WO2007077457A2 - Treatment of equine laminitis with 5-ht1b/ 1d antagonists - Google Patents
Treatment of equine laminitis with 5-ht1b/ 1d antagonists Download PDFInfo
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- WO2007077457A2 WO2007077457A2 PCT/GB2007/000033 GB2007000033W WO2007077457A2 WO 2007077457 A2 WO2007077457 A2 WO 2007077457A2 GB 2007000033 W GB2007000033 W GB 2007000033W WO 2007077457 A2 WO2007077457 A2 WO 2007077457A2
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- biphenyl
- oxadiazol
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- 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.
- 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 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).
- predisposing factors include grain overload, lush pasture, colic, retained placenta, exhaustion, excessive concussion of the hoof and excessive cold water.
- 5-hydroxytryptamine 5- HT
- enterochromaffin cells 5-hydroxytryptamine
- 5-HT also known as serotonin
- SNS central nervous system
- 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.
- CNS 1 5-HT is thought to be involved in a control of appetite, mood, anxiety, hallucinations, sleep, vomiting and pain perception.
- 5-HT 5-HT
- tryptophan hydroxylase an enzyme that catalyzes the hydrolysis of 5-HT
- aromatic L-amino acid decarboxylase an enzyme that catalyzes the hydrolysis of 5-HT
- 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.
- 5-HT receptors 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 1B 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- ⁇ D receptors and those in the brains of higher animals. 5-HTi B and 5-HT 10 receptors have a 77% amino acid sequence homology and share very similar pharmacological profiles, and are therefore often referred to as 5- HTIB/D receptors.
- 5-HT-i B receptors are found in rat and mouse brain, with a particularly high concentration located in the substantia nigra, globus pallidus and dorsal subiculum.
- 5-HTID receptors are found throughout the CNS of several species, and in vascular smooth muscles. Both 5-HT- ⁇ 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-HT 1B /ID receptors are also implicated in feeding behaviour, anxiety, depression, cardiac function, thermoregulation, sexual behaviour and movement.
- 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-
- the paper proposes that differences in the 5-HTIB/ID receptors in the arterial and venous components of equine digital circulation may be of significance in the pathogensis of acute equine laminitis.
- 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.
- 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.
- R 1 represents hydrogen, halogen, Ci -6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, Ci -6 alkoxy, hydroxy Ci -6 alkyl, Ci -6 alkylOCi -6 alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO 2 R 29 , CONR 30 R 31 , NR 30 R 31 ;
- R 2 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
- 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 -6 alkylOCi -6 alkyl, acyl, aryl, acyloxy, nitro, trifluoromethyl, cyano, CO 2 R 29 , CONR 30 R 31 or NR 30 R 31 ;
- D is CONH or NHCO
- 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;
- R 27 and R 28 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;
- R 29 , R 30 and R 31 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.
- R 1 represents a hydrogen atom, a halogen atom, a C h alky! group or a Ci_
- R 2 represents a phenyl group, having phenyl ring B 1 substituted by a group selected from
- R 3 and R 4 which may be the same or different, each independently represents a hydrogen atom, a halogen atom, a hydroxy group, a Ci -6 alkoxy group, a Ci -6 alkyl group or a halogenated Ci -6 alkyl group;
- R 5 , R 7 and R 8 which may be the same or different, each independently represent a hydrogen atom or a Ci -6 alkyl group;
- R 6 represents a hydrogen atom, a -NR 8 R 9 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 -SO 2 R 10 group;
- R 9 represents a hydrogen atom, a Ci -6 alkyl group, a Ci -6 acyl group, a benzoyl group or a -SO 2 R 10 ;
- R 10 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 NR 7 and S(O) ⁇ ⁇ ; 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.
- R 3 is attached at the para-position relative to the amide linkage.
- R 4 is a hydrogen atom.
- 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- ⁇ alkoxy group and a C 1-6 alkyl group.
- the phenyl ring B is substituted by a methyl group.
