Patent Grant
10786490
This invention relates to compounds for use in therapeutic treatment of the human body. In particular, it relates to compounds with selective EP4 receptor antagonism which are useful for treating cartilage disease, or preventing or delaying the onset or the progression of the said disease.
This invention also relates to a pharmaceutical composition for the treatment of cartilage disease which comprises a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (Va) or (Vb), or a pharmaceutically acceptable salt thereof. This invention relates to a method for the treatment of cartilage disease in an animal subject including a mammalian subject, which comprises administering to the animal subject including a mammalian subject a compound of the formula (I), (II), (III), (IV), (Va) or (Vb), or a pharmaceutically acceptable salt thereof. Further this invention relates to a method for the treatment of cartilage disease in an animal subject including a mammalian subject, which comprises administering to the animal subject including a mammalian subject in need a therapeutically effective amount of a compound of the formula (I), (II), (III), (IV), (Va) or (Vb), or a pharmaceutically acceptable salt thereof.
An articular disorder is a disease whose major lesion is a degeneration of an articular cartilage. Cartilage is the organization composed by collagen and proteoglycan. Due to various causes, the synthesizing ability of proteoglycan in this cartilage organization declines, and proteoglycan starts to be released from the organization. The release of type-I collagenase (metalloprotease I) is simultaneously increased, and collagen of the cartilage organization is resolved. The destruction of the cartilage organization proceeds due to a series of these responses. And it undergoes, depending on the stage of the lesion, a hyperplasia of a synovial membrane, a destruction of a subcartilaginous bone, a hyperplasia or a neoplasia of a circumarticular cartilage, which are followed by a deformation of the cartilage, which may lead to dysfunction in a serious case. While the articular disorder occurs most frequently in a knee joint, it occurs also in the joints of elbows, thighs, legs and fingers. Among the articular diseases, the disease which is observed in the largest number of patients is an osteoarthritis, and it is considered to occur increasingly in an elderlies-dominating society in near future, since one of its causes is considered to be the aging of a human. For treating this, an analgesic antiinflammatory agent or a hyaluronic acid formulation is employed to remedy the pain due to cartilage degeneration or subcartilaginous bone destruction. However, all therapeutic methods are only nosotropic, and exhibit no sufficient effects. Suppression of cartilage destruction, promotion of chondrogenesis and induction of cartilage cell differentiation are considered to be effective in prevention and treatment of a cartilage disease.
In the field of therapeutic and prophylactic agents against cartilage diseases which are no more than nosotropic currently, a novel cartilage disease preventing and/or treating agent which is rather radical and excellent in terms of the characteristics required in a useful pharmaceutical (e.g., such as stability, absorption, bioavailability) is demanded.
Prostaglandin E2 (PGE2) is a potent modulator involved in the pathogenesis of a variety of diseases such as inflammation, pain, arthritis, and cancer. PGE2 binds to at least four subtypes of PGE receptor, designated EP1, EP2, EP3, and EP4. Molecular pharmacology studies have revealed that all subtypes are 7-transmembrane spanning receptors that belong to the G-protein coupled receptor superfamily. EP1 activation stimulates the release of intracellular calcium; EP2 and EP4 stimulation both activate adenylate cyclase but differ in their response to certain ligands; and EP3 stimulation inhibits adenylate cyclase via inhibitory G-proteins (NPL 1).
Many compounds which show EP4 receptor antagonism have been reported. However it has never been reported that compounds with selective EP4 receptor antagonism which are useful for treating cartilage disease.
As mentioned above, for treating cartilage disease, all therapeutic methods are only nosotropic, and exhibit no sufficient effects. Therefore the compounds which are truly effective for cartilage disease are strongly desired.
In particular, an object of the present invention is to provide compounds with selective EP4 receptor antagonism which are useful for treating cartilage disease, or preventing or delaying the onset or the progression of cartilage disease.
An object of the present invention is to provide a pharmaceutical composition for the treatment of cartilage disease which comprises a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), (Va) or (Vb), or a pharmaceutically acceptable salt thereof. An object of the present invention is to provide a method for the treatment of cartilage disease in an animal subject including a mammalian subject, which comprises administering to the animal subject including a mammalian subject a compound of the formula (I), (II), (III), (IV), (Va) or (Vb), or a pharmaceutically acceptable salt thereof. Further an object of the present invention is to provide a method for the treatment of cartilage disease in an animal subject including a mammalian subject, which comprises administering to the animal subject including a mammalian subject in need a therapeutically effective amount of a compound of the formula (I), (II), (III), (IV), (Va) or (Vb), or a pharmaceutically acceptable salt thereof.
The present inventors made much effort to develop a pharmaceutical capable of exerting a direct effect on a cartilage cell to suppress a cartilage destruction and also capable of promoting cartilaginous osteoanagenesis, and finally discovered that a compound of formula (I), (II), (III), (IV), (Va) or (Vb), or a pharmaceutically acceptable salt thereof guarantees beneficial effects on cytokine-induced cartilage calcification in a full-depth articular explants model, rat mono-iodoacetate and/or meniscal transection model, rat meniscal transection and/or ovariectomised model, which clearly are useful for prevention and/or treatment of a cartilage disease.
