1,5-Diaryl-pyrrole-3-carboxamide derivatives and their use as cannabinoid receptor modulators

Description

FIELD OF INVENTION

The present invention relates to certain pyrrole carboxamide compounds of formula I, to processes for preparing such compounds, to their use in the treatment of obesity, psychiatric and neurological disorders, and to pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

It is known that certain CB₁modulators (known as antagonists or inverse agonists) are useful in the treatment of obesity, psychiatric and neurological disorders (WO01/70700 and EP 656354). However, there is a need for CB₁modulators with improved physicochemical properties and/or DMPK properties and/or pharmacodynamic properties.

1,5-Diarylpyrrole-3-carboxamides are reported to have antifungal activity in Il Farmaco 1988, vol XLIII, N9 665, M. Scalzo et al, Il Farmaco 1988, vol 43, N9 677, M. Scalzo et al, Il Farmaco 1989, vol 44, N1 65, C. G. Porretta et al, and Eur. J Med. Chem 1992, 27, 701 F Cerretto et al. All compounds disclosed in these documents are disclaimed from the compound claims of the present application.

U.S. Pat. No. 6,248,894 discloses certain pyrroles have anti-fungal activity. All compounds disclosed in this document are disclaimed from the compound claims of the present application.

WO01/58869 discloses that certain 1-(2-morpholinoethyl)pyrrolecarboxamides are useful in treating respiratory diseases.

DESCRIPTION OF THE INVENTION

The invention relates to a compound of formula (I)
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and pharmaceutically acceptable salts, prodrugs, solvates and crystalline forms thereof, in which

R¹and R²independently represent phenyl, thienyl or pyridyl each of which is optionally substituted by one, two or three groups represented by Z;
Z represents a C_1-3alkyl group, a C_1-3alkoxy group, hydroxy, halo, trifluoromethyl, trifluoromethylthio, difluoromethoxy, trifluoromethoxy, trifluoromethylsulphonyl, nitro, amino, mono or di C_1-3alkylamino, mono or di C_1-3alkylaimdo, C_1-3alkylsulphonyl, C_1-3alkoxycarbonyl, carboxy, cyano, carbamoyl, mono or di C_1-3alkyl carbamoyl, sulphamoyl and acetyl; and
R³is H, a C_1-3alkyl group, a C_1-3alkoxymethyl group, trifluoromethyl, a hydroxyC_1-3alkyl group, an aminoC_1-3alkyl group, C_1-3akoxycarbonyl, carboxy, cyano, carbamoyl, mono or di C_1-3alkylcarbamoyl, acetyl, or hydrazinocarbonyl of formula —CONHNR^aR^bwherein R^aand R^bare as defined for R⁴and R⁵respectively and;
X is CO or SO₂;
Y is absent or represents NH optionally substituted by a C_1-3alkyl group;
R⁴and R⁵independently represent:
a C_1-6alkyl group;
an (amino)C_1-4alkyl-group in which the amino is optionally substituted by one or more C_1-3alkyl groups;
an optionally substituted non-aromatic C_3-15carbocyclic group;
a (C_3-12cycloalkyl)C_1-3alkyl-group;
a group —(CH₂)_r(phenyl )_sin which r is 0,1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 and the phenyl groups are optionally independently substituted by one, two or three groups represented by Z;
naphthyl;
anthracenyl;
a saturated 5 to 8 membered heterocyclic group containing one nitrogen and optionally one of the following: oxygen, sulphur or an additional nitrogen wherein the heterocyclic group is optionally substituted by one or more C_1-3alkyl groups, hydroxy or benzyl;
1-adamantylmethyl;
a group —(CH₂)_tHet in which t is 0,1, 2, 3 or 4, and the alkylene chain is optionally substituted by one or more C_1-3alkyl groups and Het represents an aromatic heterocycle optionally substituted by one, two or three groups selected from a C_1-5alkyl group, a C_1-5alkoxy group or halo;
or R⁴represents H and R⁵is as defined above;
or R⁴and R⁵together with the nitrogen atom to which they are attached represent a saturated 5 to 8 membered heterocyclic group containing one nitrogen and optionally one of the following: oxygen, sulphur or an additional nitrogen; wherein the heterocyclic group is optionally substituted by one or more C_1-3alkyl groups, hydroxy or benzyl;
R⁶is H, a C_1-3alkyl group, a C_1-3alkoxymethyl group, trifluoromethyl, a hydroxyC_1-3alkyl group, an aminoC_1-3alkyl group, C_1-3alkoxycarbonyl, carboxy, cyano, carbamoyl, mono or di C_1-3alkylcarbamoyl, acetyl, or hydrazinocarbonyl of formula —CONHNR^aR^bwherein R^aand R^bare as defined for R⁴and R⁵respectively and;
with the proviso that when R⁶is methyl then the group X—Y—NR⁴R⁵does not represent CONHC₆H₁₃, CONHC₁₂H₂₅, CONH₂, CONHCH₃, CON(CH₃)₂,

