CA2022380A1 - Medicaments - Google Patents

Abstract

A B S T R A C T

MEDICAMENTS

The invention relates to the use of compounds of the general formula (I) (I) and physiologically acceptable salts and solvates thereof, in which Im represents an imidazolyl group of formula:

or and R1 represents a hydrogen atom or a group selected from C1-6alkyl, C3-6alkenyl, C3-10alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, phenyl, phenylC1-3alkyl, phenylmethoxymethyl, phenoxyethyl, phenoxymethyl, -CO2R5, -COR5, -CONR5R6 or -SO2R5 (wherein R5 and R6, which may be the same or different each represents a hydrogen atom, a C1-6alkyl or C3-7cycloalkyl group, or a phenyl or phenylC1-4alkyl group, in which the phenyl group is optionally substituted by one or more C1-4alkyl, C1-4alkoxy or hydroxy groups or halogen atoms, with the proviso that R5 does not represent a hydrogen atom when R1 represents a group -CO2R5 or -SO2R5);
one of the groups represented by R2, R3 and R4 is a hydrogen atom or a C1-6alkyl, C3-7cycloalkyl, C3-6alkenyl, phenyl or phenylC1-3alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1-6alkyl group;
and n represents 2 or 3, for the treatment of a condition involving excessive eating, for example bulimia.

Description

2~223~û

MEDICAMENTS

This invention relates to a new medical use for a group of heterocyclic compounds and pharmaceutical compositions containing them. In particular it rel8tes to the use of certain lactam derivatives in the treatment of conditions involving excessive eating.
French Patent Specificstion No. 2625678 discloses the use of various quinuclidine benzamides and thiobenzamides, together with their N-oxides, hydrates and salts in the treatment of increased weight and obesity of various causes. The use of 4-amino-5-chloro-2-methoxy-N-(quinuclidin-3-yl~benzamide (which has the approved name zacopride), a compound which is known to be an antagonist of 5-hydroxytryptamine (5-HT) at 5-HT~ receptors, is specifically described.
UK Patent Specification No. 2153821B discloses the use of various 1,2,3,9-tetrahydro-3-[(imidazol-1-yl)methyl]-4H-carbazol-4-ones and their salts and solvates in the treatment of inter alia obesity.
UK2153821B describes these tetrahydrocarbazolones as potent and selective antagonists of 5-HT at 'neuronal' 5-HT receptors of the type located on terminals of primary afferent nerves, receptors of this type now being designated as 5-HT~ receptors.
U.K. Patent Specification No. 22û9335A discloses compounds of the general formula (I):
R

. . N Im ! 11 11 ( 1 ~I) / \N/ ~ n Il In the above formula Im represents an imidazolyl group of formula:

~223~a I _ i or '!~
R~ R~
and Rl represents a hydrogen atom or a group selected from Cl_~alkyl, C~_~alkenyl, C3_lualkynyl, C3_~cycloalkyl, C~_,cycloalkylCl_4 alkyl, phenyl, phenylCl_3alkyl, phenylmethoxymethyl, phenoxyethyl, phenoxymethyl, -CO~R~, -CORa, -CONR~R~ or -SO~R~ Iwherein R~ and R6, which may be the same or different, each represents a hydrogen atom, a Cl_~ alkyl or C~_/
cycloalkyl group, or a phenyl or phenylCl_4alkyl group, in which the phenyl groupiis optionally substituted by one or more Cl_4 alkyl, Cl_4 alkoxy or hydroxy groups or halogen atoms, with the proviso that R~
does not represent a hydrogen atom when Rl represents a group -CO~Ra or -SO~R~);
one of the groups represented by R~, R~ and R4 is a hydrogen atom or a Ci_~alkyl, C~_,cycloalkyl, C~_balkenyl, phenyl or phenylCl_~alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a Cl_~ alkyl group;
and n represents 2 or 3.
Suitable physiologically acceptable salts of the compounds of ger,eral formula (I) include acid addition salts formed with organic or inorganic acids for example, hydrochlorides, hydrobromides, sulphates, alkyl- or arylsulphonates (e.g. methanesulphonates or p-toluenesulphonates), phosphates, acetates, citrqtes, succinates, tartrates, fumarates and maleates. The solvates may, for example, be hydrates.
The compounds of formula (I) are described in UK2209335A as potent and selective antagonists of 5-HT at 5-HT3 receptors, and as being of use in the treatment of conditions such as anxiety, psychotic disorders (e.g. schizophrenia and mania); nausea and vomiting (particularly that associated with cancer chemotherapy and radiotherapy); gastric stasis; symptoms of gastrointestinal dysfunction such as dyspepsia, peptic ulcer, reflux oesophagitis, _ _ . _ . _ ~ _ _ _ _ . . . .. _ _ . _ _ . _ _ , _ . . .. _ . . . . . . . . . .. ..

