ZA200610054B - Benzymidazolone carboxylic acid derivatives - Google Patents

Description

Benzimidazolone Carboxylic Acid Derivatives

Background of the Invention

This invention relates to benzimidazolone carboxylic acid derivatives. These compounds have selective 5-HT, receptor agonistic activity. The present invention also relates to a pharmaceutical composition, method of treatment and use, comprising the above derivatives for the treatment of disease conditions mediated by 5-HT, receptor activity; in particular 5-HT, receptor agonistic activity. in general, 5-HT, receptor agonists are found to be useful for the treatment of a variety of diseases such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer’s disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes and apnea syndrome (See TiPs, 1992, 13, 141; Ford A. P. D. W. et al., Med.

Res. Rev., 1993, 13, 633; Gullikson G. W. et al., Drug Dev. Res., 1992, 26, 405; Richard M. Eglen et al,

TiPS, 1995, 16, 391; Bockaert J. Et al., CNS Drugs, 1, 6; Romanelli M. N. et al., Arzheim Forsch./Drug

Res. 1993, 43, 913; Kaumann A. et al, Naunyn-Schmiedeberg’s. 1991, 344, 150; and Romanelli M. N. et al., Arzheim Forsch. /Drug Res., 1993, 43, 913). ~ W084/00449 discloses benzimidazolone compounds as 5-HT, agonists or antagonists and/or 5-HT, antagonists. Especially, compounds represented by the following formula is disclosed as Example 10: 0] —EN

NH

N

CL

N

EN Compound A

There is a need to provide new 5-HT, agonists that are good drug candidates. In particular, preferred compounds should bind potently to the 5-HT, receptor whilst showing little affinity for other receptors and show functional activity as agonists. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favorable pharmacokinetic properties. When targeted against receptors in the central nervous system they should cross the blood brain barrier freely and when targeted selectively against receptors in the peripheral nervous system they should not cross the blood brain barrier.

They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated.

Summary of the Invention

In this invention, it has now been found out that (1) replacing the quinuclidine ring with a piperidine/pyrrolidine ring improves affinity for 5-HT, receptor, and/or (2) introduction of the carboxy moiety decreases affinity for dofetilide that results the prevention of the QT prolongation.

Therefore, it has now surprisingly been found that compounds of this invention have stronger selective 5-HT, agonistic activity and/or improved dofetilide affinity, compared with the prior art, and thus are useful for the treatment of disease conditions mediated by 5-HT, activity such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer’s disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes and apnea syndrome (especially caused by an opioid administration).

The present invention provides a compound of the following formula (1): 0 Rm

DN UN «

N

R1 (1) or a pharmaceutically acceptable salt or solvate thereof, wherein

Ais an alkylene group having 1 to 4 carbon atoms, said alkylene group being unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents can be taken together with the carbon atoms to which they are attached to form a 3-, 4-, 5- or 6-membered ring optionally containing at least one heteroatom selected from N, O, and S;

R'is an isopropyi group or a cyclopentyl group;

R? is a hydrogen atom, a halogen atom or a hydroxy group;

R® is a carboxy group, a tetrazolyl group, a 5-oxo-1 ,2,4-oxadiazole-3-yl group or a 5-oxo0-1,2,4-thiadiazole-3-yl group; and : m is the integer 1 or 2.

One embodiment of the invention provides a compound of formula (I), as set forth above, or a pharmaceutically acceptable salt or solvate thereof, wherein:

Ais an alkylene group having 1 to 4 carbon atoms, said alkylene group being unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents can be taken together with the carbon atoms to which they are attached to form a 6-membered ring optionally containing at least one heteroatom selected from N, O, and S;

R' is an isopropyl group or a cyclopentyl group;

Risa hydrogen atom, a halogen atom or a hydroxy group;

R3is a carboxy group, a tetrazoly! group, a 5-oxo-1 ,2,4-oxadiazole-3-yl group or a 5-oxo-1,2,4-thiadiazole-3-yl group; and m is the integer 1 or 2. :

One embodiment of the invention provides a compound of formula (1), as set forth above, or a pharmaceutically acceptable salt or solvate thereof, wherein:

Ais an alkylene group having 1 to 4 carbon atoms, said alkylene group being substituted with 1to 4 substituents independently selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents can be taken together with the carbon atoms to which they are attached to fom a 5-membered ring optionally containing at least one heteroatom selected from N, O, and S;

R' is an isopropyl group or a cyclopentyl group;

R? is a hydrogen atom, a halogen atom or a hydroxy group;

R® is a carboxy group, a tetrazolyl group, a 5-ox0-1,2,4-oxadiazole-3-yl group or a 5-oxo-1,2,4-thiadiazole-3-yl group; and m is the integer 1 or 2.

One embodiment of the invention provides a compound of formula (1), as set forth above, or a pharmaceutically acceptable salt or solvate thereof, wherein:

Ais an alkylene group having 1 to 4 carbon atoms, said alkylene group being substituted with 1 to 4 substituents independently selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-atkyl group having 1 to 4 carbon atoms and an afkoxy-alky! group having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents can be taken together with the carbon atoms to which they are attached to form a 3 to 4-membered ring optionally containing at least one heteroatom selected from N, O, and S;

R'is an isopropyl group or a cyclopentyl group;

R? is a hydrogen atom, a halogen atom or a hydroxy group;

R? is a carboxy group, a tetrazoly! group, a 5-oxo-1 ,2,4-oxadiazole-3-yl group or a 5-0x0-1,2,4-thiadiazole-3-yl group; and m is the integer 1 or 2.

Also, the present invention provides the use of a compound of formula (1), or a pharmaceutically acceptable salt or solvate thereof, each as described herein, for the manufacture of a medicament for the treatment of a condition mediated by 5-HT, receptor activity; in particular, 5-HT, agonistic activity.