and with the further proviso that when R¹and R²independently represent phenyl then Z is not an ortho methyl group.

In a particular group of compounds of formula I Z represents a C_1-3alkyl group, a C_1-3alkoxy group, hydroxy, halo, trifluoromethyl, trifluoromethylthio, difluoromethoxy, trifluoromethoxy, trifluoromethylsulphonyl, amino, mono or di C_1-3alkylamino, mono or di C_1-3alkylamido, C_1-3alkylsulphonyl, C_1-3alkoxycarbonyl, carboxy, cyano, carbamoyl, mono or di C_1-3alkyl carbamoyl, sulphamoyl and acetyl.

Further values of R¹, R², R³, X—Y—NR⁴R⁵and R⁶in compounds of formula I now follow. It will be understood that such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.

In one group of compounds of formula I, R¹represents phenyl optionally substituted by halo or C_1-3alkoxy located in the 2 and 4 positions of the phenyl ring. In such compounds R¹is selected from phenyl, 4-chlorophenyl, 2,4-dichlorophenyl and 4-methoxyphenyl.

In a second group of compounds of formula I, R²represents phenyl optionally substituted by halo or C_1-3alkoxy located in the 2 and 4 positions of the phenyl ring. In such compounds R¹is selected from phenyl, 2,4-dichlorophenyl and 2,4-dimethoxyphenyl.

In a third group of compounds of formula I, X—Y—NR⁴R⁵represents CONHPh or CONH(1-piperidyl).

In a fourth group of compounds of formula I, X—Y—NR⁴R⁵represents CONH(1-piperidinyl).

In a fifth group of compounds of formula I, X—Y—NR⁴R⁵represents CO(1-piperidinyl). In a sixth group of compounds of formula I, R⁶represents methyl.

One group of compounds of the present invention relates to compounds of the general formula (II)
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and pharmaceutically acceptable salts, prodrugs, and solvates in which

m represents 0,1, 2 or 3
R⁷represents a C_1-6alkyl group, trifluoromethyl, a C_1-6alkoxy group, difluoromethoxy, trifluoromethoxy, or halo wherein when m is 2 or 3 then the groups R¹may be the same or different;
n represents 0,1, 2 or 3;
R⁸represents a C_1-6alkyl group, trifluoromethyl, a C_1-6alkoxy group, difluoromethoxy, trifluoromethoxy, or halo wherein when n is 2 or 3 then the groups R²may be the same or different;
R⁹represents 1-piperidinyl, 1-piperidinylamino or anilino wherein the phenyl ring is optionally substituted by one or more of the following: a C_1-6alkyl group, trifluoromethyl, a C_1-6alkoxy group, difluoromethoxy, trifluoromethoxy or halo; and
R¹⁰represents a C_1-6alkyl, C_1-6alkoxy, or a C_1-6alkylamino group;
with the proviso that the compound is not 1-{[1-(4-chlorophenyl)-5-phenyl-2-methyl-1H-pyrrol-3-yl]carbonyl}piperidine or 1-{[1-(2,4-dichlorophenyl)-5-phenyl-2-methyl-1H-pyrrol-3-yl]carbonyl}piperidine.