~223~

flatulence and irritable bowel syndrome; migraine; and pain. It is also stated that the compounds may be used in the treatment of dependency on drugs and substances of abuse, depression, and dementia and other cognitive disorders.
It has now been found that compounds which are antagonists of 5-HT at 5-HT~ receptors, such as the compounds of formula (I), are useful for the treatment of conditions involving excessive eating, in particular bulimia. Bulimia (and more specifically bulimia nervosa) is a condition in which there is an abnormal desire for food, particularly rich, sweet, and highly palatable foods, which leads to over-indulgence and bouts of binge eating. This is combined with an overconcern for body size, such that excessive eating is often i followed by purging and/or vomiting. The compounds of formula (I) are also useful for the treatment of other conditions which involve excessive eating, such as obesity and seasonal affective disorder (SAD).
The ability of 5-HT~ receptor antagonists, such as the compounds of formula (I), to suppress the intake of palatable foods has been demonstrated in rats. Thus in rats familiarised with eating an enriched sweetened mash, administration of a 5-HT~ receptor antagonist resulted in significant reductions in food intake.
Accordingly the invention provides a method of treatment of a subject suffering from bulimia or another condition involving excessive eating, which comprises administering to the subject an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.
References in this specification to treatment include prophylactic treatment as well as the acute alleviation of symptoms.
The use of all optical isomers of compounds of general formula (I) and their mixtures including the racemic mixtures thereof, and all the geometric isomers of compounds of formula (I), is embraced by the invention.
A preferred group of compounds of formula (I) for use according to the invention is that wherein Rl represents a hydrogen atom or a 2~223~

C~_4 alkyl, C3_4alkenyl, C3_4alkynyl, C5_6cycloalkyl, C~_6cycloalkylmethyl, phenylCi_~ alkyl, phenylmetho~ymethyl, N,N-diCl_3alkylcarboxamido or Cl_3alkylsulphonyl group; R2 represents a hydrogen atom; and R3 and R4 each represent a hydrogen atom or a Cl_3 alkyl group.
A particularly preferred group of compounds of formula (I) for use according to the invention is that wherein pl represents a methyl, n-propyl, prop-2-ynyl, cyclopentyl, cyclopentylmethyl, benzyl or N, N-dimethylcarboxamido group; R~ and R~ each represent a hydrogen atom;
and R4 represents a methyl group.
Within the above preferred and particularly preferred groups of compounds, an especially important group of compounds is that in which n represents 2.
Another preferred group of compounds of flormula (I) for use sccording to the invention is that wherein Rl represents a hydrogen atom or a C~_4alkyl (e.g. methyl, ethyl, n-propyl or isopropyl) group;
R~ and R~ each represent a hydrogen atom; R4 represents a methyl group; and n is 2.
~ preferred compound for use according to the invention is:
2,3,4,5-tetrahydro-2-~(5-methyl-lH-imidazol-4-yl)methyl]-5-propyl-lH-pyrido[4,3-b]indol-1-one and its physiologically acceptable salts and solvates.
Other preferred compounds for use according to the invention are:
5-ethyl-2,3,4,5-tetrahydro-2-[(5-methyl-lH-imidazol-4-yl)methyl]-lH-pyrido[4,3-b]indol-1-one;
25 2,3,4,5-tetrahydro-5-(1-methylethyl)-2-[(5-methyl-lH-imidazol-4-yl) methyl]-lH-pyrido[4,3-b]indol-1-one;
2,3,4,5-tetrahydro-2-~(5-methyl-lH-imidazol-4-yl)methyl]-lH-pyrido-[4,3-b]indol-1-one;
and their physiologically acceptable salts and solvates.
A particularly preferred compound for use according to the invention is 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-lH-imidazol-4-yl)methyl]-lH-pyrido[4,3-b]indol-1-one and its physiologically acceptabie salts and solvates. Preferred salts of this compound are the hydrochloride and maleate, of which the hydrochloride is particularly preferred.

2~238~

In a further aspect, the invention provides a pharmaceutical composition which comprises an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate (e.g.
hydrate) thereof, for use in medicine, particularly human medicine, for the treatment of bulimia or another condition involving excessive eating.
In a yet further aspect, the invention provides for the use of a compound of formula (1) or a physiologically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of bulimia or another condition involving excessive eatinq.
Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically accepta~ble carriers or excipients.
Thus the compounds of formula (I) and their physiologically acceptable salts and solvates may be formulated for oral, buccal, parenteral, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflstion (either through the mouth or the nose).
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 sgents (e.g. pre3elatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stesrate, 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 fractionated vegetable oils); and preservatives (e.g.