- this/these is/are preferably attached at a position ortho to the bond of the phenyl ring B with the phenyl ring A.
- 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) 33
- R 1 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , Z and k are as defined for general formula (II) and
- R 11 represents a substituent group selected from
- R 12 represents optional substitution by one or two substituents selected from a halogen atom, a hydroxy group, a Ci -6 alkoxy group and a d- ⁇ 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) R 12 ) selected from a halogen atom, a hydroxy group, a CV ⁇ alkoxy group and a Ci -6 alkyl group.
- the phenyl ring B is substituted by a methyl group.
- auxiliary substituent 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 R 11 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.
- R 1 represents a hydrogen atom or a C ⁇ 6 alkyl, especially methyl, group.
- R 6 represents a Ci -6 alkyl, especially methyl, group optionally substituted by a Ci -6 alkoxy, especially methoxy, group.
- R 3 is a halogen atom, especially a fluorine or chlorine atom, a hydroxy group, a C 1-6 alkoxy group, especially methoxy group, or a halogenated Ci -6 alkyl or alkoxy group, especially ethoxy.
- R 5 is a C 1 - 3 alkyl, especially methyl, group.
- a yet more preferred group of compounds of general formula (II) are those represented by general formula (IV)
- R 6 , R 7 , R 8 , R 9 and R 10 are as defined for general formula (II) and R 13 represents a substituent group selected from
- R 14 represents a hydrogen atom or a Ci -6 alkyl, especially methyl, group
- R 15 represents a halogen atom, especially a fluorine or chlorine atom, a hydroxy group, a Ci -6 alkyl or alkoxy, especially methoxy, group, a Ci -6 alkyl, especially methyl, group or a halogenated Ci -6 alkoxy, especially ethoxy, group;
- R 16 represents a Ci ⁇ alkyl, 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-
- 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.
- P is a 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;
- R 21 , R 22 and R 23 are independently hydrogen, halogen, Ci -6 alkyl, C 3 - 6 cycloalkyl, C 3 - 6 cycloalkenyl, Ci -6 alkoxy, hydroxyCi -6 alkyl, Ci -6 alkyl0Ci. 6 alkyl, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO 2 R 29 , CONR 30 R 31 or NR 30 R 31 where R 29 , R 30 and R 31 , NR 30 R 31 are independently hydrogen or Ci -6 alkyl;
- R 24 and R 25 are independently hydrogen or d- ⁇ aikyl
- R 26 is hydrogen, halogen, hydroxy, C 1-6 aikyl or Ci -6 alkoxy;
- R 27 and R 28 are independently hydrogen, C h alky!, 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
- P is a 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur.
- 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.
- P is oxadiazolyl.
- R 21 and R 22 are Ci -6 alkyl, in particular methyl.
- R 23 is hydrogen.
- R 24 and R 25 are both hydrogen.
- R 27 and R 28 as heterocyclic rings include pyrrolidine, morpholine, piperazine and piperidine.
- Optional substituents for such rings include Ci -6 alkyl.
- R 27 and R 28 are both C 1-6 alkyl, in particular methyl.
- R 26 is hydrogen, halogen, hydroxy, Ci -6 alkyl or d- ⁇ alkoxy.
- R 26 is C 1-6 alkoxy such as methoxy.
- D is CONH.
- B is oxygen, CH 2 or NR 32 where R 32 is phenyl Ci -6 alkyl such as phenethyl.
- R 32 is phenyl Ci -6 alkyl such as phenethyl.
- m is 2
- n 1
- the groups G(CR 24 R 25 ) m NR 27 R 28 and R 26 can be attached to the phenyl ring at any suitable position.
- the group G(CR 24 R 25 ) m NR 27 R 28 is meta to the amide linkage and the group R 26 is para to the amide linkage.
- the groups R 21 , R 22 and R 23 can be attached to their respective rings at any suitable position.
- m is 2 and R 27 and R 28 are both d- ⁇ alkyl.