Further values of R⁷, R⁸, R⁹, R¹⁰in compounds of formula I now follow. It will be understood that such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.

In one group of compounds of formula II, m is 2 and the groups R⁷are located in the 2 and 4 positions of the phenyl ring. In such compounds R⁷is selected from chloro and methoxy and the groups R⁷may be the same or different.

In a second group of compounds of formula II, n is 2 and the groups R⁸are located in the 2 and 4 positions of the phenyl ring. In such compounds R⁸is selected from chloro and methoxy and the groups R⁸may be the same or different.

In a third group of compounds of formula II, R⁹represents anilino.

In a fourth group of compounds of formula II, R⁹represents 1-piperidinyl

In a fifth group of compounds of formula II, R⁹represents 1-piperidinylamino.

In a sixth group of compounds of formula II, R¹⁰represents methyl.

“Pharmaceutically acceptable salt”, where such salts are possible, include pharmaceutically acceptable acid addition salt. A suitable pharmaceutically acceptable salt of a compound of Formula I is, for example, an acid-addition salt of a compound of Formula I which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid.

Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof as well as mixtures in different proportions of the separate enantiomers, where such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates. Isomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation The enantiomers may be isolated by separation of racemate for example by fractional crystallisation, resolution or HPLC. The diastereomers may be isolated by separation of isomer mixtures for instance by fractional crystallisation, HPLC or flash chromatography. Alternatively the stereoisomers may be made by chiral synthesis from chiral starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, with a chiral reagent. All stereoisomers are included within the scope of the invention.

The following definitions shall apply throughout the specification and the appended claims.

Unless otherwise stated or indicated, the term “alkyl” denotes either a straight or branched alkyl group. Examples of said alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl sec-butyl and t-butyl. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl and tertiary butyl.

Unless otherwise stated or indicated, the term “alkoxy” denotes a group O-alkyl, wherein alkyl is as defined above.

Unless otherwise stated or indicated, the term “halo” shall mean fluorine, chlorine, bromine or iodine.

Specific compounds of the invention are:

2-methyl-N,1,5-triphenyl-1H-pyrrole-3-carboxamide;
1-(4-chlorophenyl)-2-methyl-N,5-diphenyl-1H-pyrrole-3-carboxamide;
1-(4-methoxyphenyl)-2-methyl-N,5-diphenyl-1H-pyrrole-3-carboxamide;
5-(2,4dichlorophenyl)-2-methyl-N,1-diphenyl-1H-pyrrole-3-carboxamide;
1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-methyl-N-phenyl-1H-pyrrole-3-carboxamide;
5-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-2-methyl-N-phenyl-1H-pyrrole-3-carboxamide;
5-(2,4-dimethoxyphenyl)-2-methyl-N,1-diphenyl-1H-pyrrole-3-carboxamide;
1-(4-chlorophenyl)-5-(2,4-dimethoxyphenyl)-2-methyl-N-phenyl-1H-pyrrole-3-carboxamide;
5-(2,4-dimethoxyphenyl)-1-(4-methoxyphenyl)-2-methyl-N-phenyl-1H-pyrrole-3-carboxamide;
2-methyl-1,5-diphenyl-N-piperidin-1-yl-1H-pyrrole-3-carboxamide;
1-(4chlorophenyl)-2-methyl-5-phenyl-N-piperidin-1-yl-1H-pyrrole-3-carboxamide;
1-(4-methoxyphenyl)-2-methyl-5-phenyl-N-piperidin-1-yl-1H-pyrrole-3-carboxamide;
5-(2,4-dichlorophenyl)-2-methyl-1-phenyl-N-piperidin-1-yl-1H-pyrrole-3-carboxamide;
1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-methyl-N-piperidin-1-yl-1H-pyrrole-3-carboxamide;
5-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-2-methyl-N-piperidin-1-yl-1H-pyrrole-3-carboxamide;
1-{[5-(2,4-dimethoxyphenyl)-2-methyl-1-phenyl-1H-pyrrol-3-yl]carbonyl}piperidine;
1-(4-chlorophenyl)-5-(2,4-dimethoxyphenyl)-2-methyl-N-piperidin-1-yl-1H-pyrrole-3-carboxamide; and
5-(2,4-dimethoxyphenyl)-1-(4methoxyphenyl)-2-methyl-N-piperidin-1-yl-1H-pyrrole-3-carboxamide;
1-[(2-methyl-1,5-diphenyl-1H-pyrrol-3-yl)carbonyl]piperidine;
1-{[1-(4methoxyphenyl)-2-methyl-5-phenyl-1H-pyrrol-3-yl]carbonyl}piperidine;
1-{[5-(2,4-dichlorophenyl)-2-methyl-1-phenyl-1H-pyrrol-3-yl]carbonyl}piperidine;
1-{[1-(4chlorophenyl)-5-(2,4dichlorophenyl)-2-methyl-1H-pyrrol-3-yl]carbonyl}piperidine;
1-{[5-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-2-methyl-1H-pyrrol-3-yl]carbonyl}piperidine;
1-{[1-(4-chlorophenyl)-5-(2,4-dimethoxyphenyl)-2-methyl-1H-pyrrol-3-yl]carbonyl}piperidine; and
1-{[5-(2,4-dimethoxyphenyl) -1-(4-methoxyphenyl)-2-methyl-1H-pyrrol-3-yl]carbonyl}piperidine;
and where applicable, optical isomers, tautomers, stereoisomers and racemates thereof as well as pharmaceutically acceptable salts, solvates and crystalline forms thereof.