Preferably, the present invention also provides the use of a compound of formula (l) or a pharmaceutically acceptable salt or solvate thereof, each as described herein, for the manufacture ofa medicament for the treatment of diseases selected from gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer’s disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes and apnea syndrome.

Also, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, each as described herein, together with a pharmaceutically acceptable carrier for said compound.

Further, the present invention provides a method of treatment of a condition mediated by 5-HT, receptor activity, in a mammalian subject, which comprises administering to a mammal in need of such 40 treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, each as described herein.

Examples of conditions mediated by 5-HT, receptor activity include, but are not limited to, gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer’s disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes and apnea syndrome. : Also, the present invention provides a compound of formula (XI)

RE. ol

GY , 00 ~ or a sait thereof, wherein: :

R? is a hydrogen atom, a hydroxy group or a halogen atom;

R® is a hydrogen atom or an amino-protecting group;

Y is an alkoxy group having 1 to 4 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an imidazolyl group, a phtalimidyl group, succinimidy! group or suifonyl group; and mis1or2. '

Also, the present invention provides a compound of formula (IXa) 6 Rr?

R NL Jig (Xa) wR : or a salt thereof, wherein:

Ais an alkylene group having 1 to 4 carbon atoms, said alkylene group being unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of a halogen atom, an atkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents can be taken together with the carbon atoms to which they are attached to form a 3 to 6-membered ring optionally containing at least one heteroatom selected from N, O, and S;

R?is a hydrogen atom, a hydroxy group or a halogen atom;

R* is a hydroxy group or a carboxy-protecting group;

R® is a hydrogen atom or an amino-protecting group; and mis 1or2.

The compounds of the present invention may show less toxicity, good absorption, distribution, good solubility, less protein binding affinity, less drug-drug interaction, and good metabolic stability.

Detailed Description of the Invention

In the compounds of the present invention:

Where Ais an alkylene group having 1 to 4 carbon atoms, this may be a straight chain group, and examples include, but are not limited to, a methylene, ethylene, trimethylene and tetramethylene. Of these, methylene and ethylene are preferred; and ethylene is most preferred.

Where the substituent of Ais an alkyl group having 1 to 4 carbon atoms, this may be a straight or branched chain group, and examples include, but are not limited to, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Of these, alkyl groups having from 1 to 3 carbon atoms are preferred; methyl, ethyl, propyl and isopropyl are more preferred; and methyl and ethyl are most preferred.

Where the substituent of Y is an alkoxy group having 1 to 4 carbon atoms, this represents the 5 oxygen atom substituted by the said atkyl group, and examples include, but are not limited to, a methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy and tert-butyloxy. Of these, alkyl groups having from 1 to 2 carbon atoms are preferred; methoxy are more preferred.

Where the substituent of Y is a dialkylamino group having 2 to 8 carbon atoms, this represents the amino group substituted by two of the said alkyl group, and examples include, but are not limited to, a dimethylamino, N-methyl-N-ethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, and N,N-di(1-methylpropyl)amino. Of these, dialkylamino groups having from 2 to 4 carbon atoms are preferred; dimethylamino, N-methyl-N-ethylamino, and diethylamino are more preferred.

Where the substituent of A is a hydroxy-alkyl group having 1 to 4 carbon atoms, this may be a straight or branched chain group, and examples include, but are not limited to, a hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-1-methylethyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl, 3-hydroxy-2-methylpropyl and 3-hydroxy-1-methylpropyl.

Of these, hydroxy-alkyl groups having from 1 to 3 carbon atoms are preferred; hydroxymethyl, } 2-hydroxyethyl, and 2-hydroxypropyi are more preferred; and hydroxymethyl and 2-hydroxyethyl are most preferred.

Where the substituent of Ais an alkoxy-alkyl group having 2 to 6 carbon atoms, this may be a straight or branched chain group, and examples include, but are not limited to, a methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 1-methoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 2-methoxypropyl, 2-methoxy-1-methylethyl, 4-methoxybutyl, 4-ethoxybuty!, 3-methoxybutyl, 2-methoxybutyl, 3-methoxy-2-methyipropyl and 3-methoxy-1-methylpropyl. Of these, alkyloxy-alkyl groups having from 2 to 4 carbon atoms are preferred; methoxymethyl, 2-methoxyethyl and 3-methoxypropyl are more preferred; and 2-methoxyethyl and 3-methoxypropyi are most preferred.

Where any 2 non-halogen substituents of A can be taken together with the carbon atoms to which they are attached to form a 3, 4, 5, or 6-membered ring optionally containing at least one heteroatom selected from N, O and S. Such a ring may be a cycloalkyl or heterocyclyl group and examples include a cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, methyicyclopropyl, ethylcyclopropyl, methylcyclobutyl, methyicyclopentyl, methylcyciohexyl, ethylcyclohexyl, hydroxycyclopropyl, hydroxycyclobuty, hydroxycyclopentyl, hydroxycyclohexyl, methoxycyclopropyl, methoxycyclobutyl, methoxycyclopentyl, methoxycyclohexyl, tetrahydrofuryl and tetrahydropyranyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxycyclohexyl and tetrahydropyranyl, and most preferably cyclobutyl, cyclopentyl, cyclohexyl and tetrahydropyranyl.

Where the R® is the amino-protecting group, this represents a protecting group capable of being cleaved by chemical means, such as hydrogenolysis, hydrolysis, electrolysis or photolysis.and such amino-protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999), and examples include, but are not limited to, benzyl, C,H;0(C=0)-, 40 CHs(C=0)-, t-butyldimethylsilyl, t-butyldiphenyisilyl, benzyloxycarbonyl and t-buthoxycarbonyl. Of these groups, t-buthoxycarbonyl is preferred.