- the compound is: N-[3-(Dimethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4'(5-methyl-1,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,
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 CNS1 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-HT1B 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-ιD receptors and those in the brains of higher animals. 5-HTiB
and 5-HT10 receptors have a 77% amino acid sequence homology and share very similar pharmacological profiles, and are therefore often referred to as 5- HTIB/D receptors.
5-HT-iB receptors are found in rat and mouse brain, with a particularly high concentration located in the substantia nigra, globus pallidus and dorsal subiculum. 5-HTID receptors are found throughout the CNS of several species, and in vascular smooth muscles. Both 5-HT-ιB 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-HT1B/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-HTi-like and 5-HΪ2 receptors were both present. Additionally, the paper proposes that the 5~HTHike receptor does not resemble the 5-HTiA 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-HTIB/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-HTIB/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, C3-6 cycloalkyl, C3-6 cycloalkenyl, Ci-6 alkoxy, hydroxy Ci-6 alkyl, Ci-6 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, C3-6 cycloalkyl, C3-6 cycloalkenyl, C1-6 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 C3-6 cycloalkyl, C3-6 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, C1-6 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 C1-6 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 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.
According to a first preferred aspect of the invention, there is provided the use of a compound of general formula (II):
R1 represents a hydrogen atom, a halogen atom, a Chalky! group or a Ci_
6alkoxy group;
R2 represents a phenyl group, having phenyl ring B1 substituted by a group selected from
(i)
(iv)
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; R3 and R4, which may be the same or different, each independently represents a hydrogen atom, a halogen atom, a hydroxy group, a Ci-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-6alkyl 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)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-β alkoxy group and a C1-6 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)
33
12
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 Ci-6alkoxy group and a d-β 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 CVβ 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 C^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 Ci-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 C1-6 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
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 Ci-6 alkyl, especially methyl, group or a halogenated Ci-6 alkoxy, especially ethoxy, group;
R16 represents a Ci^alkyl, 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-oxadiazol~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-5I-(5-methyl-
1 ,3,4-oxadiazol-2-yl)[1 , 1 '-biphenyl]-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-piperazinyl)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]-2l-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]-4l-(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-4l-(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-4I-(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'-(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-4'-(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-carboxamicle; o. N-[4-methoxy-3-(4-methyl-1 -piperazinyl)phenyl]-2'-methyl-4'-(1 ,2,3- thiadiazol-4-yI)[1,1'-biphenyl]-4-carboxamide; p. N-[4-methyl-3-(4-methyl-1 -piperazinyl)phenyl]-2'-methyl-4l-(5-methyl-
1 ,3,4-oxadiazol-2-yl)[1.1'-biphenylH-carboxamide; q. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4l-(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-4l-[5-methyl-1 ,2,4-
oxadiazol-3-yl][1 , 1 '-biphenyl]-4-carboxamide; v. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2I-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-4l-(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'-
(amidinyl)[1,1'-biphenyl]-4-carboxamide; y. N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-
(aminocarbonyl)[1 , 1 '-biphenyl]-4-carboxamide;
z. N-[4-hydroxy-3-(4-methyl-1-piperazinyl)phenyl3-2'-methyl-4'-(5-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] benzamide 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):
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-6alkyl, C3-6cycloalkyl, C3-6cycloalkenyl, 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 Ci-6alkyl;
R24 and R25 are independently hydrogen or d-βaikyl;
R26 is hydrogen, halogen, hydroxy, C1-6aikyl or Ci-6alkoxy; R27 and R28 are independently hydrogen, Chalky!, 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 0, 1 or 2, NR32 where R32 is hydrogen, Ci-6alkyl or phenylCi.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 Ci-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 C1-6alkyl, in particular methyl. Suitably R26 is hydrogen, halogen, hydroxy, Ci-6alkyl or d-βalkoxy.
Preferably R26 is C1-6alkoxy such as methoxy.
Preferably D is CONH.