It should be understood that the present invention includes each of the above compounds and any combination of two or more these compounds that is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 of these compounds.

Methods of Preparation

The compounds of the invention may be prepared as outlined below according to any of the following methods. However, the invention is not limited to these methods, the compounds may also be prepared as described for structurally related compounds in the prior art. Compounds of formula I in which X is CO may be prepared by reacting a compound of formula III
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in which R¹, R², R³, and R⁶are as previously defined and L represents hydroxy or halo e.g. chloro, with an amine of formula IV

R⁴R⁵YNH₂ IV

in which R⁴and R⁵are as previously defined in an inert solvent, for example dichloromethane, and optionally in the presence of a catalyst, for example a basic catalyst, eg 4-dimethylamino-pyridine, or optionally in the presence of a base for example triethylamine, at a temperature in the range of −25° C. to 150° C., and when L is hydroxy optionally in the presence of a coupling agent, for example a carbodiimide, eg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

Compounds of formula I in which X is SO₂may be prepared by reacting a compound of formula V
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in which R¹, R², R³and R⁶are as previously defined and A represents halo with an amine of formula IV

R⁴R⁵NH₂ IV

in an inert solvent, for example dichloromethane, and optionally in the presence of a catalyst, for example a basic catalyst, eg 4-dimethylamino-pyridine, at a temperature in the range of −25° C. to 150° C.

Compounds of formula III may be prepared as described in the Examples and by other methods known to those skilled in the art. Certain compounds of formula III are novel and are claimed as a further aspect of the present invention as useful intermediates.

The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.

Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative and in some occasions, more convenient manner, the individual process steps mentioned hereinbefore may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. chemical transformations may be performed upon different intermediates to those associated hereinbefore with a particular reaction).

The expression “inert solvent” refers to a solvent which does not react with the starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.

Pharmaceutical Preparations

The compounds of the invention will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient either as a free base, or a pharmaceutically acceptable organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses.

Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are about 0.001-10 mg/kg body weight, preferably 0.01-1 mg/kg body weight.

Oral formulations are preferred particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.5 mg to 500 mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg and 250 mg.