Specifically, the gist of the present invention is as follows:
[1] Use of a compound with EP4 antagonistic activity, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cartilage diseases in an animal subject including a mammalian subject;
[2] Use of a compound of the formula (I), (II), (III), (IV), (Va) or (Vb), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cartilage diseases in an animal subject including a mammalian subject:
wherein Y1, Y2, Y3, and Y4 are independently selected from N, CH and C(L); R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, C1-8 alkoxy, halo-substituted C1-8 alkoxy, C1-8 alkyl-S(O)m-, Q1-, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C1-8 alkyl)amino, C1-4 alkyl-C(═O)—N(R3)— or C1-4 alkyl-S(O)m-N(R3)—, wherein said C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl are optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1-, Q1-C(═O)—, Q1-O—, Q1-S(O)m-, Q1-C1-4 alkyl-O—, Q1-C1-4 alkyl-S(O)m-, Q1-C1-4 alkyl-C(O)—N(R3)—, Q1-C1-4 alkyl-N(R3)— or C1-4 alkyl-C(O)—N(R3)—;
Q1 is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, R3N(R4)C(═O)—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)N(R4)— or NH2(HN═)C—;
A is a 5 or 6 membered monocyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with up to 3 substituents selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, acetyl, R3N(R4)C(═O)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)N(R4)— and NH2(HN═)C—;
B is halo-substituted C1-6 alkylene, C3-7 cycloalkylene, C2-6 alkenylene, C2-6 alkynylene, —O—C1-5 alkylene, C1-2 alkylene-O—C1-2 alkylene or C1-6 alkylene optionally substituted with an oxo group or C1-3 alkyl;
W is NH, N—C1-4 alkyl, O, S, N—OR5 or a covalent bond;
R2 is H, C1-4 alkyl, OH or C1-4 alkoxy;
Z is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, R3C(═O)N(R4)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, NH2 (HN═)C—, Q2-S(O)m-, Q2-O—, Q2-N(R3)— or Q2-;
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, halo-substituted C1-4 alkoxy, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)N(R4)—, NH2(HN═)C—, R3N(R4)C(═O)—, R3N(R4)S(O)m-, Q2, Q2-C(═O)—, Q2-O—, Q2-C1-4 alkyl-O—, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0, 1 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl;
R5 is H, C1-4 alkyl, C1-4 alkyl-(O═)C— or C1-4 alkyl-O—(O═)—C—; and
Q2 is a 5 to 12 membered monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl-(O═)C—, R3(R4)C(═O)N—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, C1-4 alkyl-C(═O)NH— or NH2(HN═)C—;
wherein A represents a phenyl group or a pyridyl group;
B represents an aryl group or a heteroaryl group;
E represents a 1,4-phenylene group;
R1 and R2 independently represent a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a haloalkyl group having from 1 to 4 carbon atoms, a haloalkoxy group having from 1 to 4 carbon atoms, a cyano group or an aminocarbonyl group;
R3 and R4 independently represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; or R3 and R4 may be joined together to form an alkylene chain having 2 to 6 carbon atoms;
R5 represents —CO2H, CO2W,
R6 represents an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 7 ring atoms, an aryl group or a heteroaryl group;
X represents a methylene group, an oxygen atom or a sulfur atom;
said aryl groups have from 6 to 10 carbon atoms;
said heteroaryl groups are 5 to 10-membered aromatic heterocyclic groups containing from 1 to 3 heteroatoms selected from the group consisting of sulfur atom, oxygen atom and nitrogen atom;
said aryl groups and said heteroaryl groups referred to in the definitions of B are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents alpha;
said 1,4-phenylene group referred to in the definition of E is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents beta;
said aryl groups and said heteroaryl groups referred to in the definitions of R6 and alpha are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents beta;
said substituents alpha are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, two adjacent alpha groups are optionally joined together to form an alkylene or an alkenylene chain having 3 or 4 carbon atoms, aminocarbonyl groups, alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, aminosulfinyl groups, aminosulfonyl groups, hydroxy groups, hydroxyalkyl groups having from 1 to 4 carbon atoms, nitro groups, amino groups, carboxy groups, alkoxycarbonyl groups having from 2 to 5 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms, alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoylamino groups having from 1 to 4 carbon atoms, alkanoyl (alkyl)amino groups having from 1 to 6 carbon atoms, alkanoylaminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and alkyl part, alkanoyl (alkyl)aminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and each alkyl part, alkylsulfonylamino groups having from 1 to 4 carbon atoms, mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms, mono- or di-alkylaminosulfinyl groups having from 1 to 6 carbon atoms, mono- or dialkylaminosulfonyl groups having from 1 to 6 carbon atoms, aminoalkyl groups having from 1 to 4 carbon atoms, mono- or di-alkylamino groups having from 1 to 6 carbon atoms, mono- or di-alkylaminoalkyl groups having from 1 to 6 carbon atoms in each alkyl part, aralkyl groups having from 7 to 10 carbon atoms, heteroarylalkyl groups having from 1 to 4 carbon atoms in the alkyl part, heteroarylalkoxy groups having from 1 to 4 carbon atoms in the alkoxy part and alkylsulfonylamino groups having from 1 to 4 carbon atoms;
said substituents beta are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms and cyano groups;
W is a pharmaceutically acceptable ester prodrug group; with the proviso R1 and R2 do not represent a hydrogen atom simultaneously;
wherein X represents —CH— or a nitrogen atom;
Y represents —NR4, an oxygen atom or a sulfur atom;
R4 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms;
Z represents a hydrogen atom or a halogen atom;
R1 represents an alkyl group having from 1 to 6 carbon atoms optionally substituted with an alkoxy group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 7 carbon atoms; a cycloalkyl group having from 3 to 7 carbon atoms optionally substituted with an alkyl group having from 1 to 3 carbon atoms; a phenyl group optionally substituted with one or more substituents alpha; or a group Het1 optionally substituted with one or more substituents alpha;
Het1 represents a heterocyclic group having from 4 to 7 ring atoms which contains either from 1 to 4 nitrogen ring heteroatoms or from 0 to 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulfur ring heteroatom;
R2 and R3 independently represent a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; or R2 and R3 together form an alkylene chain having from 3 to 6 carbon atoms; and
said substituent alpha is selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, hydroxy groups, alkoxy groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, hydroxy alkyl groups having from 1 to 4 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms in alkoxy and alkyl groups, alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoyl groups having from 2 to 5 carbon atoms, alkenyl groups having from 2 to 4 carbon atoms, alkynyl groups having from 2 to 4 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, nitro groups, amino groups, mono- or di-alkylamino groups having from 1 to 4 carbon atoms, aminosulfonyl groups, alkoxycarbonyl groups having from 1 to 4 carbon atoms, alkylsulfonylamino groups having from 1 to 4 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms and a mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms;
or a pharmaceutically acceptable ester of such compound;
wherein X and Y are independently selected from the group consisting of: N and C(R11), wherein each R11 is independently selected from the group consisting of: hydrogen, halo and C1-4alkyl;
B is selected from the group consisting of: —C(R5)(R6)—, —O—, —S—, —S(O)—, —SO2—, —C(R5)(R6)—C(R7)(R8)—, —O—C(R5)(R6)—, —S—C(R5)(R6)—, —S(O)—C(R5)(R6)— and —SO2—C(R5)(R6)—; C is selected from the group consisting of aryl and heteroaryl, or a fused analog of aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from R10;
E is selected from the group consisting of: —C(O)OH, —C(O)OC1-4alkyl, tetrazolyl and
wherein R is selected from the group consisting of: C1-4alkyl, aryl and heteroaryl, or a fused analog of aryl or heteroaryl, wherein aryl and heteroaryl or the fused analogs thereof are optionally substituted with one to three substituents independently selected from R10;
R1 to R8 are independently selected from the group consisting of: H, halo, —O—R12, C1-6 alkyl and C3-6cycloalkyl, and one or more pairs of R1 and R2, R5 and R6, and R7 and R8 may be joined together with the carbon atom to which they are attached to form a 3- to 5-membered monocyclic cycloalkyl ring, and R5 and R6 or R7 and R8 may be joined together to form carbonyl;
R9 is independently selected from the group consisting of: halo, hydroxyl and C1-4alkyl;
R10 is selected from the group consisting of: halo, cyano, C1-4alkyl, C1-4fluoroalkyl, C1-4 alkoxy, C1-4thioalkoxy and C1-4fluoroalkoxy; and
each R12 is selected from the group consisting of: H, C1-4alkyl, C3-6cycloalkyl and heterocyclyl;
[3] The use of [2], wherein the compound of (I), (II), (III), (IV), (Va) or (Vb) is selected from:
[4] The use of [2] or [3], wherein the compound of (I), (II), (III), (IV), (Va) or (Vb) is selected from:
[5] The use of [4], wherein the compound of (I), (II), (III) or (IV) is selected from:
[6] The use of any one of [2] to [5], wherein the compound of the formula (I), (II), (III), (IV), (Va) or (Vb), or the pharmaceutically acceptable salt is used in combination with one or more additional compounds known to be useful in the treatment or prevention of cartilage disease or the symptoms thereof;
[7] The use of [6], wherein the one or more additional compounds known to be useful in the treatment or prevention of cartilage disease or the symptoms thereof are selected from NSAIDs, COX-2 inhibitors, steroids, matrix metalloproteinase inhibitors and hyaluronic acid;
[8] A pharmaceutical composition for the treatment of cartilage disease which comprises a therapeutically effective amount of a compound of the formula (I), (II), (III), (IV), (Va) or (Vb) in [2] or a pharmaceutically acceptable salt thereof;
[9] The pharmaceutical composition of [8], which further comprises a therapeutically effective amount of one or more additional compounds known to be useful in the treatment or prevention of cartilage disease or the symptoms thereof;
[10] A method for the treatment of cartilage disease in an animal subject including a mammalian subject, which comprises administering to the animal subject including a mammalian subject a compound of the formula (I), (II), (III), (IV), (Va) or (Vb) in [2] or a pharmaceutically acceptable salt thereof;
[11] The method of [10], which further comprises administering a therapeutically effective amount of one or more additional compounds known to be useful in the treatment or prevention of cartilage disease thereof;
[12] A method for the treatment of cartilage diseases, which comprises administering to an animal subject including a mammalian subject in need a therapeutically effective amount of a compound of the formula (I), (II), (III), (IV), (Va) or (Vb) in [2] or a pharmaceutically acceptable salt thereof;
[13] The method of [12], which further comprises administering a therapeutically effective amount of one or more additional compounds known to be useful in the treatment or prevention of cartilage disease thereof; and
[14] A compound of the formula (I), (II), (III), (IV), (Va) or (Vb) in [2] or a pharmaceutically acceptable salt thereof for use in the treatment of cartilage diseases in an animal subject including a mammalian subject.
