WO2007077457A9

WO2007077457A9 - Treatment of equine laminitis with 5-ht1b/ 1d antagonists

Info

Publication number: WO2007077457A9
Application number: PCT/GB2007/000033
Authority: WO
Inventors: Jonathan Elliott; Simon Reeves Bailey
Original assignee: Royal Veterinary College; Jonathan Elliott; Simon Reeves Bailey
Priority date: 2006-01-06
Filing date: 2007-01-05
Publication date: 2007-10-18
Also published as: WO2007077457A3; WO2007077457A2

Abstract

There is provided the use of a compound of general formula (I): in which: R1 represents hydrogen, halogen, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6alkylOC1-6 alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R29, CONR30 R31 or NR30R31; R2 represents a phenyl group, having phenyl ring B, substituted by a group selected from i) a 5 to 7 membered heterocyclic ring containing three heteroatoms selected from oxygen, nitrogen or sulphur, optionally substituted by a substituent selected from halogen, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C1-6 alkoxy, hydroxy C1-6 alkyl, C1-6 alkyl OC1-6 alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2R29, CONR30 R31 NR30 R31, or NR30R31, formula (ii): or formula (iii): and optionally further substituted by one or two auxiliary substituents selected from a halogen atom, a hydroxy group, a C1-6 alkyl group, or by an auxiliary substituent selected from C3-6 cycloalkyl, C3-6 cycloalkenyl, hydroxy C1-6 alkyl, C1-6 alkylOC1-6alkyl, acyl, aryl, acyloxy, nitro, trifluoromethyl, cyano, CO22R29, CONR30 R31, or NR30 R31; D is CONH or NHCO; E is formula (A): or G-(CR24 R25)-NR27R28 where R5 represents a hydrogen atom or a C1-6 alkyl group, G is oxygen, S(O)p where p is 0, 1, or 2, NR32 where R32 is hydrogen, C1-6 alkyl or phenyl C1-6 alkyl, or G is CR24 = CR25 or CR24 R25 where R24 and R25 are independently hydrogen or C1-6 alkyl; F is hydrogen, a halogen atom, a hydroxy group, a C1-6 alkoxy group, a C1-6 alkyl group or a halogenated C1-6 alkyl group; R27 and R28 are independently hydrogen, C1-6 alkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5-to 7-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulphur; R29, R30 and R31 are independently hydrogen or C1-6 alkyl; m is 1 to 4; and n is 1 or 2 or a physiologically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of laminitis.

Description

Treatment of Equine Laminitis

This invention relates to the use of benzanilide and biphenylamide derivatives in the treatment of laminitis, and in particular in the treatment of equine laminitis. Equine laminitis is a common, painful and potentially very serious condition that can lead to lameness and disability in horses and ponies. Laminitis is the failure of the laminae which form the supportive bond between the coffin bone and the inner wall of the hoof. It is very prevalent in certain countries such as, for example, the United Kingdom and the USA, and is often associated with animals being fed a rich diet of protein and/or carbohydrate, such as lush spring pasture.

There are three phases of laminitis: developmental, acute, and chronic. The developmental phase is often completely undetectable, occurring before any clinical signs of laminitis are noticeable. Acute laminitis occurs anywhere from 1 to 3 days after the initial damage to the laminae and includes the events leading up to and the onset of lameness. Signs of acute laminitis include lameness, reluctance to move, characteristic posturing to try and take the weight off the toe of the hoof (e.g. pointing with a leg, recumbency), increased digital pulses, pain to pressure or percussion over the toe area and various systemic changes such as anorexia, anxiety, increased respiration and pulse rates.

Acute laminitis can progress to the chronic stage. The chronic stage ensues after persistent lameness (greater than 2 days), or when the coffin bone rotates and/or sinks as a result of some degree of loss of integrity of the supporting laminae. Rotation (the more common phenomenon) results from the laminae at the front of the foot separating. Sinking of the coffin bone results from the entire laminar junction letting go from the body of the hoof. Rotation and/or sinking of the coffin bone can be mild or severe, in severe cases the bone driving down into the hoof capsule and possibly through the sole, damaging vascular structures and crushing the living tissue of the sole and coronet. This causes unrelenting pain, can leave the hoof prone to infection and often manifests itself through a characteristic lameness.

The clinical signs of laminitis represent the end result of a multi-systemic condition, which has many predisposing factors, leading to a common pathogenic pathway culminating in reduced capillary perfusion, ischaemia, and necrosis of the laminae (Hood et al. 1993). Such predisposing factors include grain overload, lush pasture, colic, retained placenta, exhaustion, excessive concussion of the hoof and excessive cold water.

Although the pathophysiology of laminitis remains unclear, haemodynamic studies of experimentally induced laminitis have suggested that increased vascular resistance occurs specifically on the venous side of the laminar capillary bed (Allen et al. 1990) and that the extensive arteriovenous anastomoses found in the digital circulation further contribute to laminar ischaemia (Robinson 1990; Molyneux et al. 1994). In view of the observed link between gastrointestinal disturbances and acute laminitis, and the possible importance of platelets in the pathophysiology of this and other ischaemic diseases (Seibold 1985), researchers began to look at 5-hydroxytryptamine (5- HT), which is formed from dietary tryptophan in enterochromaffin cells in the gut, as a possible vasoactive mediator which may be involved in the haemodynamic disturbances leading to laminitis.

5-HT, also known as serotonin, is an important neurotransmitter and local hormone, and its function in humans, rat and mice has been widely studied. It is found in three main areas of the body: the intestinal wall, the central nervous system (CNS) and blood vessels. 5-HT is implicated in a wide range of physiological and pathophysiological pathways including the contraction of smooth muscles, vasodilation, peristalsis, platelet aggregation and homeostasis.

In the CNS, 5-HT is thought to be involved in a control of appetite, mood, anxiety, hallucinations, sleep, vomiting and pain perception.

Although serotonin may be obtained from a variety of dietary sources, endogenous 5-HT is synthesized in situ from tryptophan through the actions of the enzymes tryptophan hydroxylase and aromatic L-amino acid decarboxylase. 5-HT is synthesized throughout the body, and interacts with 5-HT receptors present on the surface of many cells. The effect of serotonin is dependant on the amount that is secreted, and the type of receptor with which it interacts.

Over the past decade, more than 14 different 5-HT receptors have been cloned and sequenced. These receptors are grouped into seven families, with as many as five sub-types in a family. As shown in Table 1 , 5-HT receptors are found throughout the body and are thought to be involved in a number of clinical disorders.

5-HT-i_B receptors were one of the first 5-HT-Hike receptors to be described, found in rodent brain. Similarities were later found between rodent 5- HT-iB and 5-HT-i_D receptors and those in the brains of higher animals. 5-HTi_B and 5-HT-iD receptors have a 77% amino acid sequence homology and share very similar pharmacological profiles, and are therefore often referred to as 5- HT-i B/D receptors.

5-HTIB receptors are found in rat and mouse brain, with a particularly high concentration located in the substantia nigra, globus pallidus and dorsal subiculum. 5-HT-ID receptors are found throughout the CNS of several species, and in vascular smooth muscles. Both 5-HT-i_B and 5-HT-ID receptors mediate vasoconstriction of cerebral blood vessels, and are thought to play a role in migraine headache (Slassi 2002) and the pathophysiology of cerebrovascular diseases such as obsessive-compulsive disorders. 5-HTI_B/ID receptors are also implicated in feeding behaviour, anxiety, depression, cardiac function, thermoregulation, sexual behaviour and movement.

Weller et al. (1994) conducted a study to examine the potency of a series of 5-HT receptor antagonists on the contraction of equine digital veins, and concluded that 5-HT-i-like and 5-HΪ2 receptors were both present. Additionally, the paper proposes that the 5-HTHike receptor does not resemble the 5-HT-IA receptor.

Bailey & Elliot (1998a) compared the contractile effects, in vitro, of 5-HT on equine digital arteries with those on other equine peripheral arteries. They found that digital arteries were 17 and 41 times more sensitive to the vasoconstrictor effects of 5-HT compared with equivalent sized segments of facial and tail arteries, respectively, whereas equine coronary arteries showed no vasoconstrictor response to 5-HT. They also concluded that 5-HT is present in equine plasma at concentrations capable of causing a significant degree of contraction in equine digital blood vessels but which are well below the threshold of contraction of other peripheral vascular beds.

Bailey and Elliott (1998b) investigated the pharmacological profile of 5- HT1B/1D receptors mediating vasoconstriction of equine digital blood vessels and compared the function of digital arteries and veins. This was done by looking at the potency and efficacy of a series of 5-HT receptor agonists and assessing the effects of 5-HT receptor antagonists on the responses to the agonists. The results indicated that 5-HTIB/ID receptors mediating vasoconstriction of horse digital blood vessels are different on the arterial and venous side of circulation.