.. _ .. _ _ . _ _ _ _ _ ... _ . . . . . . . . . _ , . . . ... . . . .

---` 2~223~

methyl or propyl-p-hydroxybenzo~tes or sorbic eoid). The preparations may also contain buffer salts, flavourlng, oolouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds of formula (I) may be formulated for parenteral sdministration by injection e.g. by 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 ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
The compounds of formula (I) may also be formulated in rectal compositions such 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 compounds may also be formulated as depot preparations. Such long acting formuiations may be sdministered by implantation (for example subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of formula (I) 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.
A proposed dose of a compound of formula (I) for use according to the invention for administration to a subject (of approximately 70kg body weight) is 0.001 to lOOmg, for example 0.01 to 50mg, more preferably 0.1 to 20mg, of the active ingredient per unit dose, expressed as the weight of free base. The unit dose may be administered, for example, l to 4 times per day. The dose will depend 7 2022~3~
on the route of administI~tion. It will be ~ppreclated 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.
Compounds of general formula (I) and physiologically acceptable salts or solvates thereof, may be prepared by the methods described in U.K. Patent Specification No. 2209335A.
The following examples illustrate the preparation of 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-lH-imidazol-4-yl)methyl]-lH-pyrido~4,3-b]indol-1-one and its hydrochloride salt, covered by formula (I). Temperatures are in UC. Thin layer chromatograpy (t.l.c.) was carried out on silica.

Example 1 2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-lH-imidazol-4-yl)methyl]-lH-pyridoC4,3-b]indol-1-one A mixture of 2,3,4,5-tetrahydro-5-methyl-lH-pyrido~4,3-b]indol-1-one (49.979), p-toluenesulphonic acid monohydrate (9.509) and 4-hydroxymethyl-5-methylimidazole hydrochloride (20.259) in N-methylpyrrolidinone (250m~) was stirred and heated to 125 (over lh) The reaction was then heated at 125-130U for 4.5h, during which time two further portions of 4-hydroxymethyl-5-methylimidazole hydrochloride (17.519 and 6.889) were added. The reaction mixture was coGled, diluted with water (lOOm~), and the stirred mixture was treated slowly with 8~ aqueous sodium bicarbonate (750m~). The resultant suspension was stirred in an ice bath for lh and then filtered to give a solid (57.649). A portion of this solid (11.099) was dissolved in dichloromethane (307mR) and ethanol (166mR), boiled with decolourising charcoal for lOmin and then filtered. The dichloromethane was distilled off at atmospheric pressure until the temperature of the mixture was at 65U. The stirred mixture was cooled 30 and the resulting precipitate was filtered off to give the title compound (9.289), t.l.c. (dichloromethane : ethanol: 0.88 ammonia, 50:8:1) Rf 0.55 .

`` 20~23~
_ 9 _ lH-n~m.r (DMSO-db):~ 2.20(3H,s~, 3.03(2H,t), 3.64(2H,m), 3.71(3H,s), 4.50(2H,s), 7.19(2H,m), 7.44(1H,s), 7.50(1H,d), 7.99(1H,d), 11.76(1H,s).

Example 2 2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-lH-imidazol-4-yl)methyl]-lH-pyrido[4,3-b]indol-1-one hydrochloride 2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-lH-imidazol-4-yl)methyl]-lH-pyrido[4,3-b]indol-1-one (1.009) was suspended in ethanol (40ml) and concentrated hydrochloric acid (l.OOml) was added. The mixture was warmed to 40u and charcoal (0.259) was added. The resulting suspension was stirred and warmed for 5 min. and then filtered. The filtrate was evaporated in vacuo to ca. 20ml and was sllowed to cool t` to 20U. Ether (40ml) was added with stirring over 5 min., and ~he mixture was stored at 4u overnight. The resulting precipitate was filtered off, washed with ether (2xlOml), dried in vacuo at room temperature for 2h and then at 70~ for 7 h to give the title compound (0.959), m.p. 288-291U.
Analysis Found: C,61.4; H,5.8; N,16.7; Cl, 10.7;
Cl,Hl~N40.HCl requires C,61.7; H,5.8; N,16.9; Cl, 10.7 The following examples illustrate pharmaceuticsl formulations for use sccording to the invention, containing 2,3,4,5-tetrahydro-5-methyl-2- [(5-methyl-lH-imidszol-l-yl)methyl]-lH-pyrido-[4,3-b]indol-1-one hydrochloride as the active ingredient. Other 25 physiologically acceptable salts and/or solvates of this compound, and other compounds of formula (I) and their physiologically acceptable salts and/or solvates 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.
The tablets may be film coated with suitable film forming materials, such as hydroxypropyl methylcellulose, using standard 35 techniques. Alternatively the tablets may be sugar coated.