Namely, the present inventors have discovered that a compound of formula (I), (II), (III), (IV), (Va) or (Vb), or a pharmaceutically acceptable salt thereof shows: 1) dose-dependent inhibition of cartilage destruction in ex vivo bovine cartilage explant model, 2) dose-dependent inhibition of cartilage destruction and serum biochemical markers associated with cartilage degradation in the rat mono-iodoacetate and/or meniscal transection model, and 3) inhibition of cartilage destruction and serum biochemical markers associated with cartilage degradation in a dose-dependent manner in the rat meniscal transection and/or ovariectomised model.
These results clearly show that a compound of formula (I), (II), (III), (IV), (Va) or (Vb), or a pharmaceutically acceptable salt thereof is useful for the treatment and/or prevention of cartilage disease.
In the section “Brief Description of Drawings”, the sign “+/−” represents “plus or minus”.
The present invention features the use of an EP4 receptor antagonist in the manufacture of a medicament for the treatment of cartilage diseases.
In a further aspect the invention features a method of treating cartilage diseases in an animal subject including a mammalian subject, for example, a mammal, including man, comprising administration of an effective amount of an EP4 receptor antagonist.
The term “animal subject,” as used herein, includes a mammalian subject or a non-mammalian subject. Examples of suitable mammalian subject may include, without limit, human, rodents, companion animals, livestock, and primates. Suitable rodents may include, but are not limited to, mice, rats, hamsters, gerbils, and guinea pigs. Suitable companion animals may include, but are not limited to, cats, dogs, rabbits, and ferrets. Suitable livestock may include, but are not limited to, horses, goats, sheep, swine, cattle, llamas, and alpacas. Suitable primates may include, but are not limited to, chimpanzees, lemurs, macaques, marmosets, spider monkeys, squirrel monkeys, and vervet monkeys. Examples of suitable non-mammalian subject may include, without limit, birds, reptiles, amphibians, and fish. Non-limiting examples of birds include chickens, turkeys, ducks, and geese.
In a further aspect the invention features a pharmaceutical composition comprising an EP4 receptor antagonist for use in the treatment of cartilage diseases.
Preferably, the EP4 receptor antagonist used in this invention is a selective EP4 receptor antagonist.
In another preferred aspect, the EP4 receptor ligand (antagonist), which is disclosed in WO 02/32900, is an aryl or heteroaryl fused imidazole compound of the following Formula (I)
or a pharmaceutically acceptable salt thereof,
wherein
Y1, Y2, Y3, and Y4 are preferably independently selected from N, CH and C(L);
R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, C1-8 alkoxy, halo-substituted C1-8 alkoxy, C1-8 alkyl-S(O)m-, Q1-, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C1-8 alkyl)amino, C1-4 alkyl-C(═O)—N(R3)— or C1-4 alkyl-S(O)m-N(R3)—, wherein said C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl are optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1-, Q1-C(═O)—, Q1-O—, Q1-S(O)m-, Q1-C1-4 alkyl-O—, Q1-C1-4 alkyl-S(O)m-, Q1-C1-4 alkyl-C(O)—N(R3)—, Q1-C1-4 alkyl-N(R3)— or C1-4 alkyl-C(O)—N(R3)—;
Q1 is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, R3N(R4)C(═O)—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)N(R4)— or NH2(HN═)C—;
A is a 5 or 6 membered monocyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with up to 3 substituents selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, acetyl, R3N(R4)C(═O)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)N(R4)— and NH2(HN═)C—;
B is halo-substituted C1-6 alkylene, C3-7 cycloalkylene, C2-6 alkenylene, C2-6 alkynylene, —O—C1-5 alkylene, C1-2 alkylene-O—C1-2 alkylene or C1-6 alkylene optionally substituted with an oxo group or C1-3 alkyl;
W is NH, N—C1-4 alkyl, O, S, N—OR5 or a covalent bond;
R2 is H, C1-4 alkyl, OH or C1-4 alkoxy;
Z is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, R3C(═O)N(R4)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, NH2 (HN═)C—, Q2-S(O)m-, Q2-O—, Q2-N(R3)— or Q2-;
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, halo-substituted C1-4 alkoxy, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)N(R4)—, NH2(HN═)C—, R3N(R4)C(═O)—, R3N(R4)S(O)m-, Q2-, Q2-C(═O)—, Q2-O—, Q2-C1-4 alkyl-O—, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0, 1 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl;
R5 is H, C1-4 alkyl, C1-4 alkyl-(O═)C— or C1-4 alkyl-O—(O═)—C—; and
Q2 is a 5 to 12 membered monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl-(O═)C—, R3(R4)C(═O)N—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, C1-4 alkyl-C(═O)NH— or NH2(HN═)C—.
In the compounds of formula (I),
Y1, Y2, Y3, and Y4 are preferably independently selected from N, CH and C(L);
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, mono- or di-(C1-4 alkyl)amino, halo-substituted C1-4 alkoxy, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)N(R4)—, R3N(R4)C(═O)—, R3N(R4)S(O)m-, Q2-, Q2-C(═O)—, Q2-O—, Q2-C1-4alkyl-O—, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0, 1 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5 to 12 membered monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4alkyl, C1-4alkenyl, C1-4 alkynyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4alkoxy, C1-4 alkylthio, mono- or di-(C1-4 alkyl)amino, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl-(O═)C—, R3(R4)C(═O)N—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl or C1-4 alkyl-C(═O)NH—.