A compound of the invention may also be combined with other anti-obesity agents such as Orlistat or a monoamine reuptake inhibitor, for example Sibutramine. Furthermore, a compound of the invention may also be combined with therapeutic agents that are useful in the treatment of disorders or conditions associated with obesity (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatorheic hepatitis, osteoarthritis and some cancers) and psychiatric and neurological conditions.

According to a further aspect of the invention there is also provided a pharmaceutical formulation including any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.

Pharmacological Properties

The compounds of formula (I) are useful for the treatment of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, and neurological disorders such as dementia, neurological disorders(e.g. Multiple Sclerosis), Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease. The compounds are also potentially useful for the treatment of immune, cardiovascular, reproductive and endocrine disorders, septic shock and diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea). The compounds are also potentially useful as agents in treatment of extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms. The compounds may also eliminate the increase in weight which normally accompanies the cessation of smoking.

In another aspect the present invention provides a compound of formula I as claimed in any previous claim for use as a medicament.

In a further aspect the present invention provides the use of a compound of formula I including the compounds in the provisos in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis), Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea), and extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms.

In a still further aspect the present invention provides a method of treating obesity, psychiatric disorders such as psychotic disorders such as schizophrenia and bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis), Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea), and extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms comprising administering a pharmacologically effective amount of a compound of formula I including the compounds in the provisos to a patient in need thereof.

The compounds of the present invention are particulary suitable for the treatment of obesity, e.g. by reduction of appetite and body weight, maintenance of weight reduction and prevention of rebound.

Combination Therapy

The compounds of the invention may be combined with another therapeutic agent that is useful in the treatment of disorders associated with the development and progress of obesity such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes and atherosclerosis. For example, a compound of the present invention may be used in combination with a compound that affects thermogenesis, lipolysis, fat absorption, satiety, or gut motility. The compounds of the invention may be combined with another therapeutic agent that decreases the ratio of LDL:HDL or an agent that causes a decrease in circulating levels of LDL-cholesterol. In is patients with diabetes mellitus the compounds of the invention may also be combined with therapeutic agents used to treat complications related to micro-angiopathies.

The compounds of the invention may be used alongside other therapies for the treatment of obesity and its associated complications the metabolic syndrome and type 2 diabetes, these include biguanide drugs, insulin (synthetic insulin analogues) and oral antihyperglycemics (these are divided into prandial glucose regulators and alpha-glucosidase inhibitors).

In another aspect of the invention, the compound of formula I, or a pharmaceutically acceptable salt thereof may be administered in association with a PPAR modulating agent. PPAR modulating agents include but are not limited to a PPAR alpha and/or gamma agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof. Suitable PPAR alpha and/or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art.

In addition the combination of the invention may be used in conjunction with a sulfonylurea The present invention also includes a compound of the present invention in combination with a cholesterol-lowering agent. The cholesterol-lowering agents referred to in this application include but are not limited to inhibitors of HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase). Suitably the HMG-CoA reductase inhibitor is a statin

In the present application, the term “cholesterol-lowering agent” also includes chemical modifications of the HMG-CoA reductase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive.

The present invention also includes a compound of the present invention in combination with an inhibitor of the ileal bile acid transport system (IBAT inhibitor). The present invention also includes a compound of the present invention in combination with a bile acid binding resin.

The present invention also includes a compound of the present invention in combination with a bile acid sequestering agent, for example colestipol or cholestyramine or cholestagel According to an additional further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration one or more of the following agents selected from:

a CETP (cholesteryl ester transfer protein) inhibitor;
a cholesterol absorption antagonist;
a MTP (microsomal transfer protein) inhibitor;
a nicotinic acid derivative, including slow release and combination products;
a phytosterol compound;
probucol;
an anti-coagulant;
an omega-3 fatty acid;
another anti-obesity compound;
an antihypertensive compound for example an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an andrenergic blocker, an alpha andrenergic blocker, a beta andrenergic blocker, a mixed alpha/beta andrenergic blocker, an andrenergic stimulant, calcium channel blocker, an AT-1 blocker, a saluretic, a diuretic or a vasodilator;
a Melanin concentrating hormone (MCH) antagonist;
a PDK inhibitor; or
modulators of nuclear receptors for example LXR, FXR, RXR, and RORalpha;
an SSRI;
a serotonin antagonist;
or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.