Where the R* is the carboxy-protecting group, this represents a protecting group capable of being cleaved by chemical means, such as hydrogenolysis, hydrolysis, electrolysis or photolysis.and such carboxy-protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene etal. (John Wiley & Sons, 1999), and examples include, methoxy, ethoxy, t-butyloxy, methoxymethoxy, 2,2,2-trichioroethoxy, benzyloxy, diphenylmethoxy, trimethylsilyloxy, t-butyidimethylsilyloxy and allyloxy. Of these groups, t-butyloxy, methoxy or ethoxy is preferred.

Where R' and the substituent of A represent a halogen atom, these may be a fluorine, chiorine, bromine or iodine atom. Of these, a fluorine or a chlorine atom is preferred.

The term “treating” and “treatment”, as used herein, refers to curative, palliative and prophylactic treatment, including reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

As used herein, the article “a” or “an” refers to both the singular and plural form of the object to which it refers unless indicated otherwise. : Preferred classes of compounds of the present invention are those compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, each as described herein, in which: (A) R'is an isopropyl group; (B) R? is a hydrogen atom, a fluorine atom or a hydroxy group; (C) R?is a hydrogen atom; (D) R®is a carboxy group or a tetrazolyl group; (E) R®is a carboxy group; (F) Ais an alkylene group having 1 to 2 carbon atoms, said alkylene group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms ‘and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents can be taken together with the carbon atoms to which they are attached to form a 6-membered ring optionally containing at least one heteroatom selected from N, O and §; (G) Ais an alkylene group having from 1 to 2 carbon atoms, said alkylene group being substituted with 2 geminal substituents independently selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alky! group having 2 to 6 carbon atoms, wherein non-halogen geminal substituents can be taken together with the carbon atom to which they are attached to form a 6-membered ring optionally containing at least one heteroatom selected from N, O and S; (H) Ais an alkylene group having 1 to 2 carbon atoms, said alkylene group being substituted with 2 substituents independently selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 said substituents can be taken together with the carbon atoms ta which they are attached to form a 5-membered ring optionally containing at least one heteroatom selected from N, O, and S; 40 (1) Ais an alkylene group having 1 to 2 carbon atoms, said alkylene group being substituted with 2 geminal substituents independently selected from the group consisting of an alkyl group having 1to4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-atkyl group having 2 to 6 carbon atoms, wherein said geminal substituents can be taken together with the carbon atom to which they are attached to form a 5-membered ring optionally containing at least one heteroatom selected from N, O, and S; (J) Ais an alkylene group having 1 to 2 carbon atoms, said alkylene group being substituted with 2 substituents independently selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein said substituents can be taken together with the carbon atoms to which they are attached to form a 3 to 4-membered ring optionally containing at least one heteroatom selected from N, O, and S; (K) Ais an alkylene group having 1 to 2 carbon atoms, said alkylene group being substituted with 2 geminal substituents independently selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyt group having 2 to 6 carbon atoms, wherein said geminal substituents can be taken together with the carbon atom to which they are attached to form a 3 to 4-membered ring optionally containing at least one heteroatom selected from N, O, and S; (L) Ais

Sm eR % A SO

XBR XE EES

So Sn , ox hs Sn hl ht

BSI sR At Xe hehe Ire or , 0 (0)

OCH, OCH;3 (M)Ais 10S fe! oS fo) ie or ;

O . (N) Ais

SA foe}

O

(O) Ais ge (P) Ais

XK

"or (Q) m is the integer 2.

Particularly preferred compounds of the present invention are those compounds of formula (1) or a pharmaceutically acceptable salt or solvate thereof in which ) (R) R'is an isopropyl group; R? is a hydrogen atom, a fluorine atom or a hydroxy group; Ris a carboxy group or a tetrazolyl group; Ais an alkylene group having 1 to 2 carbon atoms, said alkylene group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents can be taken together with the carbon atoms to which they are attached to form a 6-membered ring optionally containing at least one heteroatom selected from N, O, and S; and m is the integer 2; (S) R'is an isopropyl group; R? is a hydrogen atom; Ris a carboxy group or a tetrazolyl group; Ais an alkylene group having 1 to 2 carbon atoms, said alkylene group being substituted with 2 geminal substituents independently selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl ’ group having 2 to 6 carbon atoms, wherein said geminal substituents can be taken together with the carbon atom to which they are attached to form a 6-membered ring optionally containing at least one heteroatom selected from N, O, and S; and m is the integer 2; (T) R'is an isopropyl group; R? is a hydrogen atom; R®is a carboxy group or a tetrazolyl group; Ais ana nn fepile or . 0” ; and mis the integer 2; (VU) R'is an isopropyl group; R? is a hydrogen atom, a fluorine atom or a hydroxy group; R®is a carboxy group; A is alkylene group having 1 to 2 carbon atoms, said alkylene group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 non-halogen geminal substituents can be taken together with the carbon atom to which they are attached to form a 6-membered ring optionally containing at least one heteroatom selected from N, O, and S; and m is the integer 2; wv) R' is an isopropy! group; R? is a hydrogen atom, a fluorine atom or a hydroxy group; R® is a carboxy group; Ais

Man Mn “ “i [eRe 0”. and mis the integer 2; (W)R' is an isopropyl group; R? is a hydrogen atom, a fluorine atom or a hydroxy group; R®is a carboxy group or a tetrazolyl group; A is an alkylene group having 1 to 2 carbon atoms, said alkylene group being substituted with 2 substituents independently selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 fo 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 said substituents can be taken together with the carbon atoms to which they are attached to fom a 5-membered ring optionally containing at least one heteroatom selected from N, O, and S; and mis the integer 2; (X) R' is an isopropyl group; R? is a hydrogen atom; R%is a carboxy group or a tetrazolyl group; A is an alkylene group having 1 to 2 carbon atoms, said alkylene group being substituted with 2 geminal substituents independently selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein said geminal substituents can be taken together with the carbon atom to which they are attached to form a 5-membered ring optionally containing at least one heteroatom selected from N, O, and S; and m is the integer 2;

