims 10 to 12 containing 9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one. therapeutic agent. 14,1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4
Claim 1, wherein the unit dose of -on is 0.1 to 10 mg.
3. The therapeutic agent according to 3. 15. The therapeutic agent according to any one of claims 10 to 15, which is in a form adapted for oral, buccal, parenteral or rectal administration. 16. The therapeutic agent according to claim 15, for oral administration in the form of a tablet. 17. The therapeutic agent according to claim 15, wherein the drug and dexamethasone are administered together with, but separately from, dexamethasone for parenteral administration in the form of a formulation adapted for intravenous administration. 18. The therapeutic agent according to any one of claims 10 to 17, containing at least one physiologically acceptable carrier or excipient. 19. 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole- combined for separate administration
A twin pack comprising separate unit dosage forms of 4-one or a physiologically acceptable salt or solvate thereof and dexamethasone or a physiologically acceptable salt or ester thereof.