The venous receptor has a very similar pharmacology to the 5-HT-|_D receptor in humans, whilst the arterial receptor has a similar pharmacology to the 5-HT-IB receptor in rodents. Nevertheless, it is currently believed that these equine receptors should be collectively referred to as 5-HT-IB/ID- The paper proposes that differences in the 5-HT-IB/ID receptors in the arterial and venous components of equine digital circulation may be of significance in the pathogensis of acute equine laminitis.

However, none of these publications have investigated the role of 5-HT in resistance blood vessels of an equine digit. The resistance blood vessels or the capillaries, as opposed to the larger arteries and veins, regulate blood flow and so considerably control the rate of perfusion of equine digits. There is no published data on the types of receptors that exist on these resistance blood vessels nor, if receptors are present, whether they have a role to play in controlling blood perfusion. Bailey et al. (2000b) examined the kinetics of active uptake of radiolabeled [³H]5-HT by equine platelets in vitro, the uptake of 5-HT into platelets being an important mechanism by which low plasma concentrations are maintained. The paper concluded that naturally occurring monoamines, that may be released from the gut, for example, due to carbohydrate overload, are capable of inhibiting platelet 5-HT uptake by a mechanism which remains to be established, a phenomenon which may lead to an increase in free plasma 5-HT concentration. The paper postulates that such a mechanism leading to an increase in 5-HT levels may result in increased digital vascular resistance and therefore may be important in the pathophysiology of acute laminitis.

Amines produced in the large intestine, such as tryptamine, have been shown to cause a decrease in equine digital blood flow. This occurs at low concentrations below the threshold for causing systemic cardiovascular changes (Bailey et al, 2004). The data we present herein further suggests that these amines have a role to play in regulating digital perfusion and that this mechanism may lead to laminitis. It is therefore appropriate to consider alleviating the effects of gut derived amines on equine digit blood flow using an agent that acts as an appropriate antagonist. We have therefore speculated that gut derived amines may have a regulatory effect on the resistance vessels of equine digits and that this effect can be reversed by the use of an appropriate antagonist.

Table 1 lists some of the known agonists and antagonists specific for the different types of 5-HT receptors. These compounds are commonly used in pharmacological studies to investigate the role of a receptor in a particular pathway or pathophysiology. A host of other compounds are known, but many of these target two or more receptors at once, and are therefore not useful in the study of a single receptor type. To date, there has been little work in horses and the majority of work has been carried out on rats and mice as 5-HT receptors in these species have the highest amino acid sequence homology to 5-HT receptors in humans.

In spite of the considerable amount of work carried out and data accumulated on the pathophysiological mechanisms involved in laminitis, there is still a strong need for an effective treatment for the disease, and in particular a treatment which may be readily administered.

We have now found that a particular set of benzanilide derivatives act as 5-HT_1B/ID receptors antagonists in equine digital veins and that at least some selectivity in comparison to 5- HT-IB/ID receptors in equine arteries is exhibited.

According to a broad aspect of the invention there is provided the use of a compound of general formula (I):

in which R¹ represents hydrogen, halogen, Ci_-6 alkyl, C_3-6 cycloalkyl, C_3-6 cycloalkenyl, C_1-6 alkoxy, hydroxy Ci_-6 alkyl, C₁^ alkylOCi_-6 alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂R²⁹, CONR³⁰ R³¹, NR³⁰ R³¹; R² represents a phenyl group, having phenyl ring B, substituted by a group selected from i) a 5 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, optionally substituted by a substituent selected from halogen, Ci_-6 alkyl, C_3-6 cycloalkyl, C_3-6 cycloalkenyl, C_1-6 alkoxy, hydroxyCi_-6 alkyl, Ci_-6 alkylOCi_-6 alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂ R²⁹, CONR³⁰R³¹, or NR³⁰R³¹,

and optionally further substituted by one or two auxiliary substituents selected from a halogen atom, a hydroxy group, a Ci_-6 alkoxy group and a Ci_-6 alkyl group, or by an auxiliary substituent selected from C_3-6 cycloalkyl, C_3-6 cycloalkenyl, hydroxyCi_-6 alkyl, Ci_-6alkylOCi_-6 alkyl, acyl, aryl, acyloxy, nitro, trifluoromethyl, cyano, CO₂R²⁹, CONR³⁰R³¹ or NR³⁰R³¹ ;

D is CONH or NHCO;

or G-(CR²⁴R²⁵J-NR²⁷R²⁸ where R⁵ represents a hydrogen atom or a Ci_-6 alkyl, group, G is oxygen, S(O)_P where P is O, 1, or 2, NR³² where R³² is hydrogen, C_1-6 alkyl or phenyl Ci_-6 alkyl, or G is CR²⁴ = CR²⁵ or CR²⁴R²⁵ where R²⁴ and R²⁵ are independently hydrogen or Ci_-6 alkyl;

F is hydrogen, a halogen atom, a hydroxy group, a Ci_-6 alkoxy group, a Ci_-6 alkyl group or a halogenated C_1-6 alkyl group;

R²⁷ and R²⁸ are independently hydrogen, Ci_-6 alkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5-to 7 - membered heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulphur;

R²⁹, R³⁰ and R³¹ are independently hydrogen or C_1-6 alkyl; m is 1 to 4; and n is 1 or 2 or a physiologically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of laminitis.

According to a first preferred aspect of the invention, there is provided the use of a compound of general formula (II):

in which

R¹ represents a hydrogen atom, a halogen atom, a C_halky! group or a Ci_

₆alkoxy group;

R² represents a phenyl group, having phenyl ring B₁ substituted by a group selected from

(i)

and optionally further substituted by one or two auxiliary substituents selected from a halogen atom, a hydroxy group, a Ci-β alkoxy group and a C_1-6 alkyl group; R³ and R⁴, which may be the same or different, each independently represents a hydrogen atom, a halogen atom, a hydroxy group, a Ci-β alkoxy group, a C_1-6 alkyl group or a halogenated C_1-6 alkyl group;

R⁵, R⁷ and R⁸, which may be the same or different, each independently represent a hydrogen atom or a C_1-6 alkyl group; R⁶ represents a hydrogen atom, a -NR⁸R⁹ group or a Ci_-6alkyl group optionally substituted by one or two substituents selected from a hydroxy group, a Ci_-6 alkoxy group, a Ci-β acyloxy group or a -SO₂R¹⁰ group;

R⁹ represents a hydrogen atom, a C_1-6 alkyl group, a C_1-6 acyl group, a benzoyl group or a -SO₂R¹⁰; R¹⁰ represents a C_1-6 alkyl group, a phenyl group, or a phenyl group optionally substituted with a methyl group;

Z represents an oxygen atom, a NR⁷ and S(O)ι_<; and k represents zero, 1 or 2, or a physiologically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of laminitis. A preferred group of compounds of general formula (II) is that in which the phenyl ring B is attached to the phenyl ring A at a position para to the bond of ring A with the amide group.

A further preferred group of compounds of general formula (II) is that in which the substituent (i) to (viii) on the phenyl ring B is attached at a position meta or para, more preferably para, to the bond of the phenyl ring B to the phenyl ring A.

Also preferred is the group of compounds of general formula (II) in which R³ is attached at the para-position relative to the amide linkage. A further preferred group of compounds of general formula (II) is that in which R⁴ is a hydrogen atom.

Preferably, for R¹⁰, the methyl substituted phenyl group is a p- toluenesulphonyl group.

A yet further preferred group of compounds of general formula (II) is that in which the phenyl ring B is additionally substituted by one or two auxiliary substituents selected from a halogen atom, a hydroxy group, a Ci-6 alkoxy group and a Ci_-6 alkyl group. Suitably, the phenyl ring B is substituted by a methyl group. When the phenyl ring B is substituted by said one or two auxiliary substituents, this/these is/are preferably attached at a position ortho to the bond of the phenyl ring B with the phenyl ring A. In particular, if a 2'-methyl is present on phenyl ring B, the group is positional ortho to the bond joining phenyl rings A and B.