More preferably Y1, Y2, Y3, and Y4 are independently selected from N, CH and C(L);
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, mono- or di-(C1-4 alkyl)amino, halo-substituted C1-4 alkoxy, cyano, HO—C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)N(R4)—, R3N(R4)C(═O)—, R3N(R4)S(O)m-, Q2-, Q2-C(═O)—, Q2-O—, Q2-C1-4alkyl-O—, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0, 1 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5 or 6 membered monocyclic aromatic ring, containing up to 3 heteroatoms selected from N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo,
more preferably Y1, Y2, Y3, and Y4 are independently selected from N, CH and C(L);
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, mono- or di-(C1-4 alkyl)amino, halo-substituted C1-4 alkoxy, cyano, HO—C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)N(R4)—, R3N(R4)C(═O)—, R3N(R4)S(O)m-, Q2-, Q2-C(═O)—, Q2-O—, Q2-C1-4alkyl-O—, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0, 1 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5 or 6 membered monocyclic aromatic ring, optionally containing 1 sulfur atom wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo,
more preferably Y1, Y2, Y3, and Y4 are independently selected from N, CH and C(L);
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, cyano, HO—C1-4 alkyl, acetyl, R3N(R4)C(═O)—, R3N(R4)S(O)m-, Q2-, Q2-C(═O)—, Q2-O—, Q2-C1-4alkyl-O—, or two adjacent L groups are joined together to form a methylenedioxy group;
m is 0, 1 or 2
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5 or 6 membered monocyclic aromatic ring system,
more preferably Y1, Y2, Y3, and Y4 are independently selected from N, CH and C(L);
L is chloro, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, —C(═O)NH2, trifluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group,
more preferably Y1, Y2, Y3 and Y4 are selected from the group consisting of
a) Y1 and Y3 are C(L), Y2 is CH and Y4 is N;
b) Y1 is CH, Y2 and Y3 are C(L) and Y4 is N;
c) Y1, Y2 and Y3 are C(L) and Y4 is N;
d) Y1 and Y3 are C(L), Y2 is N and Y4 is CH;
e) Y1 is C(L) and Y2, Y3 and Y4 are CH;
f) Y1, Y3 and Y4 are CH, and Y2 is C(L);
g) Y1, Y2 and Y3 are CH, and Y4 is C(L);
h) Y1 and Y2 are C(L), and Y3 and Y4 are CH;
i) Y1 and Y3 are C(L), and Y2 and Y4 are CH;
j) Y1 and Y4 are CH, and Y2 and Y3 are C(L);
k) Y1 and Y2 are CH, Y3 is C(L) and Y4 is N;
l) Y1 and Y3 are CH, Y2 is C(L) and Y4 is N;
m) Y1, Y2, Y3 and Y4 are CH;
n) Y1 and Y2 are C(L), Y3 is CH and Y4 is N;
o) Y1, Y2 and Y4 are CH, and Y3 is C(L);
p) Y1 and Y2 are C(L), Y3 is N and Y4 is CH;
q) Y1 and Y3 are C(L), and Y2 and Y4 are N;
r) Y1 is C(L), Y2 and Y3 are CH, and Y4 is N;
s) Y2 is C(L), Y1 and Y3 are CH, and Y4 is N; and
t) Y1, Y2 and Y3 are C(L), and Y4 is CH
L is chloro, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, —C(═O)NH2, trifluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group,
most preferably Y1, Y2, Y3 and Y4 are selected from the group consisting of
a) Y1 and Y3 are C(L), Y2 is CH and Y4 is N;
b) Y1 is CH, Y2 and Y3 are C(L) and Y4 is N;
c) Y1, Y2 and Y3 are C(L) and Y4 is N;
d) Y1 and Y3 are C(L), Y2 is N and Y4 is CH;
e) Y1 is C(L) and Y2, Y3 and Y4 are CH;
f) Y1, Y3 and Y4 are CH, and Y2 is C(L);
g) Y1, Y2 and Y3 are CH, and Y4 is C(L);
h) Y1 and Y2 are C(L), and Y3 and Y4 are CH;
i) Y1 and Y3 are C(L), and Y2 and Y4 are CH;
j) Y1 and Y4 are CH, and Y2 and Y3 are C(L); and
k) Y1, Y2 and Y3 are C(L), and Y4 is CH
L is chloro, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, —C(═O)NH2, trifluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
In the compounds of Formula (I),
R1 is preferably H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, C1-8 alkoxy, halo-substituted C1-8 alkoxy, C1-8 alkyl-S(O)m-, Q1-, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C1-8 alkyl)amino, C1-4alkyl-C(═O)—N(R3)— or C1-4alkyl-S(O)m-N(R3)—, wherein said C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl are optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1-, Q1-C(═O)—, Q1-O—, Q1-S(O)m-, Q1-C1-4alkyl-O—, Q1-C1-4 alkyl-S(O)m-, Q1-C1-4alkyl-C(O)—N(R3)—, Q1-C1-4 alkyl-N(R3)— or C1-4alkyl-C(O)—N(R3)—;
Q1 is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, HO(O═)C—, C1-4 alkyl-O(O)C—, R3N(R4)C(═O)—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)N(R4)— or NH2(HN═)C—;
m is 0, 1 or 2; and
R3 and R4 are independently selected from H and C1-4 alkyl,
In the compounds of Formula (I),
more preferably R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, Q1-, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C1 alkyl)amino, wherein said C1, alkyl is optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl, cyano, indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1-, Q1-C(O)—, Q1-O—, Q1-S— or Q1-C1-4 alkyl-O—, or C1-4alkyl-C(O)—N(R3)—;
Q1 is a 5 to 12 membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S, and is optionally substituted with halo, C1-4 alkyl, C1-4 alkylsulfonyl and C1-4 alkylC(═O)—;
m is 0, 1 or 2; and
R3 is H or C1-4 alkyl,
In the compounds of Formula (I),
more preferably R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, Q1-, or mono- or di-(C1-8 alkyl)amino wherein said C1-8 alkyl is optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1-, Q1-C(═O)—, Q1-O—, Q1-S—, Q1-C1-4 alkyl-O—, or C1-4alkyl-C(O)—N(H)—;
Q1 is a 5 or 6 membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S; and
m is 0, 1 or 2,
In the compounds of Formula (I),
more preferably R1 is C1-5 alkyl, C3-7 cycloalkyl, or Q1-, mono- or di-(C1-8 alkyl)amino wherein said C1-5 alkyl is optionally substituted with C1-3 alkyl, hydroxy, oxo, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1-, or C1-4alkyl-C(O)—N(H)—; and
Q1 is a 5 to 12 membered monocyclic aromatic ring system optionally containing up to 2 heteroatoms selected from N and S,
In the compounds of Formula (I),
more preferably R1 is C1-5 alkyl, mono- or di-(C1-8 alkyl)amino, pyrrolidinyl, or pyridyl optionally substituted with C1-3 alkyl, hydroxy, oxo, a 5 or 6 membered monocyclic aromatic ring, wherein said 5 or 6 membered monocyclic aromatic ring contains 1 or 2 heteroatoms selected from N and S, or C1-4alkyl-C(O)—N(H)—,
In the compounds of Formula (I),
most preferably R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl, methylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl.
In the compounds of Formula (I), R2 is preferably H or C1-4 alkyl, most preferably H.
In the compounds of Formula (I), A is preferably a 5 or 6 membered monocyclic aromatic ring optionally containing up to 2 heteroatoms selected from O, N, and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with up to 2 substituents selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy and halo-substituted C1-4 alkoxy, more preferably 5 or 6 membered monocyclic aromatic ring optionally substituted with halo, C1-4 alkyl or C1-4 alkoxy, more preferably 5 or 6 membered monocyclic aromatic ring system optionally substituted with halo or C1-4 alkyl, more preferably 5 or 6 membered monocyclic aromatic ring system, most preferably phenyl or pyridyl.