Therefore in an additional feature of the invention, there is provided a method for for the treatment of obesity and its associated complications in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

Therefore in an additional feature of the invention, there is provided a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the present invention there is provided a kit comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provided a kit comprising:

a) a compound of formula I, or a pharmaceutically acceptable salt thereof, in a first unit dosage form;
b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; in a second unit dosage form; and
c) container means for containing said first and second dosage forms.

According to a further aspect of the present invention there is provided a kit comprising:

a) a compound of formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form;
b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a second unit dosage form; and
c) container means for containing said first and second dosage forms.

According to another feature of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the the treatment of obesity and its associated complications in a warm-blooded animal, such as man. According to another feature of the invention there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and one of the other compounds is described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man According to a further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.

Furthermore, a compound of the invention may also be combined with therapeutic agents that are useful in the treatment of disorders or conditions associated with obesity (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatorheic hepatitis, osteoarthritis and some cancers) and psychiatric and neurological conditions.

EXAMPLES

The invention will now be described in more detail with the following examples that are not to be construed as limiting the invention.

ABBREVIATIONS

DCM—dichloromethane

DMF—dimethylformamide

DMAP—4-dimethylaminopyridine

EDC—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

TEA—triethylamine

TEA—trifluoroacetic acid

DMSO dimethyl sulfoxide

t triplet

s singlet

d doublet

q quartet

qvint quintet

m multiplet

br broad

bs broad singlet

dm doublet of multiplet

bt broad triplet

dd doublet of doublets

General Experimental Procedures

Mass spectra were recorded on either a Micromass ZQ single quadrupole or a Micromass LCZ single quadrupole mass spectrometer both equipped with a pneumatically assisted electrospray interface (LC-MS). ¹H NMR measurements were performed on a Varian Inova 500, operating at ¹H frequency 500 MHz. Chemical shifts are given in ppm. Purifications were performed on a semipreparative HPLC with a mass triggered fraction collector, Shimadzu QP 8000 single quadrupole mass spectrometer equipped with 19×100 mm C8 column. As the mobile phase, acetonitrile and buffered phase (0.1 M NH₄Ac:acetonitrile 95:5) were used.

Alternatively ¹H NMR and ¹³C NMR measurements were performed on a Varian Mercury 300 or Varian UNITY plus 400, 500 or 600 spectrometers, operating at ¹H frequencies of 300, 400, 500 and 600 MHz, respectively, and at ¹³C frequencies of 75, 100, 125 and 150 MHz, respectively. Measurements were made on the delta scale (δ).

Unless otherwise stated, chemical shifts are given in ppm with the solvent as internal standard.

Synthesis of Intermediates

Preparation A

The following intermediates were prepared according to Scalzo, M. et al., Farmaco, Ed. Sci. (1988), 43(9), 665-676.

(a) Ethyl 2-acetyl-4-oxo-4-phenylbutanoate

¹H-NMR ((CD₃)₂SO) δ 7.98 (d, 2H), 7.65 (t, 1H), 7.53 (t, 2H), 4.13 (m, 3H), 3.56 (ddd, 2H), 2.32 (s, 3H), 1.18 (t, 3H).

(b) Ethyl 2-acetyl-4-(2,4-dichlorophenyl)-4-oxobutanoate

¹H-NMR ((CD₃)₂SO) δ 7.81-7.54 (m, 3H), 4.20-4.10 (m, 3H), 3.52-3.39 (m, 2H), 2.30 (s, 3H), 1.18 (t, 3H).

¹H-NMR ((CD₃)₂SO) δ 7.68 (dd, 1H), 6.67 (s, 1H), 6.61 (m, 1H), 4.10 (m, 3H), 3.91, (d, 3H), 3.84 (d, 3H), 3.41 (m, 2H), 2.28 (d, 3H), 1.17 (dt, 3H). MS m/z 309 (M+H)⁺.