A preferred group of compounds of general formula (II) are those represented by general formula (III)

in which

R¹, R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, Z and k are as defined for general formula (II) and

R¹¹ represents a substituent group selected from

R¹² represents optional substitution by one or two substituents selected from a halogen atom, a hydroxy group, a C-i-βalkoxy group and a Ci_₆ alkyl group, and Z represents an oxygen atom. Preferred groups of compounds of general formula (II) and (III) are those in which the phenyl ring B is additionally substituted by an auxiliary substituent (i.e. in the case of general formula (III) R¹²) selected from a halogen atom, a hydroxy group, a Ci-6 alkoxy group and a Ci_-6 alkyl group. Suitably, the phenyl ring B is substituted by a methyl group. When the phenyl ring B is substituted by said auxiliary substituent, this is preferably attached at a position ortho to the bond of the phenyl ring B with the phenyl ring A. Further preferred groups of compounds of general formula (II) and (III) are those in which the phenyl ring B is substituted by (i.e. in the case of general formula (III), the R¹¹ substituent is) the substituent (i), (iii), (vii) or (viii), especially the substituent (i) and optionally further substituted by one or two auxiliary substituents selected from a halogen atom, a hydroxy group, a Ci_-6 alkoxy group and a Ci_-6 alkyl group.

Also preferred are those compounds of general formula (II) and (III) in which R¹ represents a hydrogen atom or a Ci_₆ alkyl, especially methyl, group.

Other preferred groups of compounds of general formula (II) and (III) are those in which R¹ is attached at the ortho position relative to the amide linkage.

Other preferred groups of compounds of general formula (II) and (III) are those in which Z represents an oxygen atom.

Further preferred groups of compounds of general formula (II) and (III) are those in which R⁶ represents a C_1-6 alkyl, especially methyl, group optionally substituted by a Ci_₆ alkoxy, especially methoxy, group.

Other preferred groups of compounds of general formula (II) and (III) are those in which R³ is a halogen atom, especially a fluorine or chlorine atom, a hydroxy group, a Ci_-6 alkoxy group, especially methoxy group, or a halogenated Ci_-6 alkyl or alkoxy group, especially ethoxy. Yet further preferred groups of compounds of general formula (II) and (III) are those in which R⁵ is a C1-3 alkyl, especially methyl, group.

A yet more preferred group of compounds of general formula (II) are those represented by general formula (IV)

in which

R⁶, R⁷, R⁸, R⁹ and R¹⁰ are as defined for general formula (II) and

R¹³ represents a substituent group selected from

(l)

R¹⁴ represents a hydrogen atom or a Ci_-6alkyl, especially methyl, group; R¹⁵ represents a halogen atom, especially a fluorine or chlorine atom, a hydroxy group, a Ci_-6 alkyl or alkoxy, especially methoxy, group, a C_1-6 alkyl, especially methyl, group or a halogenated Ci_-6 alkoxy, especially ethoxy, group;

R¹⁶ represents a Ci.₃alkyl, especially methyl, group, and Z is oxygen.

Suitable compounds falling within one or more or general formula (II) - (IV) include: a. N-[4-methoxy-3-(4-methyl-1 -piperazinyl)phenyl]-2'-methyl-4'-(3-methyl-

1 ,2,4-oxadiazoI~5-yl)[1 , 1 '-biphenyl]-4-carboxamide; b. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl- 1 ,3,4-oxadiazol-2-yl)[1 ,1'-biphenyl]-4-carboxamide; c. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-5^I-(5-methyl- 1 ,3,4-oxadiazol-2-yl)[1 , 1 '-biphenylJ-4-carboxamide; d. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2¹-methyl -4'-(5- (methoxymethyl)-i ,2,4-oxadiazol-3-yl][1 , 1 -biphenyl]-4-carboxamide; e. N-[4-methoxy-3-(4-methyl-1-piperazinyI)phenyl]-2-methyl-4'-(5-methyl-

1 ,2,4-oxadiazol-3-yl)[1 , 1 '-biphenyl]~4-carboxamide; f. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2^l-methyl-4'-(3- (Dimethylamino)-I ,2,4-oxadiazol-5-yl)[1 , 1 '-biphenyl]-4-carboxamide; g. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-4^l-(5-methyl-1,2,4- oxadiazol-3-yl)[1 , 1 '-biphenyl]~4-carboxamide; h. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-4'-(1-methyl-1 H-1 ,2,3- triazol-4-yl)[1 , 1 '-biphenyl]-4-carboxamide; i. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-((5-

(methylsulphonyl)methyl)-1 ,2,4-oxadiazol-3-yl)[1 , 1 '~biphenyl]-4- carboxamide; j. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-

1 ,3,4-thiadiazol-2-yl)[1 , 1 -biphenyl]-4-carboxamide; k. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-

(hydroxymethyl)-i ,2,4-oxadiazol-3-yl)[1 , 1 '-biphenyl]-4-carboxamide; I. N-[4-chloro-3-(4-methyl-1 -piperazinyl)phenyl]-2'-methyl-4^I-(5-methyl-

1 ,2,4-oxadiazol-3-yl)[1 , 1 '-biphenyl]-4-carboxamide; m. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4¹-(3-methyl-

1 ,2,4-thiadiazol-5-yl)[1 , 1 '-biphenyl]-4-carboxamide; n. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-chloro-4'-(5-methyl-

1 ,3,4-oxadiazol-2-yl)[1 ,1'-biphenyl]-4-carboxamide; o. N-[4-methoxy-3-(4-methyl-1 -piperazinyl)phenyl]-2'-methyl-4'-(1 ,2,3- thiadiazol-4-yl)[1 , 1 '-biphenyl]-4-carboxamide; p. N-[4-methyl-3-(4-methyl-1 -piperazinyQphenyl^'-methyM'^δ-methyl-

1 ,3,4-oxadiazol-2-yl)[1 ,1 '-biphenyl]-4-carboxamide; q. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4^l-(1,5- dimethyl-1 H-1 ,2,4-triazol-3-yl)[1 , 1 '-biphenyl]-4-carboxamide; r. 2-chloro-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-4'-(5-methyl- 1 ,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-carboxamide; s. N-[2-fluoro-4-methoxy-5-(4-methyl-1-piperazinyl)phenyl]-2-methyl-4'-(5- methyl-1 ,2,4-oxadiazol-3-yl)[1 , 1 '-biphenyl]-4-carboxamide; t. N-[4-chloro-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-

1 ,3,4-oxadiazol-2-yl)[1 ,1 -biphenyl]-4-carboxamide; u. N-[4-bromo-3-(4-methyl-1-piperazinyl)phenyl]-2'methyl-4^l-[5-methyl-1 ,2,4- oxadiazol-3-yl][1 , 1 -biphenyl]-4-carboxamide; v. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2^I-methyl-4'-(1 ,3,4- oxadiazol-2-yl)[1 , 1 '-biphenyl]-4-carboxamide; w. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4^l-(5-methyl- 1 ,2,4-oxadiazol-3-yl)[1 , 1 '-biphenyl]-4-carboxamide; x. N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2'-methyl-4^I-

(amidinyl)[1 ,1 -biphenylH-carboxamide; y. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-

(aminocarbonyl)[1 ,1 '-biphenyl]-4-carboxamide; z. N-^-hydroxy-S-C^methyl-i-piperazinyOphenylJ^'-methyl^'-CS-methyl-

1 ,3,4-oxadiazol-2-yl)[1 ,1'-biphenyl]-4-carboxamide; and aa. N-[4-fluoroethoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5- methyl-1 ,2,4-oxadiazol-3-yl)[1 , 1 '-biphenyl]-4~carboxamide bb. 3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl] benzamidθ dihydrochloride and their physiologically acceptable salts and solvates.

Preferred compounds include compound (b) and compounds (I) to compound (bb) and their physiologically acceptable salts and solvates.

Particularly preferred compounds include (b), (w), (x), (y), (z), (aa) and (bb) and their physiologically acceptable salts and solvates.

According to a second preferred aspect of the invention, there is provided the use of a compound of general formula (V):

in which

P is a 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;

R²¹, R²² and R²³ are independently hydrogen, halogen, Ci-βalkyI, C₃-₆cycloalkyl, C_3-6cycloalkenyl, Ci_-6alkoxy, hydroxyCi_-6alkyl, Ci_-6alkyl0Ci..₆alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂R²⁹, CONR³⁰R³¹ or NR³⁰R³¹ where R²⁹, R³⁰ and R³¹, NR³⁰R³¹ are independently hydrogen or C_1-6alkyl;

R²⁴ and R²⁵ are independently hydrogen or Ci_-6alkyl;

R²⁶ is hydrogen, halogen, hydroxy, C_1-6alkyl or Ci_-6alkoxy; R²⁷ and R²⁸ are independently hydrogen, C_1-6alkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7- membered heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulphur;

D is CONH or NHCO; G is oxygen, S(O)₉ where p is 0, 1 or 2, NR³² where R³² is hydrogen, C_1-6alkyl or phenylC_1-6alkyl, or G is CR²⁴=CR²⁵ or CR²⁴R²⁵ where R²⁴ and R²⁵ are independently hydrogen or Ci.₆alkyl; m is 1 to 4; and n is 1 or 2; or a physiologically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of laminitis.