9 2~223~0 Direct Compre8sion Tablet mq/tsblet Active Ingredient 0.562 Microcystalline cellulose NF 31.250 Lactose (snhydrous) NF 111.303 Pregelatinised maize starch BP 6.250 Magnesium Stearate 0.625 Compression weight 150.0 * of a grade suitable for direct compression.
The active ingredient is passed through a 60 mesh sieve, blended with the lactose, microcystalline cellulose, pregelatinised maize starch and magnesium stearate. The resultant mix is compressed into tablets using a suitable tablet machine fitted with 7.0mm, normal lS concave punches.

INOECTION FOR INTRAVENOUS ADMINISTRATION

mg/m~

20 Active ingredient 0.0562 0.562 Sodium Chloride BP as required as required Water for Injection BP to l.Om~ l.Om~

Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted, using acid or alkali, to that of 25 optimum stability snd/or facilitate solution of the active ingredient. Alternatively, suitable buffer salts may be used.
The solution is prepared, clarified and filled into appropriate size ampoules sealed by fusion of the glass. The injection is sterilised by heating in an autoclave using one of the acceptable 30 cycles. Alternatively, the solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions. The .. .. ~

- - 10 - 2~22'3~0 solution may be pscked under an inert stmosphere of nitrogen or other suitable gas.

SUPPOSI~ORY

Active Ingredient 0.562mg * Witepsol H15 to 1.09 * Witepsol H15 is a proprietary grade of Adeps Solidus Ph. Eur.

A suspension of the active ingredient is prepared in the molten Witepsol and filled, using suitable machinery, into 19 size suppository moulds.
j:

Claims (10)

1. A pharmaceutical composition for the treatment of a condition involving excessive eating comprising as active ingredient a compound of the general formula (I) (I) or a physiologically acceptable salt or solvate thereof, in which Im represents an imidazolyl group of formula:

or and R1 represents a hydrogen atom or a group selected from C1-6alkyl, C3-6alkenyl, C3-10alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, phenyl, phenylC1-3alkyl, phenylmethoxymethyl, phenoxyethyl, phenoxymethyl, -CO2R5, -COR5, -CONR5R6 or -SO2R5 (wherein R5 and R6, which may be the same or different each represents a hydrogen atom, a C1-6alkyl or C3-7cycloalkyl group, or a phenyl or phenylC1-4alkyl group, in which the phenyl group is optionally substituted by one or more C1-4alkyl, C1-4alkoxy or hydroxy groups or halogen atoms, with the proviso that R5 does not represent a hydrogen atom when R1 represents a group -CO2R5 or -SO2R5);
one of the groups represented by R2, R3 and R4 is a hydrogen atom or a C1-6alkyl, C3-7cycloalkyl, C3-6alkenyl, phenyl or phenylC1-3alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1-6alkyl group;
and n represents 2 or 3.

2. A pharmaceutical composition as claimed in Claim 1 for the treatment of bulimia or a related disorder.

3. A pharmaceutical composition as claimed in Claim 1 or 2 wherein R1 represents a hydrogen atom or a C1-4alkyl, C3-4alkenyl, C3-4alkynyl, C5-6cycloalkyl, C5-6cycloalkylmethyl, phenylC1-2alkyl, phenylmethoxymethyl, N,N-diC1-3alkylcarboxamido or C1-3alkylsulphonyl group; R2 represents a hydrogen atom;
and R3 and R4 each represent a hydrogen atom or a C1-3alkyl group.

4. A pharmaceutical composition as claimed in any of Claims 1 to 3 wherein n is 2.

5. A pharmaceutical composition as claimed in Claim 1 or 2 wherein R1 represents a hydrogen atom or a C1-4alkyl group; R2 and R3 each represent a hydrogen atom; R4 represents a methyl group; and n is 2.

6. A pharmaceutical composition as claimed in Claim 1 or 2 wherein the compound of formula (I) is 2,3,4,5-tetrahydro-5-methyl-2[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one or a physiologically acceptable salt or solvate thereof.

7. A pharmaceutical composition as claimed in Claim 6 wherein the compound is in the form of a hydrochloride salt.

8. A pharmaceutical composition as claimed in any of Claims 1 to 7 in a form adapted for oral, buccal, parenteral, rectal or transdermal administration or in a form adapted for administration by inhalation or insufflation.

9. A pharmaceutical composition as claimed in any of Claims 1 to 8 in unit dose form containing from 0.001 to 100 mg of active ingredient per unit dose expressed as the weight of free base.

10. A pharmaceutical composition as claimed in Claim 9 wherein the amount of active ingredient per unit dose is from 0.1 to 20 mg.