Y) R' is an isopropyl group; R? is a hydrogen atom; R?is a carboxy group or a tetrazolyl group; Ais a “ ; and m is the integer 2; (2) R'is an isopropyl group; R? is a hydrogen atom, a fluorine atom or a hydroxy group; R®is a carboxy group; A is alkylene group having 1 to 2 carbon atoms, said alkylene group being substituted with 2 substituents independently selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1to 4 carbon atoms and an alkoxy-alkyt group having 2 to 6 carbon atoms, wherein any 2 said substituents can be taken together with the carbon atoms to which they are attached to form a 5-membered ring optionally containing at least one heteroatom selected from N, O, and S; and m is the integer 2; (AA) R'is an isopropyl group; R? is a hydrogen atom, a fluorine atom or a hydroxy group; R® is a carboxy group; Ais n, ie] ; and m is the integer 2; (AB) R'is an isopropyl group; R? is a hydrogen atom, a fluorine atom or a hydroxy group;R® is a carboxy group or a tetrazolyl group; A is an alkylene group having 1 to 2 carbon atoms, said alkylene group being substituted with 2 substituents Independently selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, a hydroxy-atkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein said substituents can be taken together with the carbon atoms to which they are attached to form a 3 to 4-membered ring optionally containing at least one heteroatom selected from N, O, and S; and m is the integer 2; (AC) R'is an isopropyl group; R? is a hydrogen atom; Ris a carboxy group or a tetrazolyl group; Ais an alkylene group having 1 to 2 carbon atoms, said alkylene group being substituted with 2 geminal substituents independently selected from the group consisting of an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2to 6 carbon atoms, wherein said geminal substituents can be taken together with the carbon atom to which they are attached to form a 3 to 4-membered ring optionally containing at least one heteroatom selected from N, O, and S; and m is the Integer 2;. (AD) R'is an isopropyl group; R? is a hydrogen atom; R®is a carboxy group or a tetrazolyl group; Ais

Mo, el : and m is the integer 2; (AE) R' is an isopropyl group; R? is a hydrogen atom, a fluorine atom or a hydroxy group;R® is a carboxy group; A is alkylene group having 1 to 2 carbon atoms, said alkylene group being substituted with 2 substituents independently selected from the group consisting of a halogen atom, an alky! group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents can be taken together with the carbon atoms to which they are attached to form a 3 to 4-membered ring optionally containing at least one heteroatom selected from N, O, and S; and m is the integer 2; {AF) R'is an isopropyl group; R? is a hydrogen atom, a fluorine atom or a hydroxy group; R® is a carboxy group; Ais

Mu, es : and m is the integer 2; (AG) R!' is an isopropy! group, R? is a hydrogen atom, a fluorine atom or a hydroxy group, R®is a carboxy group, Ais

Ped fe! 9 fo) or :

Oo and m is the integer 2; or (AH) R' is an isopropyl group; R? is a hydrogen atom; R3is a carboxy group or a tetrazolyl group; Ais 10S ie’ > fo) ie or ;

Oo and m is the integer 2.

One embodiment of the invention provides a compound selected from the group consisting of: 4-{j4-({[(3-isopropyl-2-ox0-2,3-dihydro-1H-benzimidazol-1 -yl)carbonyl]amino}methyl)piperidin-1-yfjmethyi}t etrahydro-2H-pyran-4-carboxylic acid; 1-{[4-({[(3-isopropyl-2-oxo0-2,3-dihydro-!H-benzimidazol-1 -yl)carbonyllamino}methyl)piperidin-1-ylimethyf} cyclohexanecarboxylic acid; 1-{[4-({[(3-isopropyl-2-ox0-2,3-dihydro-1 H-benzimidazol-1 -yl)carbonylJamino}methyl)piperidin-1 -yllmethyi} cyclopentanecarboxylic acid; 1-{[4~({[(3-isopropyi-2-ox0-2,3-dihydro-/ H-benzimidazol-1 -yl)carbonylJamino}methyl)piperidin-1-yllmethyi} cyclopropanecarboxylic acid; 1-{[4-hydroxy-4-({[(3-isopropy}-2-oxo-2,3-dihydro-1 H-benzimidazol-1-yl)carbonylJlamino}methylpiperidin-1 -yllmethyl}cyclohexanecarboxylic acid; 1-{[4-({[(3-isopropyl-2-0x0-2,3-dihydro-/ H-benzimidazol-1 -yl)carbonyl)amino}methyl)piperidin-1-yljmethyl}

cyclobutanecarboxylic acid; and a pharmaceutically acceptable salt or solvate thereof.

One embodiment of the invention provides a compound from the group consisting of: 4-{[4-({[(3-isopropyi-2-ox0-2,3-dihydro-1 H-benzimidazol-1-yi)carbonyljamino}methyl)piperidin-1 -yijmethyi}t etrahydro-2H-pyran-4-carboxylic acid; 1-{{4-({{(3-isopropy}-2-ox0-2,3-dihydro-1H-benzimidazol-1 -yl)carbonyllamino}methyl)piperidin-1-yljmethyl} cyclohexanecarboxylic acid; and a pharmaceutically acceptable salt and solvate thereof.

One embodiment of the invention provides a compound from the group consisting of: 1-{[4-{{[(3-isopropy}-2-ox0-2,3-dihydro-1H-benzimidazol-1 -yi)carbonyl]lamino}methyl)piperidin-1-yijmethyl} cyclopentanecarboxylic acid; and a pharmaceutically acceptable salt and solvate thereof.