Suitably P is a 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur. Examples of suitable heterocyclic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl. The heterocyclic rings can be linked to the remainder of the molecule via a carbon atom or, when present, a nitrogen atom. Preferably P is oxadiazolyl.

Preferably R²¹ and R²² are C_1-6alkyl, in particular methyl. Preferably R²³ is hydrogen. Preferably R²⁴ and R²⁵ are both hydrogen.

Examples of R²⁷ and R²⁸ as heterocyclic rings include pyrrolidine, morpholine, piperazine and piperidine. Optional substituents for such rings include Ci_-6alkyl. Preferably R²⁷ and R²⁸ are both Ci_-6alkyl, in particular methyl. Suitably R²⁶ is hydrogen, halogen, hydroxy, C_1-6alkyl or Ci_-6alkoxy.

Preferably R²⁶ is C_1-6alkoxy such as methoxy.

Preferably D is CONH.

Preferably B is oxygen, CH₂ or NR³² where R³² is phenyl C_halky! such as phenethyl. Preferably m is 2

Preferably n is 1

The groups G(CR²⁴R²⁵)_mNR²⁷R²⁸ and R ²⁶ can be attached to the phenyl ring at any suitable position. Preferably the group G(CR²⁴R²⁵)_mNR²⁷R²⁸ is meta to the amide linkage and the group R²⁶ is para to the amide linkage. The groups R²¹, R²² and R²³ can be attached to their respective rings at any suitable position.

In preferred embodiments, m is 2 and R²⁷ and R²⁸ are both Ci_-6alkyl.

In particularly preferred embodiments, the compound is: N-[3-(Dimethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4'(5-methyl-1,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Diethylaminoethoxy)-4-methoxyphenyl]-2^l-methyl-4'(5-methyl-1,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Diisopropylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4^I(5-methyl-1 ,2,4-

oxadiazol-3-yl)biphenyl-4-carboxamide, N-[3-(2-Dimethylamino-1-methylethoxy)-4-methoxyphenyl]-2^l-methyl-4'(5-methyl-

1 ,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-2-Dimethylaminopropoxy)-4-methoxyphenyl]-2^l-methyl-4'(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide, N-[3-(2-Methylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4^I(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-2-Aminoethoxy)-4-methoxyphenyl]-2'-methyl-4'(5-methyl-1 ,2,4-oxadiazol-3- yl)biphenyl-4-carboxamide,

N-[3-(2-Piperidin-1-ylethoxy)-4-methoxyphenyl]-2'-methyl-4^l(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Morpholin-4-ylethoxy)-4-methoxyphenyl]-2'-methyl-4'(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4'(3-methyl-1 ,2,4- oxadiazol-5-yl)biphenyl-4-carboxamide, N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4'(5-methyl-1 ,3,4- oxadiazol-2-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4'(1 ,3,4-oxadiazol-2- yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)phenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3- yl)biphenyl-4-carboxamide,

N-[5-(2-Dimethylaminoethoxy)-2,4-diiodophenyl]-2'-methyl-4^l(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-[(2-Dimethylaminoethyl)amino]-4-methyloxyphenyl]-2'-methyl-4'-(5-methyl-

1 ,2,4-oxadiazol-3-yl)-biphenyl-4-carboxamide, N-[3-(3-Dimethylaminopropoxy)-4-methyloxyphenyl]-2'-methyl-4'(5-nnethyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-fS-CS-DimethylaminopropylH-methyloxyphenyl^'-methyWXδ-methyl-i ^^- oxadiazol-3-yl)biphenyl-4-carboxamide, N-[3-(3-Dimethylaminoprop-1-enyl)-4-methoxyphenyl]-2^l-methyl-4^l-(5-methyl-

1 ,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[4-(3-Dimethylaminopropoxy)phenyl]-2'methyl-4'-(5-nnethyl-1 ,2,4-oxadiazol-3- yl)biphenyl-4-carboxamide,

N-[3-2-(Pyrrolidin-1-ylethoxy)-4-methoxyphenyl]-2'-methyl-4^l(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2^l-methyl-4'(5-ethyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4^I(5-dimethylamino-

1 ,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide, N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4^l-(4-methylthiazol-2- yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4^l-pyrazinyl biphenyl-

4-carboxamide,

N-[3-(2-Dimethylaminoethylthio)-4-methoxyphenyl]-2'-methyl-4'(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethylsulphinyl)-4-methoxyphenyl]-2'-methyl-4'(5-methyl-

1 ,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[5-(2-Dimethylaminoethoxy)-2-chlorophenyl]-2'-methyl-4'(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide, N-[3-(2-Dimethylaminoethoxy)-4-chlorophenyl]-2^l-methyl-4'-(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-bromophenyl]-2^l-methyl-4'-(5-methyl-1 _l2,4- oxadiazol-3-yl)biphenyl-4-carboxamide, N-[3-(2-Dimethylaminoethoxy)-4-iodophenyl]-2'-methyl-4'-(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-ethylphenyl]-2^l-methyl-4'-(5-methyl-1 ,2_I4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-isopropylphenyl]-2'-methyl-4^l-(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-4'(1 ,2,4-triazol-1-yl)-2'methyl-

(1 ,1'-biphenyl)-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-4'-(5-methyl-1 _I2,4-oxadiazol-3- yl)-1 , 1 '-biphenyl-4-carboxamidθ, N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-4'(1 ,2,4-triazol-1 -yl)-1 -1 '- biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-4^l(tθtrazol-2-yl)-1 , 1 '-biphenyl- 4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2-methyl-4'-(5-methyl-1 ,2,4- oxadiazol-3-yl)-1 , 1 'biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2-methyl-4'-(2-pyndyl)-1 , 1 '- biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2-methyl-4'-(3-pyridyl)-1 , 1 '- biphenyl)-4-carboxamide, N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2'-ethyl-4'-(5-nnethyl-1 ,2,4- oxadiazol-3-yl)-1 , 1 -biphenyl)-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2,2^l-dimethyl-4'-(5-methyl-

1 ,2,4-oxadiazol-3-yl)-1 , 1 '-biphenyl-4-carboxamide, N-[3-(N'-(2-Dimethylaminoethyl)-N'-methylamino)-4-methoxyphenyl]-2¹-methyl-4'-

(5-methyl-1 ,2,4-oxadiazol-3-yl)-1 ,1 '-biphenyl-4-carboxamide,

N-[3-(N'-(2-Dimethylaminoethoxy)-N'-phenethylaιinino)-4-methoxyphenyl]-2'- methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)-1 , 1 '-biphenyl-4-carboxamide,

N-[3-(N'-(2-Dimethylaminoethoxy)-N'-butylamino)-4-methoxyphenyl]-2'-methyl-4'- (5-methyl-1 ,2,4-oxadiazol-3-yl)-1 ,1'-biphenyl-4-carboxamide,

N-[3-(-2-Dimethylaminoethoxy)-4-methoxyphenol]-4'-(1 ,2,4-triazol-1-yl)-(1 ,1'- biphenyl)-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenol]-4'-(tetrazol-2-yl)-(1 , 1 '- biphenyl)-4-carboxamide, N-[3-(-2-Dimethylaminoethoxy)-4-methoxyphenol]-2'-methyl-4^l-(1 ,2,4-triazol-1- yl)-(1 ,1'-biphenyl)-4-carboxamide, and their physiologically acceptable salts and solvates.

It is to be understood that the present invention encompasses use of all geometric and optical isomers of the compounds of general formulae (I) to (V) and their mixtures including racemic mixtures thereof, together with the use of tautomers.

Physiologically acceptable salts of the compounds of general formula (I) -

(V) include acid addition salts formed with inorganic or organic acids, for example, hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthoates, p-toluenesulphonates, methanesulphonates, sulphamates, ascorbates, tartrates, citrates, oxalates, maleates, salicylates, fumarates, succinates, lactates, glutarates, glutaconates, acetates or tricarballylates. In the compounds of general formulae (I) - (V), the term ' Ci_-6 alkyl group¹ or ' Ci_-6 alkoxy group' means that the group is straight or branched and consists of 1 to 6 carbon atoms. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t- butoxy.

The term 'halogen' as used herein means fluorine, chlorine, bromine or iodine.

In the compounds of general formulae (I) - (V), the term 'acyl group' means an alkanoyl group such as acetyl or pivaloyl. We have found that the compounds for use according to the present invention demonstrate unexpected specificity for 5-HTIB/ID receptors in equine digital veins. As such, these compounds may provide a very useful means by which laminitis may be treated.