Preparation B

The following intermediates were prepared essentially as described: Scalzo, M. et al., Farmaco, Ed. Sci. (1988), 43(9), 665-676. As recognised by those skilled in the art, the compounds described in Preparation A were, together with the appropriately substituted aniline, used as starting materials.

(a) Ethyl 2-methyl-1,5-diphenyl-1H-pyrrole-3-carboxylate

Toluene-4-sulphonic acid monohydrate (13 mg, 0.075 mmol) was added under nitrogen to a solution of aniline (0.43 mL, 4.7 mmol) and ethyl 2-acetyl-4-oxo-4-phenylbutanoate (Preparation A (a), 1.16 g, 4.7 mmol) in ethanol (55 mL). The mixture was refluxed for 20 h, then evaporated. The crude product (1.22 g) was used in the next step without further purification. MS m/z 306 (M+H)⁺.

(b) Ethyl 1-(4-chlorophenyl)-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate

The title compound was prepared as described in Preparation B (a).

The crude product (1.61 g) was used in the next step without further purification. MS m/z 340 (M+H)⁺.

The title compound was prepared as described in Preparation B (a).

The crude product (1.68 g) was used in the next step without further purification MS m/z 336 (M+H)⁺.

(d) Ethyl 5-(2,4-dichlorophenyl)-2-methyl-1-phenyl-1H-pyrrole-3-carboxylate

The title compound was prepared as described in Preparation B (a).

The crude product (0.55 g) was used in the next step without further purification. MS m/z 374 (M+H)⁺.

(e) Ethyl 1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-methyl-1H-pyrrole-3-carboxylate

The title compound was prepared as described in Preparation B (a).

The crude product (1.32 g) was used in the next step without further purification. MS m/z 408 (M+H)⁺.

(f) Ethyl 5-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxylate

The title compound was prepared as described in Preparation B (a).

The crude product (0.72 g) was used in the next step without farther purification. MS m/z 404 (M+H)⁺.

(g) Ethyl 5-(2,4-dimethoxyphenyl)-2-methyl-1-phenyl-1H-pyrrole-3-carboxylate

The title compound was prepared as described in Preparation B (a).

The crude product (0.33 g) was used in the next step without further purification. MS m/z 366 (M+H)⁺.

(h) Ethyl 1-(4-chlorophenyl)-5-(2,4-dimethoxyphenyl)-2-methyl-1H-pyrrole-3-carboxylate

The title compound was prepared as described in Preparation B (a).

The crude product (0.36 g) was used in the next step without further purification. MS m/z 400 (M+H)⁺.

(i) Ethyl 5-(2,4-dimethoxyphenyl)-1-(4-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxylate

The title compound was prepared as described in Preparation B (a).

The crude product (0.37 g) was used in the next step without further purification. MS m/z 396 (M+H)⁺.

Preparation C

The title compounds described in Preparation B (a-i) were used as starting materials for the compounds described in Preparation C (a-i)

(a) 2-Methyl-1,5-diphenyl-1H-pyrrole-3-carboxylic acid

Sodium hydroxide (2.4 g, 60 mmol) was added to a solution of crude ethyl 2-methyl-1,5-diphenyl-1H-pyrrole-3-carboxylate (from Preparation B (a), 1.22 g, 4.0 mmol) in ethanol (25 mL). The mixture was refluxed for 3 h, then an additional portion of sodium hydroxide (0.20 g, 5.0 mmol) was added and the mixture was refluxed for an additional 90 min. The ethanol was evaporated, then HCl (75 mL, 2M aq) was added and the mixture was stirred for 7 h. The acidic aqueous solution was extracted with EtOAc, the organic layer was washed with brine, dried (MgSO₄), filtrated and concentrated to give the crude product (0.95 g). The crude product was used in the next step without further purification. MS m/z 278 (M+H)⁺.

(b) 1-(4-Chlorophenyl)-2-methyl-5-phenyl-1H-pyrrole-3-carboxylic acid