In the compounds of Formula (I), B is preferably C3-7 cycloalkylene or C1-6 alkylene optionally substituted with an oxo group or C1-3 alkyl, more preferably C1-3 alkylene optionally substituted with C1-3 alkyl, more preferably C1-2 alkylene optionally substituted with methyl, most preferably ethylene or propylene.
In the compounds of Formula (I), W is preferably NH, N—C1-4 alkyl, O or N—OH, more preferably NH, N—C1-2 alkyl or O, most preferably NH, N—CH3 or O.
In the compounds of Formula (I), Z is preferably a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N, O, and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, hydroxy, C1-4 alkoxy, nitro, amino, cyano, HO—C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, R3C(═O)N(R4)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C1-4 alkyl-C(═O)NH—, Q2-S(O)m-, Q2-O—, Q2-N(R3)— or Q2-;
m is 0, 1 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5 to 12 membered monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, mono- or di-(C1-4 alkyl)amino, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl-(O═)C—, R3(R4)C(═O)N—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl or C1-4 alkyl-C(═O)NH—,
In the compounds of Formula (I),
more preferably Z is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkoxy, nitro, amino, cyano, R3C(═O)N(R4)—, C1-4 alkyl-O(O═)C—, Q2-S(O)m-, Q2-O—, Q2-N(R3)— or Q2-;
m is 0, 1 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5 or 6 membered monocyclic aromatic ring, containing up to 3 heteroatoms selected from N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo,
In the compounds of Formula (I),
more preferably Z is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkoxy, nitro, amino, cyano, R3C(═O)N(R4)—, C1-4 alkyl-O(O═)C—, Q2-S(O)m-, Q2-O—, Q2-N(R3)— or Q2-;
m is 0, 1 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5 or 6 membered monocyclic aromatic ring or, optionally containing 1 sulfur atom wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo,
In the compounds of Formula (I),
more preferably Z is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5 to 12 membered monocyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, nitro, R3C(═O)N(R4)— or Q2-;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5 or 6 membered monocyclic aromatic ring system, more preferably Z is a 5 to 10 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5 to 10 membered monocyclic aromatic ring is optionally substituted with chloro, bromo, methyl, nitro, CH3C(═O)NH—, tBuC(═O)NH— or phenyl,
In the compounds of Formula (I),
most preferably Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with one to three substituents independently selected from chloro, bromo, methyl, acetylamino, pivaloylamino, nitro and phenyl.
A preferred group of compounds of Formula (I) includes compounds wherein
Y1, Y2, Y3, and Y4 are independently selected from N, CH and C(L);
R1 is H, C1-8 alkyl, C2-8 alkenyl, alkynyl, C3-7 cycloalkyl, C1-8 alkoxy, halo-substituted C1-8 alkoxy, C1-8 alkyl-S(O)m-, Q1-, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C1-8 alkyl)amino, C1-4alkyl-C(═O)—N(R3)— or C1-4 alkyl-S(O)m-N(R3)—, wherein said C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl are optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1-, Q1-C(═O)—, Q1-O—, Q1S(O)m-, Q1-C1-4 alkyl-O—, Q1-C1-4 alkyl-S(O)m-, Q1-C1-4alkyl-C(═O)—N(R3)—, or C1-4 alkyl-C(═O)—N(R3)—;
Q1 is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, HO(O═)C—, C1-4 alkyl-O(O)C—, R3N(R4)C(═O)—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)N(R4)— or NH2(HN═)C—;
A is a 5 or 6 membered monocyclic aromatic ring optionally containing up to 2 heteroatoms selected from O, N, and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with up to 2 substituents selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy and halo-substituted C1-4 alkoxy;
B is C3-7 cycloalkylene or C1-6 alkylene optionally substituted with an oxo group or C1-3 alkyl;
W is NH, N—C1-4 alkyl, O or N—OH;
R2 is H or C1-4 alkyl;
Z is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, hydroxy, C1-4 alkoxy, nitro, amino, cyano, HO—C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, R3C(═O)N(R4)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkyl sulfonylamino, C1-4 alkyl-C(═O)NH—, Q2-S(O)m-, Q2-O—, Q2-N(R3)— or Q2-;
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, mono- or di-(C1-4 alkyl)amino, halo-substituted C1-4 alkoxy, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)N(R4)—, R3N(R4)C(═O)—, R3N(R4)S(O)m-, Q2-, Q2-C(═O)—, Q2-O—, Q2-C1-4alkyl-O—, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0, 1 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5 to 12 membered monocyclic or bicyclic aromatic ring, optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, mono- or di-(C1-4 alkyl)amino, cyano, HO—C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl-(O═)C—, R3(R4)C(═O)N—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl or C1-4 alkyl-C(═O)NH—.
A further preferred group of compounds of Formula (I) includes compounds wherein
Y1, Y2, Y3, and Y4 are independently selected from N, CH and C(L);
R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, Q1-, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C1-8 alkyl)amino, wherein said C1-8 alkyl is optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1-, Q1-C(O)—, Q1-O—, Q1-S—, Q1-C1-4 alkyl-O—, or C1-4 alkylC(O)—N(R3)—;
Q1 is a 5 to 12 membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S, and is optionally substituted with halo, C1-4 alkyl, C1-4 alkylsulfonyl and C1-4 alkylC(═O)—;
A is a 5 or 6 membered monocyclic aromatic ring optionally substituted with halo, C1-4 alkyl or C1-4 alkoxy;
B is C3-7 cycloalkylene or C1-6 alkylene optionally substituted with an oxo group or C1-3 alkyl;
W is NH, N—C1-4 alkyl, 0 or N—OH;
R2 is H or C1-4 alkyl;
Z is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkoxy, nitro, amino, cyano, R3C(═O)N(R4)—, C1-4 alkyl-O(O═)C—, Q2-S(O)m-, Q2-O—, Q2-N(R3)— or Q2-;
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, mono- or di-(C1-4 alkyl)amino, cyano, HO—C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O)—, HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)N(R4)—, R3N(R4)C(═O)—, R3N(R4)S(O)m-, Q2-, Q2-C(═O)—, Q2-O—, Q2-C1-4alkyl-O—, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0, 1 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5 or 6 membered monocyclic aromatic ring, containing up to 3 heteroatoms selected from N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo.
A further preferred group of compounds of Formula (I) includes compounds wherein
Y1, Y2, Y3 and Y4 are independently selected from N, CH and C(L);
R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl or C3-7 cycloalkyl, wherein said C1-8 alkyl is optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1-, Q1-C(═O)—, Q1-O—, Q1-S—, Q1-C1-4 alkyl-O—, or C1-4alkyl-C(O)—N(R3)—;
Q1 is a 5 or 6 membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S;
A is a 5 or 6 membered monocyclic aromatic ring system optionally substituted with halo or C1-4 alkyl;
B is C3-7 cycloalkylene or C1-6 alkylene optionally substituted with an oxo group or C1-3 alkyl;
W is NH, N—C1-4 alkyl, 0 or N—OH;
R2 is H or C1-4 alkyl;
Z is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5 to 12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkoxy, nitro, amino, cyano, R3C(═O)N(R4)—, C1-4 alkyl-O(O═)C—, Q2-S(O)m-, Q2-O—, Q2-N(R3)— or Q2-;
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, cyano, HO—C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylC(═O), HO(O═)C—, C1-4 alkyl-O(O═)C—, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(═O)NR4—, R3N(R4)C(═O)—, R3N(R4)S(O)m-, Q2-, Q2-C(═O)—, Q2-O—, Q2-C1-4 alkyl-O—, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0, 1 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5 or 6 membered monocyclic aromatic ring or, optionally containing 1 sulfur atom wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo.