One embodiment of the invention provides a compound from the group consisting of: 1-{[4-({[(3-isopropyl-2-ox0-2,3-dihydro-1H-benzimidazol-1 -yl)carbonyllamino}methyt)piperidin-1-yljmethyi} cyclopropanecarboxylic acid; 1-{[4-({[(3-isopropyl-2-ox0-2,3-dihydro-1H-benzimidazol-1 -yl)carbonyfjamino}methyl)piperidin-1-yljmethyl} cyclobutanecarboxylic acid; and a pharmaceutically acceptable salt and solvate thereof.

Pharmaceutically acceptable salts of a compound of formula (I) include the acid addition and base salts (including disalts) thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and :

Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). A pharmaceutically acceptable salt of a compound of formula (I) may be readily prepared by mixing together solutions of the compound of formula (1) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in both unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed 40 when said solvent is water.

Pharmaceutically acceptable solvates in accordance with the invention include hydrates-and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D20, dg-acetone, de-DMSO

Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.

The resulting complexes may be ionised, partially ionised, or non-ionised. For a review of such complexes, see J Pham Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

Hereinafter all references to a compound of formula (1) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

The term “compound of the invention” or “compounds of the invention” refers to, unless indicated otherwise, a compound of formula (1) as hereinbefore defined, polymorphs, prodrugs, and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (1).

Also within the scope of the invention are so-called ‘prodrugs’ of the compounds of formula (1).

Thus certain derivatives of compounds of formula (1) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as ‘prodrugs’. Further information on the use of prodrugs may be found in ‘Pro-drugs as Novel Delivery

Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and ‘Bioreversible Carriers in Drug

Design’, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the 95 art as ‘pro-moieties’ as described, for example, in "Design of Prodrugs” by H Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include: (i) where the compound of formula (I) contains a carboxylic acid functionality (COOH), an ester thereof, for example, replacement of the hydrogen with (C4-Cs)alkyl; (iy where the compound of formula (1) contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (C4-Ce)alkanoyloxymethyl; and (iii) where the compound of formula (I) contains a primary or secondary amino functionality (-NH or -NHR where R # H), an amide thereof, for example, replacement of one or both hydrogens with (C4-Cyo)alkanoyl.

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

Finally, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (I) contains an alkeny! or alkenylene group, geometric 40 cis/trans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism (‘tautomerism’) can occur. It follows that a single compound may exhibit more than one type of isomerism. included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (1), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or

DL-arginine. _ Cisltrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (1) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine.

Concentration of the eluate affords the enriched mixture.

Sterecisomeric conglomerates may be separated by conventional techniques known to those skilled 95 in the art - see, for example, “Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York, 1994). ’

The present invention includes all pharmaceutically acceptable isotopicaily-abelled compounds of formula (1) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and °H, carbon, such as "'C, °C and "C, chlorine, such as 3c), fluorine, such as "°F, iodine, such as | and *?, nitrogen, such as *N and **N, oxygen, such as *°0, "0 and 30, phosphorus, such as *P, and sulphur, such as *S.

Certain isotopically-labelled compounds of formula (1), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ®H, and carbon-14, i.e. "C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced 40 dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as "'C, “°F, 50 and "*N, can be useful in Positron

Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds of formula (1) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying

Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

Ali of the compounds of the formula (I) can be prepared by the procedures described in the general methods presented below or by the specific methods described in the Examples section and the

Preparations section, or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the compounds of formula (1), in addition to any novel intermediates used therein.

General Synthesis

The compounds of the present invention may be prepared by a variety of processes well known for the preparation of compounds of this type, for example as shown in the following Methods A to G.

The following Methods A and B illustrate the preparation of compounds of formula (1). Methods

C through G illustrate the preparation of various intermediates.

Unless otherwise indicated, R', R? R®, m and A in the following Methods are as defined above.

The term “protecting group”, as used hereinafter, means a hydroxy, carboxy or amino-protecting group which is selected from typical hydroxy, carboxy or amino-protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999). All starting materials in the following general syntheses may be commercially available or obtained by conventional methods known to those skilled in the art, such as European Journal of Medicinal Chemistry, 12(1), 87-91; 1977 and the disclosures of which are incorporated herein by reference.

Method A

This illustrates the preparation of compounds of formula (I).

Reaction Scheme 4 fo Rr?

H Step Af 208 Jm

N N H No R®

Cp ——— C=

I R* | N wr SS RE "0 x (i)

In Reaction Scheme A, R® is R® as defined above or a group of formula -C(=O)-R’, wherein R* is a carboxy-protecting group.

The term “carboxy-protecting group”, as used herein, signifies a protecting group capable of being cleaved by chemical means, such as hydrogenolysis, hydrolysis, electrolysis or photolysis, and such carboxy-protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999). Typical carboxy-protecting groups include, but are not limited to: methoxy, ethoxy, t-butyloxy, methoxymethoxy, 2,2,2-trichloroethoxy, benzyloxy, diphenylmethoxy, trimethylsilyloxy, t-butyldimethylsilyloxy and altyloxy. Of these groups, -butyloxy, methoxy or ethoxy is preferred.

Step Al

In this step, the desired compound of formula (!) of the present invention is prepared by carbonylation of the compound of formula (It) with the compound of formula (1). The compound of formula (il) is commercially available. The compound of formula (lil) can be prepared according to .

Method C set forth below.

The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include, but are not limited to: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; and amides, such as N,N-dimethylformamide and N,N-dimethylacetamide. Of these solvents, dichloromethane is preferred.