The compounds for use according to the invention can be manufactured using known routes of chemical synthesis such as those described in EP

533,268 (Glaxo Group Limited), Liao et al. (2000) and International Publication WO 95/15954, the contents of each of which is incorporated herein by reference. Although EP 533,268 and Liao et al. (2000) disclose the compounds therein as being potentially useful as 5-HTi_D inhibitors, the uses proposed are wide ranging, suggesting that the compounds are relatively non-selective as regards the different 5-HT-ID receptors. There is nothing in these documents to suggest the compounds might be highly selective to 5-HTI_B/ID receptors in equine digital veins. The compounds according to the invention may be used in the manufacture of a medicament for the treatment or prophylaxis of laminitis induced by gut derived amines.

Low dose lipopolysaccharides (LPS) have been implicated in some forms of laminitis, and thus in a further aspect compounds according to the invention are used in the manufacture of a medicament for the treatment or prophylaxis of endotoxaemia or LPS induced laminitis. It is particularly preferred in such embodiments that the compounds according to the invention are used in conjunction with aspirin.

It will be appreciated from the above that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic and/or prophylactic agents, for instance, aspirin, preferably in a relatively low dose to inhibit platelet production of thromboxane A₂ (TxA₂), or possibly ritanserin (5-HT₂) selective receptor antagonist and/or platelet activating receptor antagonists. It is to be understood that the present invention covers the use of a compound of general formula (I) - (V) or a physiologically acceptable salt or solvate thereof in combination with one or more other therapeutic and/or prophylactic agents. The compounds of general formula (I) - (V) and their physiologically acceptable salts and solvates may be formulated for administration in any convenient way, and the invention therefore also includes within its scope use of pharmaceutical compositions comprising at least one compound of general formula (I) - (V) or a physiologically acceptable salt or solvate thereof for the treatment of laminitis. Such compositions may be presented for use in a conventional manner in admixture with one or more physiologically acceptable carriers or excipients.

The carrier(s) should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Thus, the compositions for use according to the invention may be formulated for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. A particularly preferred route of administration would be oral, for example delivered in feed. This could be formulated as a granule/paste or slow release formulation.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxypropyl methylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p- hydroxybenzoates or sorbic acid. The compositions may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.

The composition according to the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. For administration by inhalation either orally or nasally the compositions according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from a nebuliser. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.

Alternatively, for administration by inhalation the compositions according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.

The pharmaceutical formulations according to the invention may also contain other active ingredients such as antimicrobial agents, or preservatives.

The compositions according to the invention may be prepared by mixing the various ingredients using conventional means.

It will be appreciated that the amount of a compound of general formula (I) - (V) required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature and severity of the condition being treated and the age and condition of the animal, and will ultimately be at the discretion of the attendant veterinarian. In general, however, a proposed dose of the compounds of the invention for administration in equine subjects is preferably less than 1 mg/kg, of the active ingredient per unit dose which could be administered, for example, at least once in every 24 hours.

Examples of compounds and uses in accordance with the invention will now be described with reference to the accompanying drawings, in which:- Figure 1 shows the effect of GR 127935 on the responses of equine digital veins to 5-CT;

Figure 2 shows the effect of SB 216641 on (a) the responses of equine digital veins to sumatriptan and (b) the responses of equine arteries to 5-CT;

Figure 3 shows the effect of SB 216641 on (a) noradrenaline and U44069 and (b) carbachol and NECA;

Figure 4 shows the effect of washing on SB 216641 mediated response to tryptamine in equine digital veins;

Figure 5 shows (a) SB 216641 pharmacokinetics and (b) SB 216641 plasma kinetics; Figure 6 shows in vivo SB 216641 pharmacodynamics;

Figure 7 shows plasma concentration of GR127935 against time following intravenous administration to a horse;

Figure 8 is a log-|₀ plot of the plasma concentration of GR 127935 against time following intravenous administration to a horse; and Figure 9 shows plasma concentration of GR 127935 against time following oral administration to a horse. Examples

Example 1 : Experiments investigating the effects of GR 127935 on the responses of eguine digital veins to 5-carboxvamidotrvptamine(5-Cπ GR 127935 hydrochloride (available from Tocris Cookson Limited, Avonmouth, U.K.) is a reported potent antagonist that is selective for 5-HTIB and 5-HTi_D receptors. GR 127935 is N-[4-methoxy-3-(4-methyl-1- piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)[1 ,1^l-biphenyl]-4- carboxamide. Compound GR 127935 was tested for its ability to antagonise contractions of equine digital arteries to the 5-HTi -selective agonist 5-CT (available from Tocris Cookson Limited, Avonmouth, U.K.).

Rings of equine digital veins were obtained from 4 horses. Within each experiment, 4 adjacent rings from a given animal were used. One acted as a control (vehicle only added); in each of the other three vessels, 10^'8, 10^"7 and 10^"

⁶ M of the test compound was added to the bathing solution 45 min before a concentration response curve to (5-CT) was obtained. The results for each vessel ring were normalised to the response to depolarising Krebs solution (DKS) in each case. Concentration response curves were generated by computerised non-linear curve fitting to a one site logistic model. Figure 1 shows the results from the GR127935 tests. Each data point on the Figures

represents the mean ± SD from the 4 horses tested.

The results demonstrate that GR 127953 is a more effective inhibitor of venous vasoconstriction due to 5-HT_1B/D receptor activation than it was in the arteries. No inhibitory effect was observed with 10^'8 M GR127953 whereas 10^'7

M shifted the curve to the right by 3 fold (0.5 log unit) and reduced the maximum response by about one third from 22% DKS to 14% DKS. At 10^"6 M, the maximum response was reduced further. Example 2: Experiments investigating the effects of SB216641 on the responses of equine digital veins and arteries

SB216641 hydrochloride(N-[3-[3-(dimethylamino)ethoxy]-4- methoxyphenyl]-2¹-methyl-4¹-(5-methyl-1 ,2,4-oxadiazol-3-yl)-[1 , 1¹-biphenyl]-4- carboxamide hydrochloride) was obtained from Tocris Cookson Ltd, Avonmouth,

UK. Numerous in vitro and in vivo experiments were performed to investigate the effects of SB 216641 hydrochloride on equine digital veins and arteries.

(A) In vitro studies of contraction of equine digital veins and arteries Experiments were performed on equine digital veins and arteries generally utilising methodology described in Example 1. Compound SB 216641 hydrochloride was tested for its ability to antagonise contractions of equine digital veins to the agonist sumatriptan. Experiments were performed using 10^"8, 10^"7, and 10^'6 M solutions of SB 216641 hydrochloride together with a control solution. The results are shown in Figure 2a, which reveals that the 10^~8 M solution causes a three-fold rightward shift in response curve, and the 10^"7 M solution results in a complete inhibition of sumatriptan induced response. Figure 2b shows the results obtained from similar experiments on the responses of arteries to 5-CT (available from Tocris Cookson Limited, Avonmouth UK). Similar overall effects were observed compared to the data obtained from the equine digital veins, although the reduction in the response was less pronounced, indicating that SB 2166441 has some selectivity for venous receptors.

(B) In vitro studies of the effects of SB 216641 on blood vessel relaxation agents As shown in Figures 3a and 3b, SB 216641 was found to have no partial agonist activity at the 5-HTIB/D receptor, and did not potentiate responses to noradrenaline or the thromboxane-mimetic U44069. In Figure 3a it can be seen that, whilst SB 216641 essentially eliminates response to sumatriptan, there is no inhibition of thromboxane or adrenoreceptors. In Figure 3b, blood vessel relaxation caused by 10^"6 M carbachol and 10^'8 M NECA, both with and without treatment with SB 216641 , is shown. It can be seen that there is no significant inhibition of blood vessel relaxation.

(C) In vitro studies into the reversibility of tryptamine antagonism Figure 4 shows the contraction response in tissue from six equine digital vein samples in a procedure involving successive exposure of the samples to DKS, the caecal derived amine tryptamine, a solution of tryptamine and SB 216641 , washing with drug-free DKS, and re-exposing to tryptamine and then DKS. It can be seen that the response to tryptamine is still inhibited after a washing procedure that should remove any free SB 216641. It appears that the treatment with SB 216641 is not readily reversible, and indeed it is possible that SB 216641 is an irreversible antagonist.