Preferably B is oxygen, CH2 or NR32 where R32 is phenyl Ci-6alkyl 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 d-βalkyl.
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'-methyl-4'(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,
N-[3-(2-Diisopropylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4I(5-methyl-1,2,4-
oxadiazol-3-yl)biphenyl-4-carboxamide,
Claims
1. Use of a compound of general formula (I):
in which
R1 represents hydrogen, halogen, Ci-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, Ci-6 alkoxy, hydroxyC1-6 alkyl, C1-6alkyl0Ci-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, C3-6 cycloalkyl, C3-6 cycloalkenyl, C1-6 alkoxy, hydroxy Ci-6 alkyl, Ci-6 alkyl OCi-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^6 alkyl group, or by an 42
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 C1-6 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) 43
R1 represents a hydrogen atom, a halogen atom, a Ci-6 alkyl group or a C1-6 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; 44
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. 45
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) 46
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) 47
R6, R7, R8, R9 and R10 are as defined for general formula (I) and R13 represents a substituent group selected from
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 C1-6 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; 48
N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-5l-(5-methyl-
1 ,3,4-oxadiazol-2-yl)[1 ,1 '-biphenyl]-4-carboxamide;
N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2l-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]-4I-(5-methyl-1 ,2,4- oxadiazol-3-yl)[1 ,1 '-biphenyl]-4-carboxamide;
N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-4I-(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-4l-((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]-2l-methyl-4'-(5-
(hydroxymethyO-i^^-oxadiazol-S-yOli.i'-biphenylH-carboxamide; N-[4-chloro-3-(4-methyl-1-piperazinyl)phenyl]-2I-methyl-4'-(5-methyl-
1 ,2,4-oxadiazol-3-yl)[1 ,1'-biphenyl]-4-carboxamide;
N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2I-methyl-4l-(3-methyl-
1 ,2,4-thiadiazol-5-yl)[1 , 1 '-biphenyl]-4-carboxamide; 49
N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2I-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-4l-(1 ,2,3- th iad iazol-4-y l)[1 , 1 '-biphenyl]-4-carboxamide; N-[4-methyl-3-(4-methyl-1-piperazinyI)phenyl]-2l-methyl-4'-(5-methyl-
1 ,3,4-oxadiazol-2-yl)[1 ,1'-biphenyl]-4-carboxamide;
N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2l-methyl-4l-(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]-2l-methyl-4'-(1,3,4- oxadiazol-2-yl)[1 , 1 '-biphenyl]-4-carboxamide;
N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2I-methyl-4l-(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-4I-
(aminocarbonyl)[1 , 1 '-biphenyl]-4-carboxamide; 50
N-[4-hydroxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4l-(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-4l-(5-methyl-
1 ,2l4-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):
heteroatoms selected from oxygen, nitrogen or sulphur;
R21, R22 and R23 are independently hydrogen, halogen, Ci-6 alkyl, C3-6
cycloalkyl, C3-6 cycloalkenyl, Ci-6 alkoxy, hydroxyC1-6alkyl, Ci-6 alkyl OCi-6 51
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 C1-6 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. 52
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 C1-6 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]-2I-methyl-4l(5-methyl-1 ,2,4-
oxadiazol-3-yl)biphenyl-4-carboxamide, N-[3-(2-Dimethylamino-1-methylethoxy)-4-methoxyphenyl]-2'-methyl-4I(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-4l(5-methyl-1 ,2,4-
oxadiazol-3-yl)biphenyl-4-carboxamide,
N-[3-2-Aminoethoxy)-4-methoxyphenyl]-2l-methyl-4l(5-methyl-1 ,2,4-oxadiazol-3-