There is likewise no particular restriction on the nature of the carbonylating agents used, and any carbonylating agent commonly used in reactions of this type may equally be used here. Examples of such carbonylating agents include, but are not limited to: an imidazole derivative such as N,N*- carbonyldiimidazole (CDI); a chloroformate such as trichtoromethyl chioroformate and 4-nitrophenyl chloroformate; urea; and triphosgene. Of these, 4-nitrophenyl chloroformate is preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at 2 temperature of from about -78°C to about 120°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 5 minutes to about 24 hours will usually suffice.

In the case where R* is a group of formula -C(=0)-R%, the deprotection reaction will follow to yield a carboxy group. This reaction is described in detail by T. W. Greene et al., Protective Groups in

Organic Synthesis, 369-453, (1999), the disclosures of which are incorporated herein by reference. The following exemplifies a typical reaction involving the protecting group t-butyl.

The deprotection reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent.

Examples of suitable solvents include, but are not limited to: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; and aromatic hydrocarbons, such as benzene, toluene and nitrobenzene. Of these solvents, halogenated hydrocarbons are preferred. 40 The deprotection reaction is carried out in the presence of an acid. There is likewise no particular restriction on the nature of the acids used, and any acid commonly used in reactions of this type may equally be used here. Examples of such acids include, but are not limited to: acids, such as hydrochloric acid, acetic acid p-toluenesulfonic acid or trifluoroacetic acid. Of these, trifluoroacetic acid is preferred.

The deprotection reaction may be carried out in the presence of a radical scavenger. There is likewise no particular restriction on the nature of the radical scavenger used, and any radical scavenger commonly used in reactions of this type may equally be used here. Examples of such radical scavengers include, but are not limited to: HBr, dimethylsulfoxide or (CH3CH,):SiH. Of these, (CH3CH,)sSiH is preferred.

The deprotection reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0°C to about 100°C, more preferably from about 0°C to about 50°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 5 minutes to about 24 hours, more preferably from about 1 hour to about 24 hours, will usually suffice.

Method B . This illustrates an alternative preparation of the desired compound of formula 0.

Reaction Scheme B fo} R? 0 R?

Be )m 288 )m

N H N._s StepB1 N H NH

Cre Oe smo (opi

N N

R' KR (Vv) I)

Q Rr?

Step B2 JH R3

Xp RR or OHO. aR CL 0) vi) RK ®

In Reaction Scheme B, R* is as defined above; R® is an amino-protecting group; A® is A as defined above or an alkylene group having from 1 to 3 carbon atoms, said alkylene group being unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of a halogen atom, an alkyl group having from 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein 2 of said substituents may optionally be taken together with the carbon atom(s) form a 3 to 6 membered ring; and X is a halogen atom such as an iodine atom, a chlorine atom or a bromine atom.

The term “amino-protecting group”, as used herein, signifies a protecting group capable of being cleaved by chemical means, such as hydrogenolysis, hydrolysis, electrolysis or photolysis.and such amino-protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999). Typical amino-protecting groups include, but are not limited to, benzyl,

C,Hs0(C=0)-, CH4(C=0)-, t-butyidimethylsilyl, t-butyldiphenyisilyl, benzyloxycarbonyt and t-buthoxycarbonyl. Of these groups, t-buthoxycarbonyl is preferred.

Step B1

In this step, the compound of formula (V) is prepared by the deprotection of the compound of formula (IV), which may be prepared, for example, by a method similar to that described in Method A for the preparation of the compound of formula (1) from a compound of formula (Il). This deprotection method is described in detail by T. W. Greene et al. [Protective Groups in Organic Synthesis, 494-653, (1989)], the disclosures of which are incorporated herein by reference. The following exemplifies a typical method involving the protecting group t-buthoxycarbonyl.

The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include, but are not limited to: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; and alcohols, such as methanol, ethanol, propanol, 2-propanot and butanol. Of these solvents, alcohols are preferred.

The reaction is carried out in the presence of excess amount of an acid. There is likewise no particular restriction on the nature of the acids used, and any acid commonly used in reactions of this type may equally be used here. Examples of such acids include, but are not limited to: acids, such as hydrochloric acid, or trifluoroacetic acid. Of these, hydrochloric acid is preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0°C to about 100°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 5 minutes to about 24 hours, will usually suffice.

Step B2

In this step, the desired compound of formula (1) is prepared by the coupling (B2-a) of the compound of formula (V) prepared as described in Step B1 with the compound of formula (VI) or by the reductive amination (B2-b) of the compound of formula (V) with the compound of formula (VII). (B2-a) coupling with the compound of formula (V):

The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the 40 reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include, but are not limited to: halogenated hydrocarbons, such as dichloromethane,

chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexytamine, N-methylpiperidine, N-methylpyrrolidine, pyridine, 4- pyrrolidinopyridine, N,N-dimethylaniline and N,N- diethylaniline; and amides, such as N,N-dimethylformamide and N,N-dimethylacetamide. Of these, N,N-dimethylformamide or

N-methylpyrrolidine is preferred.

The reaction is carried out in the presence of a base. There is likewise no particular restriction on the nature of the base used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include, but are not limited to: amines, such as N-methyimorpholine, triethylamine, tripropylamine, tributylamine, diisopropytethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0jundec-7-ene (DBU); alkali metal hydrides, such as lithium hydride, sodium hydride and potassium hydride; and alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium t-butoxide. Of these, diisopropylethylamine is preferred. }

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such : factors as the nature of the solvent, and the starting materials. However, in general, it is convenientto carry out the reaction at a temperature of from about 0°C to about 120°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 5 minutes to about 48 hours will usually suffice. (B2-b) reductive amination: . ’ The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include, but are not limited to: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran and dioxane; alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol; acetic acid; and water. Of these solvents, halogenated hydrocarbons are preferred.