A further preferred group of compounds of Formula (I) includes compounds wherein
Y1, Y2, Y3 and Y4 are independently selected from N, CH and C(L);
R1 is C1-5 alkyl or C3-7 cycloalkyl, wherein said C1-5 alkyl is optionally substituted with C1-3 alkyl, hydroxy, oxo, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1-, or C1-4alkyl-C(O)—N(H)—;
Q1 is a 5 to 12 membered monocyclic aromatic ring system optionally containing up to 2 heteroatoms selected from N and S,
A is a 5 or 6 membered monocyclic aromatic ring system;
B is C1-3 alkylene optionally substituted with C1-3 alkyl;
W is NH, N—C1-2 alkyl or O;
R2 is H;
Z is a 5 to 12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5 to 12 membered monocyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, nitro, R3C(═O)N(R4)— or Q2-;
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, cyano, HO—C1-4 alkyl, acetyl, R3N(R4)C(═O)—, R3N(R4)S(O)m-, Q2-, Q2-C(═O)—, or two adjacent L groups are joined together to form a methylenedioxy group;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5 or 6 membered monocyclic aromatic ring system.
A further preferred group of compounds of Formula (I) includes compounds wherein
Y1, Y2, Y3 and Y4 are independently selected from N, CH and C(L);
R1 is C1-5 alkyl optionally substituted with C1-3 alkyl, hydroxy, oxo, 5 or 6 membered monocyclic aromatic ring, wherein said 5 or 6 membered monocyclic aromatic ring is containing 1 or 2 heteroatoms selected from N and S, or C1-4alkyl-C(O)—N(R3)—;
A is phenyl;
B is C1-2 alkylene optionally substituted with methyl;
W is NH, N—CH3 or O;
R2 is H;
R3 is H or C1-4 alkyl;
Z is a 5 to 10 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5 to 10 membered monocyclic aromatic ring is optionally substituted with chloro, bromo, methyl, nitro, CH3C(═O)NH—, tBuC(═O)NH— or phenyl; and
L is chloro, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, —C(═O)NH2, trifluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
A further preferred group of compounds of Formula (I) includes compounds wherein
Y1, Y2, Y3 and Y4 are independently selected from N, CH and C(L);
R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl, methylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl;
A is phenyl;
B is ethylene or propylene;
W is NH, N—CH3 or O;
R2 is H;
Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with one to three substituents independently selected from chloro, bromo, methyl, acetylamino, pivaloylamino, nitro and phenyl; and
L is chloro, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, —C(═O)NH2, trifluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
A further preferred group of compounds of Formula (I) includes compounds wherein
Y1, Y2, Y3 and Y4 are selected from the group consisting of
a) Y1 and Y3 are C(L), Y2 is CH and Y4 is N;
b) Y1 is CH, Y2 and Y3 are C(L) and Y4 is N;
c) Y1, Y2 and Y3 are C(L) and Y4 is N;
d) Y1 and Y3 are C(L), Y2 is N and Y4 is CH;
e) Y1 is C(L) and Y2, Y3 and Y4 are CH;
f) Y1, Y3 and Y4 are CH, and Y2 is C(L);
g) Y1, Y2 and Y3 are CH, and Y4 is C(L);
h) Y1 and Y2 are C(L), and Y3 and Y4 are CH;
i) Y1 and Y3 are C(L), and Y2 and Y4 are CH;
j) Y1 and Y4 are CH, and Y2 and Y3 are C(L);
k) Y1 and Y2 are CH, Y3 is C(L) and Y4 is N;
l) Y1 and Y3 are CH, Y2 is C(L) and Y4 is N;
m) Y1, Y2, Y3 and Y4 are CH;
n) Y1 and Y2 are C(L), Y3 is CH and Y4 is N;
o) Y1, Y2 and Y4 are CH, and Y3 is C(L);
p) Y1 and Y2 are C(L), Y3 is N and Y4 is CH;
q) Y1 and Y3 are C(L), and Y2 and Y4 are N;
r) Y1 is C(L), Y2 and Y3 are CH, and Y4 is N; and
s) Y2 is C(L), Y1 and Y3 are CH, and Y4 is N;
R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl, methylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl;
A is phenyl;
B is ethylene or propylene;
W is NH, N—CH3 or O;
R2 is H;
Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with one to three substituents independently selected from chloro, bromo, methyl, acetylamino, pivaloylamino, nitro and phenyl; and
L is chloro, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, —C(═O)NH2, trifluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
A further preferred group of compounds of Formula (I) includes compounds wherein
Y1, Y2, Y3 and Y4 are selected from the group consisting of
a) Y1 and Y3 are C(L), Y2 is CH and Y4 is N;
b) Y1 is CH, Y2 and Y3 are C(L) and Y4 is N;
c) Y1, Y2 and Y3 are C(L) and Y4 is N;
d) Y1 and Y3 are C(L), Y2 is N and Y4 is CH;
e) Y1 is C(L) and Y2, Y3 and Y4 are CH;
f) Y1, Y3 and Y4 are CH, and Y2 is C(L);
g) Y1, Y2 and Y3 are CH, and Y4 is C(L);
h) Y1 and Y2 are C(L), and Y3 and Y4 are CH;
i) Y1 and Y3 are C(L), and Y2 and Y4 are CH; and
j) Y1 and Y4 are CH, and Y2 and Y3 are C(L);
R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl, methylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl;
A is phenyl;
B is ethylene or propylene;
W is NH, N—CH3 or O;
R2 is H;
Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with one to three substituents independently selected from chloro, bromo, methyl, acetylamino, pivaloylamino, nitro and phenyl; and
L is chloro, methyl, trifluoromethyl, hydroxy, methoxy, cyano, acetyl, —C(═O)NH2, trifluoromethyloxy, methane sulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
Preferred individual compounds of Formula (I) are as follows:
Most preferred individual compounds of Formula (I) are following:
In another preferred aspect, the EP4 receptor ligand (antagonist), which is disclosed in WO 2005/021508, is phenyl or pyridyl amide compounds of the following Formula (II) or pharmaceutically acceptable salts thereof,
wherein A represents a phenyl group or a pyridyl group; B represents an aryl group or a heteroaryl group;
E represents a 1,4-phenylene group;
R1 and R2 independently represent a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a haloalkyl group having from 1 to 4 carbon atoms, a haloalkoxy group having from 1 to 4 carbon atoms, a cyano group or an aminocarbonyl group;
R3 and R4 independently represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; or R3 and R4 may be joined together to form an alkylene chain having 2 to 6 carbon atoms;
R5 represents —CO2H, CO2W,
R6 represents an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 7 ring atoms, an aryl group or a heteroaryl group;
X represents a methylene group, an oxygen atom or a sulfur atom;
said aryl groups have from 6 to 10 carbon atoms; said heteroaryl groups are 5 to 10-membered aromatic heterocyclic groups containing from 1 to 3 heteroatoms selected from the group consisting of sulfur atom, oxygen atom and nitrogen atom;
said aryl groups and said heteroaryl groups referred to in the definitions of B are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents alpha;
said 1,4-phenylene group referred to in the definition of E is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents beta;
said aryl groups and said heteroaryl groups referred to in the definitions of R6 and alpha are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents beta;
said substituents alpha are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, two adjacent alpha groups are optionally joined together to form an alkylene or an alkenylene chain having 3 or 4 carbon atoms, aminocarbonyl groups, alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, aminosulfinyl groups, aminosulfonyl groups, hydroxy groups, hydroxyalkyl groups having from 1 to 4 carbon atoms, nitro groups, amino groups, carboxy groups, alkoxycarbonyl groups having from 2 to 5 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms, alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoylamino groups having from 1 to 4 carbon atoms, alkanoyl (alkyl)amino groups having from 1 to 6 carbon atoms, alkanoylaminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and alkyl part, alkanoyl (alkyl)aminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and each alkyl part, alkylsulfonylamino groups having from 1 to 4 carbon atoms, mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms, mono- or di-alkylaminosulfinyl groups having from 1 to 6 carbon atoms, mono- or dialkylaminosulfonyl groups having from 1 to 6 carbon atoms, aminoalkyl groups having from 1 to 4 carbon atoms, mono- or di-alkylamino groups having from 1 to 6 carbon atoms, mono- or di-alkylaminoalkyl groups having from 1 to 6 carbon atoms in each alkyl part, aralkyl groups having from 7 to 10 carbon atoms, heteroarylalkyl groups having from 1 to 4 carbon atoms in the alkyl part, heteroarylalkoxy groups having from 1 to 4 carbon atoms in the alkoxy part and alkylsulfonylamino groups having from 1 to 4 carbon atoms;
said substituents beta are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms and cyano groups;
W is a pharmaceutically acceptable ester prodrug group; with the proviso R1 and R2 do not represent a hydrogen atom simultaneously.