(D) In Vivo SB 216641 Pharmacokinetics

Figure 5a shows pharmacokinetics for oral and intravenous dosing at a dosage of 0.3 mg/kg. An oral bioavailability of 21.5% was measured, together with an elimination half-life of 6.8 hours and a clearance of 0.012 ml/min/kg. Figure 5b shows plasma kinetics following oral dosing of 0.3 mg/kg SB 216641. A peak plasma concentration C_max of 5.85+2.61 ng/ml, at T_maχ of 1.5±0.8 hours was measured. (E) In Vivo SB 216641 Pharmacodynamics

Figure 6 shows the in vivo effects of SB 216641 (orally administered, 0.6 mg/kg) on vasoconstriction in the feet of 6 thoroughbred horses, induced by the infusion of tryptamine. Eight hours after administration of the SB 216641 or saline control, tryptamine was infused at a dose of 1.6 μg/kg/min for 30 min

(from 480-510 min, as shown), and its vasoconstrictor effects on the digit were monitored by measuring the foot temperature at the coronary band with an infared thermometer. SB 216641 abolished the change in temperature caused by tryptamine (statistically significant attenuation; p=0.03). Example 3: In vivo experiments using GR127935

Pharmacokinetic studies were undertaken in two thoroughbred horses, one receiving the drug intravenously and the other receiving the same dose orally. Blood samples were taken over the ensuing 36 to 48 hours and the animals were closely observed for any adverse effects. Both compounds were administered at a dose rate of 0.3 mg/kg by both routes. Drug plasma concentrations of heparinised plasma samples were measured.

Figure 7 shows the plasma concentration of GR127935 as a function of time following intravenous administration. GR127935 was measurable in plasma samples following intravenous administration of 0.3 mg/kg for 24 hours, and the data appear to follow first order elimination kinetics. Figure 8 shows a logarithmic plot of data points from 2 hours onwards. Simple linear regression produces the line of best fit, with an associated correlation coefficient (r²) of 0.94. Clearance of GR127935 can be calculated from the AUC (area under the curve) of the plasma concentration versus time curve (18630 ng/ml.min) and the administered dose (300 ng/kg) and was found to be 0.016 ml/min/kg. From the elimination phase of the data, the elimination rate constant (β ) was found to be

0.002 min^"1, and the elimination half-life was calculated to be 346.5 min (5.8 h).

Extrapolation of the elimination phase of the data to time zero gave C₀ of 32.3 ng/ml allowing the volume of distribution V_d(eijm), to be calculated (0.093 I/kg). Thus the apparent volume of distribution is small.

When the same drug was given orally, the plasma concentration versus time curve shown in Figure 9 was obtained. The Cmax was 5.2 ng/ml

(approximately 10^'8M) and this occurred at 240 min (4 h) following administration. Results are reported for all time points up to 36 h and it should be noted that all of these values are close to the stated working sensitivity (5 ng/ml) of the assay so the absolute accuracy of the data may be somewhat questionable. The AUC for this plasma concentration vs. time curve was calculated as 3685 ng/ml.min and this allows the oral bioavailability to be estimated at around 20%. This must be taken very much as an estimate in view of the extent to which the measured plasma concentrations approach the working sensitivity of the assay. During these experiments to determine pharmacokinetic data, the two horses involved were closely observed for any drug related effects on heart rate, blood pressure, and general demeanor. No drug related effects were observed. Although blood pressure appeared to be quite variable during the observation period, no change which correlated with the drug pharmacokinetic profiles could be discerned, and these changes are thought to be due to individual variability in blood pressure.

In summary, the pharmacokinetics of GR127935 are very promising in that this compound has a relatively small apparent volume of distribution, it can be detected in plasma following a very low dose given orally at a peak plasma concentration which it is believed is effective, and its clearance from the plasma is relatively slow (half-life around 5 to 6 hours). These data suggest that an effective dosing schedule could be devised with this compound.

References

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Medicinal Chemistry, Vol. 43, 517-525

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Weller J., Soydan J. & Elliott J. (1994). "Characterisation of the receptors involved in the vasoconstriction action of 5-hydroxytryptamine in equine digital vein". British Journal of Pharmacology, Vol. 112, 171 P Table 1: Known Agonists and antagonists of 5-HT Receptors

Subtype Location Agonists Antagonists Clinical Implication

5-HT_1A Mainly CNS 8-OH-DPAT WAY100635 Anxiety, mood buspirone, 5-CT depression

5-HT_1B CNS and some CP93129, 5-CT SDZ21009 Appetite disorders, peripheral nerves RU24969 depression, aggression, alcoholism

5-HT_1D Throughout CNS Sumatriptan GR127935 Migraine L694247, 5-CT GR55562 Depression

5-HT_1DB Mainly CNS Sumatriptan GR127935 Migraine L694247, 5-CT Depression

5-HT_1E Only CNS 5-HT None ??

5-HT_1F Mainly CNS 5-HT None Migraine? Contraction in vascular, urinary gastrointestinal and uterine functions

5-HT 2A Vascular smooth α-Methyl-5-HT Ketanserine Sexual and sleep muscle, platelets, cinanserine disorders lung, CNS, gastro pirenperone intestinal tract

5-HT_2B Mainly peripheral? α-Methyl-5-HT SB200646 Anxiety, agitation, Heart, brain, DOI tension, migraines placenta, intestine, lung, liver, kidney, stomach

5-HT₂₀ CNS α-Methyl-5-HT Mesulergine Anxiety, migraine, DOI production of cerebral spinal fluid, sleep, obesity/convulsions cognitive impairment 5-HT₃ Peripheral and 2-Methyl-5-HT Ondansertron, Emesis, anxiety, central neurones m-chlorophenyl- tropisetron depression, memory biguanide disorders

5-HT₄ Gastrointestinal Metoclopramid GR113808 Colon and bladder tract, CNS₁ heart, erenzapride SB204070 contraction and urinary bladder Cisaporide bodily secretions

5-ht₅A CNS 5-HT Methiothepin ?? and

5-htβ CNS 6-HT Methiothepin Anxiety, yawning and stretching, relaxation of smooth muscle tissue

5-htv CNS 5-HT Methiothepin ??

Claims

1. Use of a compound of general formula (I):

in which

R¹ represents hydrogen, halogen, Ci-₆ alky!, C_3-6 cycloalkyl, C_3-6 cycloalkenyl, C_1-6 alkoxy, hydroxyCi_-6 alkyl, C_1-6alkyl0C_1-6 alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂R²⁹, CONR³⁰ R³¹ or NR³⁰R³¹; R² represents a phenyl group, having phenyl ring B, substituted by a group selected from i) a 5 to 7 membered heterocyclic ring containing three heteroatoms selected from oxygen, nitrogen or sulphur, optionally substituted by a substituent selected from halogen, Ci_-6 alkyl, C_3-6 cycloalkyl, C_3-6 cycloalkenyl, Ci_-6 alkoxy, hydroxy Ci-₆ alkyl, Ci_-6 alkyl OC_1-6 alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂R²⁹, CONR³⁰ R³¹ NR³⁰ R³¹, or NR³⁰R³¹,

and optionally further substituted by one or two auxiliary substituents selected from a halogen atom, a hydroxy group, a C_1-6 alkyl group, or by an auxiliary substituent selected from C₃..₆ cycloalkyl, C₃..₆ cycloalkenyl, hydroxy Ci- ₆ alkyl, Ci.₆ alkylOCi_-6alkyl, acyl, aryl, acyloxy, nitro, trifluoromethyl, cyano, CO₂R²⁹, CONR³⁰ R³¹, or NR³⁰ R³¹;

D is CONH or NHCO;

or G-(CR²⁴ R²⁵)-NR²⁷R²⁸ where R⁵ represents a hydrogen atom or a Ci_-6 alkyl group, G is oxygen, S(O)_P where p is O, 1 , or 2, NR³² where R³² is hydrogen, Ci_-6 alkyl or phenyl Ci_-6 alkyl, or G is CR²⁴ = CR²⁵ or CR²⁴ R²⁵ where R²⁴ and R²⁵ are independently hydrogen or C_1-6 alkyl; F is hydrogen, a halogen atom, a hydroxy group, a Ci_-6 alkoxy group, a

Ci_-6 alkyl group or a halogenated Ci_-6 alkyl group;

R²⁷ and R²⁸ are independently hydrogen, Ci_-6 alkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5-to 7-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulphur;

R²⁹, R³⁰ and R³¹ are independently hydrogen or Ci_₆ alkyl; m is 1 to 4; and n is 1 or 2 or a physiologically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of laminitis.

2. Use of a compound of general formula (II)

in which

R¹ represents a hydrogen atom, a halogen atom, a Ci_-6 alkyl group or a C_1-6 alkyoxy group;

R² represents phenyl group, having phenyl ring B, substituted by a group selected from

and optionally further substituted by one or two auxiliary substituents selected from a halogen atom, a hydroxy group, a Ci_-6 alkoxy group and a C-ι-6 alkyl group; R³ and R⁴, which may be the same or different, each independently represents a hydrogen atom, a halogen atom, a hydroxy group, a C-ι-6 alkoxy group, a Ci_-6 alkyl group or a halogenated Ci_-6 alkyl group;

R⁵, R⁷ and R⁸, which may be the same or different, each independently represent a hydrogen atom or a Ci_-6 alkyl group;

R⁶ represents a hydrogen atom, a -NR⁸R⁹ group or a Ci_-6 alkyl group optionally substituted by one or two substituents selected from a hydroxy group, a Ci_-6 alkoxy group, a Ci_₆ acyloxy group or a -SO₂R¹⁰ group;

R⁹ represents a hydrogen atom, a Ci_-6 alkyl group, a Ci_-6 acyl group, a benzoyl group or a -SO₂R¹⁰;

R¹⁰ represents a Ci_-6 alkyl group a phenyl group, or a phenyl group optionally substituted with a methyl group;

Z represents an oxygen atom, a NR⁷ and S(O)κ; and k represents zero, 1 or 2, or a physiologically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of laminitis.