The reaction is carried out in the presence of a reducing reagent. There is likewise no particular restriction on the nature of the reducing reagents used, and any reducing reagent commonly used in reactions of this type may equally be used here. Examples of such reducing reagent include, but are not limited to: sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride. Of these, sodium triacetoxyborohydride is preferred. The quantity of the reducing reagent required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, that the reaction is effected under preferred conditions, 40 a chemical equivalent ratio of 1 to 3 of the reducing reagent to the starting material will usually suffice.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about -20°C to about 60°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 5 minutes to about 24 hours, will usually suffice. in the case where R* is a group of formula -C(=O)-R", the deprotection reaction will follow to yield a carboxy group. The reaction may be carried out under the same conditions as described in Step A1 of Method A.

Method C

This illustrates the preparation of the compound of formula (Ill).

Reaction Scheme C

RL Step Ct REL R? Step C2

N Jm ———————— " "HN J : sg “Th: RE TT

X y R or OHC. aR" (vin) wh (v1) (IX)

R?

Ly )m .

NR am

In Reaction Scheme C, X, A, A? , and R®, R® and are each as defined above. Therefore, when

R® is -C(=0)-R*, the above compound of formula (IX) is as follows.

R2

RE. yy hm o " .

H N_ PIS . (IXa)

A” R

Step C1

In this step, the compound of formula (IX) is prepared by the coupling of the compound of formula (V1) with a compound of formula (VI) or by the reductive amination of the compound of formuia (VIII) with the compound of formula (VII). The compound of formula (VIII) can be prepared according to Methods F and G set forth below or is commercially available. ’ Step C2

In this step, the compound of formula (Ill) is prepared by the deprotection of the compound of formula (IX) prepared as described in Step C1. The reaction may be carried out under the same conditions as described in Step B1 of Method B.

Method D

This illustrates the preparation of the compound of formula (lia).

Reaction Scheme D

ROS re StepD1 RN Re Step D2 R?

GY Sep yy dna Sy

H NH H N_Y R N_ ,R*

H-Y Ro A . A ®) ZR 0) vIn) x1) R 5 . ox)

In Reaction Scheme D, R*, R*, R® and Y are each as defined above and R’ is a silyl group such as t- butyldimethyisilyi, t-butyldiphenyisilyl, triethylsilyl or trimethylsilyl, preferably trimethylsilyl; R® and R® independently represent a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein R® and R® may optionally be taken together with the carbon atom to which they are attached to form a 3 to 6 membered ring; AP is A as defined above with proviso a methylene group and a substituted methylene group are excluded.

Step D1 in this step, the compound of formula (X1) is prepared by condensation of the compound of formula (VII) with the compound of formula (X) in the presence of paraformaldehyde. A compound of formula (VIII) can be prepared according to Method F and G or is commercially available.

In the case that Y is not an alkoxy group, the reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided 90 that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include, but are not limited to: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol;. Of these, dichloromethane or ethanol is preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to carry out the reaction at a temperature of from about 0°C to about 120°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 5 minutes to about 48 hours, will usually suffice.

Step D2

In this step, the compound of formula (lia) is prepared by Mannnich reaction of the compound of : formula (X1) with the compound of formula (XI).

The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include, but are not limited to: halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; nitriles, such as acetonitrile and benzonitrile; and amides, such as formamide,

N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide. Of these solvents, dichloromethane is preferred.

The reaction is carried out in the presence of a Lewis acid. There is likewise no particular restriction on the nature of the Lewis acids used, and any Lewis acid commonly used in reactions of this type may equally be used here. Examples of such Lewis acid include, but are not limited to: BF3, AICI,

FeCl, MgCl,, AgCl, Fe(NO3)s, CF3S03Si(CHs)s, Yb(CF3sS03)s and SnCl,. Of these, Yb(CF3 SOs), MgCla, or CF3S03Si(CHj3)s is preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such factors as the nature of the solvent, and the starting materials. However, in general, itis convenient to carry out the reaction at a temperature of from about 0°C to about 100°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 5 minutes to about 24 hours, will . usually suffice.

Method E

This illustrates the preparation of the compound of formula (lI) wherein R?is a hydrogen atom and

Ais A°.

Reaction Scheme E 0]

Ne _StepEl | HaN. A a SepB2 | Lor pe (x XIV) m Re w os | (Xviy xv)

Step E3 NG ) Step E4 HN )m

Etat m OPER LHe xvi) (lib)

In Reaction Scheme E, A%, A® and R* are each as defined above; each of R and R'is an alkyl group having 1 to 4 carbon atoms, preferably a methyl group, or an aralkyl group such as a benzyl or phenethyl group, preferably a benzyl group.

Step E1 in this step, the compound of formula (XIV) is prepared by reduction of the cyano group of the compound of formula (XIII), which is commercially available.

The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these, methanol is preferred.

The reaction is carried out in the presence of a reducing agent. There is likewise no particular restriction on the nature of the reducing agents used, and any reducing agent commonly used in reactions of this type may equally be used here. Examples of such reducing agents include, but are not limited to: metal borohydrides such as sodium borohydride and sodium cyanoborohydride; combinations of hydrogen gas and a catalyst such as palladium-carbon, platinum and Raney nickel; and hydride compounds such as lithium aluminum hydride, and diisobutyl aluminum hydride. Of these, Raney nickel is preferred.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend upon such

Ep 20 factors as the nature of the solvent, and the starting materials. However, in general, it is convenient to ‘ carry out the reaction at a temperature of from about 0°C to about 100°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the starting materials and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from about 5 minutes to about 24 hours, will usually suffice.

Step E2

In this step, the compound of formula (XVI) is prepared by reacting a compound of formula (XV), which is commercially available, with a compound of formula (XIV).

The reaction is normally and preferably effected in the presence of solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include, but are not limited to: water; and alcohols, such as methanol, ethanol, propanol, 2-propanol and butanol. Of these, a mixture of water and ethanol is preferred.