In the compounds of Formula (II),
B preferably represents an aryl or heteroaryl group such as phenyl, naphthyl, pyridyl, quinolyl or isoquinolyl. B is preferably unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents alpha; said substituents alpha are selected from the group consisting halogen atoms (e. g. fluoro, chloro), alkyl groups having from 1 to 4 carbon atoms (e. g. methyl, ethyl), alkoxy groups having from 1 to 4 carbon atoms (e. g. methoxy), haloalkoxy groups having from 1 to 4 carbon atoms (e. g. trifluoromethoxy), cyano groups, alkynyl groups having from 2 to 6 carbon atoms (e. g. ethynyl), alkanoyl groups having from 1 to 5 carbon atoms (e. g. acetyl), cycloalkyl groups having from 3 to 7 ring atoms (e. g. cyclopentyl), heteroaryl groups (e. g. 2-, 3- or 4-pyridyl, 1-methylimidazol-2-yl, thiazol-2-yl, 2-methylthiazol-4-yl), aryl groups (e. g. phenyl), aralkoxy groups having from 7 to 10 carbon atoms (e. g. benzyloxy), arylcarbonyl groups (e. g. benzoyl), two adjacent alpha groups are optionally joined together to form an alkylene chain having 3 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms (e. g. methylthio) and di-alkylaminoalkyl groups having from 1 to 6 carbon atoms in the alkyl part; said heteroaryl groups referred to in the definitions of alpha are unsubstituted or are substituted by alkyl groups having from 1 to 4 carbon atoms (e. g. methyl). In the definition of B, aryl is preferably phenyl or naphthyl and heteroaryl is a 5- to 10-membered aromatic heterocyclic group containing either from 1 to 3 nitrogen heteroatoms, or 1 or 2 nitrogen heteroatoms and/or 1 oxygen or 1 sulphur heteroatom.
More preferably B represents a phenyl group optionally substituted by substituent selected from the group consisting of substituents alpha; said substituents alpha are selected from the group consisting of halogen atoms (e. g. fluoro, chloro), alkyl groups having from 1 to 4 carbon atoms (e. g. methyl, ethyl), alkoxy groups having from 1 to 4 carbon atoms (e. g. methoxy), haloalkoxy groups having from 1 to 4 carbon atoms (e. g. trifluoromethoxy), cyano groups, alkynyl groups having from 2 to 6 carbon atoms (e. g. ethynyl), alkanoyl groups having from 1 to 4 carbon atoms (e. g. acetyl), cycloalkyl groups having from 3 to 7 ring atoms (e. g. cyclopentyl), alkylthio groups having from 1 to 4 carbon atoms (e. g. methylthio), di-alkylaminoalkyl groups having from 1 to 6 carbon atoms in the alkyl part, thiazolyl groups, isothiazolyl groups, oxazolyl groups, isoxazolyl groups, imidazolyl groups, pyridyl groups, benzyloxy groups, phenyl groups or benzoyl groups; said thiazolyl groups, isothiazolyl groups, oxazolyl groups, isoxazolyl groups, imidazolyl groups and pyridyl groups referred to in the definitions of alpha are unsubstituted or are substituted by alkyl groups having from 1 to 4 carbon atoms. More preferably B represents a phenyl group optionally substituted by substituent selected from the group consisting of substituents alpha; said substituents alpha are selected from the group consisting of fluorine atoms, chlorine atoms, methyl groups, ethyl groups, methoxy groups, trifluoromethoxy groups, cyano groups, ethynyl groups, acetyl groups, cyclopentyl groups, methylthio groups, dimethylaminoethyl groups, phenyl groups, imidazolyl groups optionally substituted by methyl groups, thiazolyl groups optionally substituted by methyl groups, pyridyl groups or benzyloxy groups. More preferably, B represents a phenyl group substituted by 1 or 2 fluoro or chloro substituents. More preferably, B represents a phenyl group substituted by 1 fluoro or chloro substituent.
Most preferably, B represents 3-fluorophenyl.
In the compounds of Formula (II),
X preferably represents a methylene group or an oxygen atom. More preferably, X represents an oxygen atom.
In the compounds of Formula (II),
preferably, R1 and R2 independently represent a hydrogen atom, a fluorine atom, a chlorine atom, trifluoromethyl, cyano or aminocarbonyl. More preferably, R1 represents a halogen atom (e. g. fluoro, chloro) and R2 represents a hydrogen atom.
In the compounds of Formula (II),
preferably, R3 and R4 independently represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms (e. g. methyl, ethyl). More preferably R3 represents an alkyl group having from 1 to 4 carbon atoms (e. g. methyl, ethyl) and R4 represents a hydrogen atom. Most preferably R3 represents a methyl group and R4 represents a hydrogen atom.
In the compounds of Formula (II),
R5 preferably represents —CO2H,
and R6 preferably represents an aryl group optionally substituted by halogen atoms or is a heteroaryl group. More preferably, R5 represents —CO2H,
and R6 represents an aryl group optionally substituted by halogen atoms. More preferably R6 represents methyl, cyclohexyl, phenyl group optionally substituted by halogen atoms (such as 2-, 3- or 4-chlorophenyl, 3-fluorophenyl), 3-methylphenyl, 3-methoxyphenyl or 5-methyl-2-pyridyl. Further more preferably R5 represents —CO2H or
Most preferably R5 represents —CO2H.