3. Use of a compound according to claim 2, in which the phenyl ring B is attached to the phenyl ring A at a position para to the bond of ring A with the amide group.

4. Use of a compound according to claim 2 or claim 3, in which the substituent (i) to (viii) on the phenyl ring B is attached at a position meta or para to the bond of the phenyl ring B to the phenyl ring A.

5. Use of a compound according to any one of claims 2 to 4, in which R³ is attached at the para-position relative to the amide linkage.

6. Use of a compound according to any one of claims 2 to 5, in which R⁴ is a hydrogen atom.

7. Use of a compound according to any one of claims 2 to 6, in which phenyl ring B is additionally substituted by one or two auxiliary substituents selected from a halogen atom, a hydroxy group, a Ci_-6 alkoxy group and a

Ci_-6 alkyl group.

8. Use of a compound of according to claim 7, in which the phenyl ring B is substituted by a methyl group.

9. Use of a compound according to any one of claims 2 to 8, in which the phenyl ring B is substituted by the substituent (i), (iii), (vii) or (viii).

10. Use of a compound according to any one of claims to 2 to 9, in which R¹ represents a hydrogen atom or a Ci-₆ alkyl group.

11. Use of a compound according to any one of claims 2 to 10, in which R¹ is attached at the ortho position relative to the amide linkage.

12. Use of a compound according to any one of claims 2 to 11 , in which Z represents an oxygen atom.

13. Use of a compound according to any one of claims 2 to 12, in which R⁶ represents a Ci_-6 alkyl group optionally substituted by a Ci_₆ alkoxy group.

14. Use of a compound according to any one of claims 2 to 13, in which R³ is a halogen atom, a hydroxy group, a Ci-₆ alkoxy group or a halogenated

Ci_-6 alkoxy group.

15. Use of a compound according to any one of claims 2 to 14, in which R⁵ is a C-₁-₃ alkyl group.

16. Use of a compound represented by of general formula (III)

in which

R¹, R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, Z and k are as defined for general formula (I) and

R¹¹ represents a substituent group selected from

R¹² represents optional substitution by one or two substituents selected from a halogen atom, a hydroxy group, a C-i-βalkoxy group and a Ci_-6alkyl group, and

Z represents an oxygen atom, or a physiologically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of laminitis.

17. Use of a compound of general formula (IV)

in which

R⁶, R⁷, R⁸, R⁹ and R¹⁰ are as defined for general formula (I) and R¹³ represents a substituent group selected from

/ (Λl)

, (-illx) ( /VI Λl) / (V -lIlx)

R¹⁴ represents a hydrogen atom or a C^₆ alkyl group;

R¹⁵ represents a halogen atom, a hydroxy group, a Ci_₆alkoxy group, a

C-_I-6 alkyl group or a halogenated C_1-6 alkoxy group;

R¹⁶ represents a Ci.₃alkyl group, and Z is oxygen. or a physiologically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of laminitis.

18. Use of a compound according to claim 2, in which the compound is selected from: N-[4-methoxy~3-(4-methyl-1 -piperazinyl)phenyl]-2'-methyl-4'-(3-methyl-

1 ,2,4-oxadiazol-5-yl)[1 ,1'-biphenyl]-4-carboxamide;

N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-

1 ,3,4-oxadiazol-2-yl)[1 ,1'-biphenyl]-4-carboxamide; N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-5^l-(5-methyl-

1 ,3,4-oxadiazol-2-yl)[1 ,1 '-biphenyl]-4-carboxamide;

N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2^l-methyl -4'-(5-

(methoxymethyl)-i ,2,4-oxadiazol-3-yl][1 , 1 '-biphenyl]-4-carboxamide; N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2-methyl-4'-(5-methyl-

1 ,2,4-oxadiazol-3-yl)[1 ,1'-biphenyl]-4-carboxamide;

N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(3-

(Dimethylamino)-1 ,2,4-oxadiazol-5-yl)[1 , 1 '-biphenyl]-4-carboxamide;

N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-4^I-(5-methyl-1 ,2,4- oxadiazol-3-yl)[1 ,1 '-biphenyl]-4-carboxamide;

N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-4^I-(1-methyl-1H-1 ,2,3- triazol-4-yl)[1 , 1 '-biphenyl]-4-carboxamide;

N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4^l-((5-

(methylsulphonyl)methyl)-1,2,4-oxadiazol-3-yl)[1 ,1'-biphenyl]-4- carboxamide;

N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-

1 ,3,4-thiadiazol-2-yl)[1 , 1 '-biphenyl]-4-carboxamide;

N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2^l-methyl-4'-(5-

(hydroxymethyO-i^^-oxadiazol-S-yOli.i'-biphenylH-carboxamide; N-[4-chloro-3-(4-methyl-1-piperazinyl)phenyl]-2^I-methyl-4'-(5-methyl-

1 ,2,4-oxadiazol-3-yl)[1 ,1'-biphenyl]-4-carboxamide;

N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2^I-methyl-4^l-(3-methyl-

1 ,2,4-thiadiazol-5-yl)[1 , 1 '-biphenyl]-4-carboxamide; N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2^I-chloro-4'-(5-methyl-

1 ,3,4-oxadiazol-2-yl)[1.1'-biphenylH-carboxamide;

N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4^l-(1 ,2,3- th iad iazol-4-y l)[1 , 1 '-biphenyl]-4-carboxamide; N-[4-methyl-3-(4-methyl-1-piperazinyI)phenyl]-2^l-methyl-4'-(5-methyl-

1 ,3,4-oxadiazol-2-yl)[1 ,1'-biphenyl]-4-carboxamide;

N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2^l-methyl-4^l-(1 ,5- dimethyl-1 H-1 ,2,4-triazol-3-yl)[1 , 1 '-biphenyl]-4-carboxamide;

2-chloro-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-4'-(5-methyl- 1 ,2,4-oxadiazol-3-yl)[1 ,1MDiphenyl]~4-carboxamide;

N-[2-fluoro-4-methoxy-5-(4-methyl-1-piperazinyl)phenyl]-2-methyl-4'-(5- methyl-1 ,2,4-oxadiazol-3-yl)[1 , 1 '-biphenyl]-4-carboxamide;

N-[4-chloro-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-

1 ,3,4-oxadiazol-2-yl)[1 ,1'-biphenyl]-4-carboxamide; N-[4-bromo-3-(4-methyl-1-piperazinyl)phenyl]-2'methyl-4'-[5-methyl-1 ,2,4- oxadiazol-3-yl][1 , 1 '-biphenyl]-4-carboxamide;

N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2^l-methyl-4'-(1,3,4- oxadiazol-2-yl)[1 , 1 '-biphenyl]-4-carboxamide;

N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2^I-methyl-4^l-(5-methyl- 1 ,2,4-oxadiazol-3-yl)[1 , 1 '-biphenyl]-4-carboxamide;

N-[4-methoxy-3-(4-methyl-(piperazin-1-yl)phenyl]-2'-methyl-4'-

(amidinyl)[1 ,1'-biphenyl]-4-carboxamide;

N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4^I-

(aminocarbonyl)[1 , 1 '-biphenyl]-4-carboxamide; N-[4-hydroxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4^l-(5-methyl- 1 ,3,4-oxadiazol-2-yl)[1 ,1 '-biphenyl]-4-carboxamide; N-[4-fluoroethoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5- methyl-1 ,2,4-oxadiazol-3-yl)[1 , 1 '-biphenyl]-4-carboxamide; and 3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl] benzamide dihydrochloride and their physiologically acceptable salts and solvates.

19. Use of a compound according to Claim 18, in which the compound is N- [4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4^l-(5-methyl- 1 ,2_l4-oxadiazol-3-yl)[1 ,1^l-biphenyl]-4-carboxamide in the manufacture of or medicament for the treatment or prophylaxis of laminitis.

20. Use of a compound according to Claim 18, in which the compound is 3- [3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl] benzamide dihydrochloride in the manufacture of a medicament for the treatment or prophylaxis of laminitis.