The reaction is carried out in the presence of a base. There is likewise no particular restriction on the nature of the base used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include, but are not limited to: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium t-butoxide; and alkali metal carbonates, such as lithium carbonate, sodium 40 carbonate and potassium carbonate. Of these, potassium carbonate is preferred.

Claims (15)

The claimed invention is:

1. A compound of the formula: Q R? cae Crm N R1 (1) or a pharmaceutically acceptable salt or solvate thereof, wherein: Ais an alkylene group having 1 to 4 carbon atoms, said alkylene group being unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alky! group having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents can be taken together with the carbon atoms to which they are attached to form a 3 to 6-membered ring optionally containing at least one heteroatom selected from N, O, and S; : R' is an isopropyl group or a cyclopentyl group; R? is a hydrogen atom, a halogen atom or a hydroxy group; R® is a carboxy group, a tetrazolyl group, a 5-oxo-1,2,4-oxadiazole-3-yl group or a 5-o0xo0-1,2,4-thiadiazole-3-yl group; and mis the integer 1 or 2.

2. The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein R' is an isopropyl group; R? is a hydrogen atom, a fluorine atom or a hydroxy group; R%is a carboxy group or a tetrazolyl group; ‘ Ais an alkylene group having 1 to 2 carbon atoms, said alkylene group being unsubstituted or substituted with 1 to 2 substituents independently selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents can be taken together with the carbon atoms to which they are attached to form a 3 to 6-membered ring ' optionally containing at least one heteroatom selected from N, O, and S; and m is the integer 2.

3. The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein R' is an isopropyl group; R?is a hydrogen atom; R3is a carboxy group or a tetrazolyl group; Ais an alkylene group having 1 to 2 carbon atoms, said alkylene group being substituted with 2 geminal substituents independently selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein said geminal substituents can be taken together with the carbon atom to which they are attached to form a 3- to 6-membered ring optionally containing at least one heteroatom selected from N, O, and S; and m is the integer 2.

4. The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 1, wherein R' is an Isopropyl group; RZis a hydrogen atom; R%is a carboxy group or a tetrazolyl group; Ais :

Mn. an Man Man 5 wy . ie “ or 0" ;and m is the integer 2.

5. The compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in claim 4, wherein R' is an isopropyl group; R’is a hydrogen atom, a fluorine atom or a hydroxy group; Risa carboxy group; . Ais an an nn, Mn. GED or 0" and m is the integer 2.

6. The compound as claimed in claim 1, which is selected from: 4-{[4-({[(3-isopropyl-2-0x0-2,3-dihydro-1H-benzimidazol-1-yl)carbonylJamino}methyl)piperidin-1-yllme thyl}tetrahydro-2H-pyran-4-carboxylic acid; 1-{[4-({[(3-isopropyl-2-ox0-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]lamino}methyl)piperidin-1-yljme thyl}cyclohexanecarboxylic acid; 1-{[4-({[(3-isopropyl-2-0x0-2,3-dihydro-1H-benzimidazol-1-yi)carbonyljamino}methyl)piperidin-1-yljme thyl}eyclopentanecarboxylic acid; 1-{[4-({{(3-isopropyl-2-0x0-2,3-dihydro-1H-benzimidazol-1-yl)carbonylJamino}methyl)piperidin-1-yljme thyl}cyclopropanecarboxylic acid; 1-{[4-hydroxy-4-({[(3-isopropyl-2-0x0-2,3-dihydro-1H-benzimidazol-1-yl)carbonyllamino}methyl)piperi din-1-yljmethyl}cyclohexanecarboxylic acid;

PCT/1B2005/001825 1-{{4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazo!-1- yl)carbonyljamino}methyl)piperidin- 1-ylJmethyl}cyclobutanecarboxylic acid; or a pharmaceutically acceptable salt or solvate thereof.

7. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6, and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition as claimed in claim 7, further comprising another pharmacologically active agent.

9. Use of the compound or the pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6, in the manufacture of a medicament for the treatment of a condition mediated by 5-HT, receptor activity, in a mammalian subject, including a human.

10. Use as claimed in claim 9, wherein said condition is gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes or apnea syndrome.

11. A compound of formula R2

RO. Ny Im xX)

N._Y or a salt thereof, wherein: R’is a hydrogen atom, a hydroxy group or a halogen atom; Ris a hydrogen atom or an amino-protecting group; Y is an alkoxy group having 1 to 4 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an imidazoly! group, a phtalimidyl group, succinimidyl group or sulfonyl group; and mis 1 or 2.

12. A compound of formula R2 Rn 0} 3 I (IXa) SAT = or a salt thereof, wherein: Ais an alkylene group having 1 to 4 carbon atoms, said alkylene group being unsubstituted or AMENDED SHEET

PCT/IB2005/001825 substituted with 1 to 4 substituents independently selected from the group consisting of a halogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxy-alkyl group having 1 to 4 carbon atoms and an alkoxy-alkyl group having 2 to 6 carbon atoms, wherein any 2 non-halogen substituents can be taken together with the carbon atoms to which they are attached to form a 3 to 6-membered ring optionally containing at least one heteroatom selected from N, O, and S; Ris a hydrogen atom, a hydroxy group or a halogen atom; Risa hydroxy group or a carboxy-protecting group; Ris a hydrogen atom or an amino-protecting group; and mis 1 or 2.

13. A compound of any one of claims 1 to 6, 11 or 12, substantially as herein described with reference to and as illustrated in any of the examples.

14. A composition of claim 7 or claim 8, substantially as herein described with reference to and as illustrated in any of the examples.

15. Use of claim 9 or claim 10, substantially as herein described with reference to and as illustrated in any of the examples. AMENDED SHEET