yl)biphenyl-4-carboxamide,
N-[3-(2-Piperidin-1-ylethoxy)-4-methoxyphenyl]-2'-methyl-4I(5-methyl-1 ,2,4-
oxadiazol-3-yl)biphenyl-4-carboxamide, N-[3-(2-Morpholin-4-ylethoxy)-4-methoxyphenyl]-2'-methyl-4I(5-methyl-1 ,2,4-
oxadiazol-3-yl)biphenyl-4~carboxamide,
N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4I(3-methyl-1 ,2,4-
oxadiazol-5-yl)biphenyl-4-carboxamide, 53
N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2I-methyl-4'(5-methyl-1 ,3,4- oxadiazol-2-yl)biphenyl-4-carboxamide,
N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2I-methyl-4I(1 ,3,4-oxadiazol-2- yl)biphenyl-4-carboxamide, N-[3-(2-Dimethylaminoethoxy)phenyl]-2'-methyl-4I-(5-methyl-1 ,2,4-oxadiazol-3- yl)biphenyl-4-carboxamide,
N-[5-(2-Dimethylaminoethoxy)-2,4-diiodophenyl]-2l-methyl-4l(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,
N-[3-[(2-Dimethylaminoethyl)amino]-4-methyloxyphenyl]-2l-methyl-4I-(5-methyl- 1 ,2,4-oxadiazol-3-yl)-biphenyl-4-carboxamide,
N-[3-(3-Dimethylaminopropoxy)-4-methyloxyphenyl]-2l-methyl-4I(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]-2Imethyl-4'-(5-methyl-1 >2,4-oxadiazol-3- yl)biphenyl-4-carboxamide,
N-[3-2-(Pyrrolidin-1-ylethoxy)-4-methoxyphenyl]-2I-methyl-4l(5-methyl-1,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,
N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2l-methyl-4'(5-ethyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,
N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2'-methyl-4I(5-dimethylamino-
1 ,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide, 54
N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2l-methyl-4'-(4-methylthiazol-2- yl)biphenyl-4-carboxamide,
N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2I-methyl-4'-pyrazinyl biphenyl-
4-carboxamide, N-[3-(2-Dimethylaminoethylthio)-4-methoxyphenyl]-2l-methyl-4l(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,
N-[3-(2-Dimethylaminoethylsulphinyl)-4-methoxyphenyl]-2l-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-4l-(5-methyl-1 )2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,
N-[3-(2-Dimethylaminoθthoxy)-4-bromophenyl]-2I-methyl-4'-(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide, N-[3-(2-Dimethylaminoethoxy)-4-iodophenyl]-2I-methyl-4l-(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,
N-[3-(2-Dimethylaminoethoxy)-4-ethylphenyl]-2I-methyl-4'-(5-methyl-1 l2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,
N-[3-(2-Dimethylaminoethoxy)-4-isopropylphenyl]-2l-methyl-4'-(5-methyl-1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,
N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-4l(1 ,2,4-triazol-1-yl)-2Imethyl-
(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, 55
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 ,1l- 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-4l-(5-methyl-1 ,2,4- oxadiazol-3-yl)-1 , 1 -biphenyl)-4-carboxamide,
N-[3-(2-Dimethylaminoethoxy)-4-methoxyphenyl]-2,2l-dimethyl-4'-(5-methyl-
1 ,2,4-oxadiazol-3-yl)-1 ,1'-biphenyl-4-carboxamide, N-[3-(Nl-(2-Dimethylaminoethyl)-NI-methylamino)-4-methoxyphenyl]-2'-methyl-4l-
(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-4I- (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, 56
N-[3-(-2-Dimethylaminoethoxy)-4-methoxyphenol]-2I-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.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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GB0600273A GB0600273D0 (en) | 2006-01-06 | 2006-01-06 | Treatment of equine laminitis |
GB0600273.7 | 2006-01-06 | ||
GB0613547A GB0613547D0 (en) | 2006-07-07 | 2006-07-07 | Treatment of equine laminitis |
GB0613547.9 | 2006-07-07 |
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WO2022074103A1 (en) * | 2020-10-08 | 2022-04-14 | Leukos Biotech, S.L. | Potent and selctive compounds as serotonin 1b receptor modulators |
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