21. Use of a compound of formula (V):

in which P is a 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur; R²¹, R²² and R²³ are independently hydrogen, halogen, Ci_-6 alkyl, C_3-6 cycloalkyl, C_3-6 cycloalkenyl, Ci-₆ alkoxy, hydroxyC_1-6alkyl, Ci_-6 alkyl OCi_-6 alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂R²⁹, CONR³⁰R³¹ or NR³⁰R³¹ where R²⁹, R³⁰ and R³¹ are independently hydrogen or Ci_-6 alkyl;

R²⁴ and R²⁵ are independently hydrogen or d-6 alkyl; R²⁶ is hydrogen, halogen, hydroxy, Ci_-6 alkyl or Ci_-6 alkoxy;

R²⁷ and R²⁸ are independently hydrogen, Ci_-6 alkyl, aralkyl, or together with the nitrogen atom to which they are attached form an optionally substituted 5- to 7-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, nitrogen or sulphur; D is CONH or NHCO;

G is oxygen, S(O)_P where p is O, 1 or 2, NR³² where R³² is hydrogen, Ci_-6 alkyl or phenyl C_1-6 alkyl, or G is CR²⁴=CR²⁵ or CR²⁴CR²⁵ where R²⁴ and R²⁵ are independently hydrogen or Ci_-6 alkyl; m is 1 to 4; and n is 1 or 2; or a physiologically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment or prophylaxis of laminitis.

22. Use of a compound according to claim 21 in which P is oxadiazoyl.

23. Use of a compound according to claim 21 or 22 in which R²¹ and R²² are Ci_-6 alkyl.

24. Use of a compound according to any one of claims 21 to 23 in which R²³ is hydrogen.

25. Use of a compound according to any one of claims 21 to 24 in which G is oxygen, CH₂ or NR³² where R³² is phenylCi_-6 alkyl.

26. Use of a compound according to any one of claims 21 to 25 in which m is 2 and R²⁷ and R²⁸ are both C_1-6 alkyl.

27. Use of a compound according to claim 21 , in which the compound is: N-[3-(Dimethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4'(5-methyl-1 ,2,4-

oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Diethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4'(5-methyl-1 ,2,4-

oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Diisopropylaminoethoxy)-4-methoxyphenyl]-2^I-methyl-4^l(5-methyl-1 ,2,4-

oxadiazol-3-yl)biphenyl-4-carboxamide, N-[3-(2-Dimethylamino-1-methylethoxy)-4-methoxyphenyl]-2'-methyl-4^I(5-methyl-

1 ,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-2-Dimethylaminopropoxy)-4-methoxyphenyl]-2'-methyl-4'(5-methyl-1,2,4-

oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Methylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4^l(5-methyl-1 ,2,4-

oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-2-Aminoethoxy)-4-methoxyphenyl]-2^l-methyl-4^l(5-methyl-1 ,2,4-oxadiazol-3-

yl)biphenyl-4-carboxamide,

N-[3-(2-Piperidin-1-ylethoxy)-4-methoxyphenyl]-2'-methyl-4^I(5-methyl-1 ,2,4-

oxadiazol-3-yl)biphenyl-4-carboxamide, N-[3-(2-Morpholin-4-ylethoxy)-4-methoxyphenyl]-2'-methyl-4^I(5-methyl-1 ,2,4-

oxadiazol-3-yl)biphenyl-4~carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4^I(3-methyl-1 ,2,4-

oxadiazol-5-yl)biphenyl-4-carboxamide, N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2^I-methyl-4'(5-methyl-1 ,3,4- oxadiazol-2-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2^I-methyl-4^I(1 ,3,4-oxadiazol-2- yl)biphenyl-4-carboxamide, N-[3-(2-Dimethylaminoethoxy)phenyl]-2'-methyl-4^I-(5-methyl-1 ,2,4-oxadiazol-3- yl)biphenyl-4-carboxamide,

N-[5-(2-Dimethylaminoethoxy)-2,4-diiodophenyl]-2^l-methyl-4^l(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-[(2-Dimethylaminoethyl)amino]-4-methyloxyphenyl]-2^l-methyl-4^I-(5-methyl- 1 ,2,4-oxadiazol-3-yl)-biphenyl-4-carboxamide,

N-[3-(3-Dimethylaminopropoxy)-4-methyloxyphenyl]-2^l-methyl-4^I(5-methyl-1 _I2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-fS-CS-DimethylaminopropylH-methyloxyphenyl^'-methyi^Xδ-methyl-i^^- oxadiazol-3-yl)biphenyl-4-carboxamide, N-[3-(3-Dimethylaminoprop-1 -enyl)-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-

1 ,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[4-(3-Dimethylaminopropoxy)phenyl]-2^Imethyl-4'-(5-methyl-1 _>2,4-oxadiazol-3- yl)biphenyl-4-carboxamide,

N-[3-2-(Pyrrolidin-1-ylethoxy)-4-methoxyphenyl]-2^I-methyl-4^l(5-methyl-1,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4^I(5-dimethylamino-

1 ,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide, N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2^l-methyl-4'-(4-methylthiazol-2- yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2^I-methyl-4'-pyrazinyl biphenyl-

4-carboxamide, N-[3-(2-Dimethylaminoethylthio)-4-methoxyphenyl]-2^l-methyl-4^l(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethylsulphinyl)-4-methoxyphenyl]-2^l-methyl-4'(5-methyl-

1 ,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[5-(2-Dimethylaminoethoxy)-2-chlorophenyl]-2'-methyl-4'(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-chlorophenyl]-2'-methyl-4^l-(5-methyl-1 ₎2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoθthoxy)-4-bromophenyl]-2^I-methyl-4'-(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide, N-[3-(2-Dimethylaminoethoxy)-4-iodophenyl]-2^I-methyl-4^l-(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-ethylphenyl]-2^I-methyl-4'-(5-methyl-1 _l2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-isopropylphenyl]-2^l-methyl-4'-(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-4^l(1 ,2,4-triazol-1-yl)-2^Imethyl-

(1 ,1 '-biphenyl)-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-4'-(5-methyl-1 ,2,4-oxadiazol-3- yl)-1 , 1 '-biphenyl-4-carboxamide, N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-4'(1 ,2,4-triazoM -yl)-1 -1 '- biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphθnyl]-4'(tetrazol-2-yl)-1 , 1 '-biphenyl-

4-carboxamide, N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2-methyl-4'-(5-methyI-1 _l2,4- oxadiazol-3-yl)-1 , 1 'biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2-methyl-4'-(2-pyridyl)-1 ,1^l- biphenyl-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2-methyl-4'-(3-pyridyl)-1 , 1 '- biphenyl)-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2'-ethyl-4^l-(5-methyl-1 ,2,4- oxadiazol-3-yl)-1 , 1 -biphenyl)-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2,2^l-dimethyl-4'-(5-methyl-

1 ,2,4-oxadiazol-3-yl)-1 ,1'-biphenyl-4-carboxamide, N-[3-(N^l-(2-Dimethylaminoethyl)-N^I-methylamino)-4-methoxyphenyl]-2'-methyl-4^l-

(5-methyl-1 ,2,4-oxadiazol-3-yl)-1 ,1 '-biphenyl-4-carboxamide,

N-[3-(N'-(2-Dimethylaminoethoxy)-N'-phenethylamino)-4-methoxyphenyl]-2'- methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)-1 , 1 '-biphenyl-4-carboxamide,

N-[3-(N'-(2-Dimethylaminoethoxy)-N'-butylamino)-4-methoxyphenyl]-2'-methyl-4^I- (5-methyl-1 ,2,4-oxadiazol-3-yl)-1 , 1 '-biphenyl-4-carboxamide,

N-[3-(-2-Dimethylaminoethoxy)-4-methoxyphenol]-4'-(1 ,2,4-triazoM -yl)-(1 ,1 '- biphenyl)-4-carboxamide,

N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenol]-4'-(tetrazol-2-yl)-(1 , 1 '- biphenyl)-4-carboxamide, N-[3-(-2-Dimethylaminoethoxy)-4-methoxyphenol]-2^I-methyl-4'-(1 _I2,4-

triazol-1 -yl)-(1 , 1 '-biphenyl)-4-carboxamide, and their pharmaceutically acceptable salts and solvates.

28. Use of a compound according to any preceding claim in the manufacture of a medicament for the treatment or prophylaxis of gut derived laminitis.

29. Use of a compound according to any one of claims 1 to 27 in the manufacture of a medicament for the treatment or prophylaxis of laminitis associated with endotoxaemia.

30. Use of a compound according to any preceding claim wherein the medicament is formulated for oral administration.

31. An equine feed composition comprising a compound as defined in any one of claims 1 to 27.

32. An equine feed composition according to claim 31 formulated for slow release of the compound as defined in any one of claims 1 to 27.