Particularly preferred compounds of the invention include those in which each variable in Formula (II) is selected from the preferred groups for each variable.
Even more preferable compounds of the invention include those where each variable in Formula (II) is selected from the more preferred groups for each variable.
A preferred individual compound of Formula (II) is selected from 4-((1S)-1-{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino} ethyl) benzoic acid; 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy) pyridin-3-yl] carbonyl} amino)ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-cyanophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy) pyridin-3-yl]carbonyl} amino)ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-chlorophenoxy)pyridin-3-yl]carbonyl}amino) ethyl]benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)benzoyl]amino} ethyl) benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-methoxyphenoxy)benzoyl]amino} ethyl) benzoic acid; 4-((1S)-1-{[5-chloro-2-(3-chlorophenoxy) benzoyl] amino} ethyl) benzoic acid; 4-[(1S)-1-({[5-chloro-2-(2, 4-difluorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(4-chloro-3-fluorophenoxy) pyridin-3-yl]carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(2-chloro-4-fluorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(2, 6-difluorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3, 4-difluorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-{(1S)-1-[({5-chloro-2-[3-(1, 3-thiazol-2-yl) phenoxy] pyridin-3-yl} carbonyl)amino] ethyl} benzoic acid; 4-[(1S)-1-({[5-chloro-2-(2,3-difluorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(2,5-difluorophenoxy)pyridin-3-yl]carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(4-chlorophenoxy) pyridin3-yl]carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(4-chloro-2-fluorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-[(S)-1-({[5-chloro-2-(2-chloro-5-fluorophenoxy) pyridin-3-yl]carbonyl}amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-methylphenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(4-fluoro-3-methylphenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3, 5-difluorophenoxy) pyridin-3-yl]carbonyl}amino) ethyl] benzoic acid; 4-((1S)-1-{[5-chloro-2-(2, 3-difluorophenoxy) benzoyl] amino} ethyl) benzoic acid; 4-((1S)-1-{[5-chloro-2-(2,4-difluorophenoxy)benzoyl]amino}ethyl) benzoic acid; 4-((1S)-1-{[5-chloro-2-(3, 4-difluorophenoxy) benzoyl] amino} ethyl) benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-chloro-5-fluorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-chloro-2-methylphenoxy) pyridin-3-yl] carbonyl}amino) ethyl] benzoic acid; 4-((1S)-1-{[5-chloro-2-(3, 5-difluorophenoxy) benzoyl]amino} ethyl) benzoic acid; 4-((1S)-1-{[5-chloro-2-(2, 5-difluorophenoxy) benzoyl]amino} ethyl) benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-chloro-2-fluorophenoxy)pyridin-3-yl]carbonyl}amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-pyridin-2-ylphenoxy) pyridin-3-yl]carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(4-pyridin-2-ylphenoxy)pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(4-pyridin-4-ylphenoxy)pyridin-3-yl]carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-chloro-5-methylphenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-((1S)-1-{[5-chloro-2-(3-methylphenoxy) benzoyl] amino} ethyl) benzoic acid; 4-((1S)-1-{[5-chloro-2-(3-chloro-5-fluorophenoxy)benzoyl] amino} ethyl) benzoic acid; 4-((1S)-1-{[5-chloro-2-(2, 6-difluorophenoxy) benzoyl] amino} ethyl) benzoic acid; 4-((1S)-1-{[5-chloro-2-phenoxypyridin-3-yl) carbonyl] amino} ethyl) benzoic acid; 4-[(1S)-1-({[5-chloro-2-(2, 3-dimethylphenoxy) pyridin-3-yl]carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(2, 3-dichlorophenoxy) pyridin-3-yl] carbonyl)amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3, 4-dichlorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3, 5-dichlorophenoxy) pyridin-3-yl]carbonyl}amino) ethyl] benzoic acid; and 4-[(1S)-1-({[5-chloro-2-(3-fluoro-4-methylphenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; or a pharmaceutically acceptable salt thereof.
A further preferred individual compound of Formula (II) is selected from 4-((1S)-1-{[5-chloro-2-(4-fluorophenoxy)benzoyl]amino} ethyl) benzoic acid; 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-cyanophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-chlorophenoxy) pyridin-3-yl]carbonyl} amino) ethyl] benzoic acid; 4-((1S)-1-{[5-chloro-2-(3-fluorophenoxy) benzoyl] amino} ethyl) benzoic acid; 4-((1S)-1-{[5-chloro-2-(3-chlorophenoxy) benzoyl] amino} ethyl) benzoic acid; 4-[(1S)-1-({[5-chloro-2-(2-chloro-4-fluorophenoxy) pyridin-3-yl]carbonyl}amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(2, 6-difluorophenoxy) pyridin-3-yl]carbonyl}amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3, 4-difluorophenoxy) pyridin-3-yl]carbonyl}amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(2, 3-difluorophenoxy) pyridin-3-yl]carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(2, 5-difluorophenoxy) pyridin-3-yl]carbonyl}amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(2-chloro-5-fluorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-methylphenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-(1 [5-chloro-2-(3, 5-difluorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-((1S)-1-{[5-chloro-2-(2, 3-difluorophenoxy) benzoyl] amino} ethyl) benzoic acid; 4-((1S)-1-{[5-chloro-2-(3, 4-difluorophenoxy) benzoyl] amino} ethyl) benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-chloro-5-fluorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-((1S)-1-{[5-chloro-2-(3, 5-difluorophenoxy) benzoyl] amino} ethyl) benzoic acid; 4-((1S)-1-{[5-chloro-2-(2, 5-difluorophenoxy) benzoyl] amino} ethyl) benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3-chloro-5-methylphenoxy) pyridin-3-yl] carbonyl}amino) ethyl] benzoic acid; 4-((1S)-1-{[5-chloro-2-(3-methylphenoxy) benzoyl] amino} ethyl) benzoic acid; 4-((1S)-1-{[5-chloro-2-(3-chloro-5-fluorophenoxy) benzoyl] amino} ethyl) benzoic acid; 4-((1S)-1-{[5-chloro-2-(2, 6-difluorophenoxy) benzoyl] amino} ethyl) benzoic acid; 4-((1S)-1-{[(5-chloro-2-phenoxypyridin-3-yl) carbonyl] amino} ethyl) benzoic acid; 4-[(1S)-1-({[5-chloro-2-(2, 3-dichlorophenoxy) pyridin-3-yl]carbonyl}amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3, 4-dichlorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid; 4-[(1S)-1-({[5-chloro-2-(3, 5-dichlorophenoxy) pyridin-3-yl]carbonyl}amino) ethyl] benzoic acid; and 4-[(1S)-1-({[5-chloro-2-(3-fluoro-4-methylphenoxy) pyridin-3-yl]carbonyl}amino) ethyl] benzoic acid; or a pharmaceutically acceptable salt thereof.
In another preferred aspect, the EP4 receptor ligand (antagonist), which is disclosed in WO 05/105732, is substituted methyl aryl or heteroaryl amide compounds of the following Formula (III)
wherein X represents —CH— or a nitrogen atom;
Y represents —NR4, an oxygen atom or a sulfur atom;
R4 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms;
Z represents a hydrogen atom or a halogen atom;
R1 represents an alkyl group having from 1 to 6 carbon atoms optionally substituted with an alkoxy group having from 1 to 6 carbon atoms or a cycloalkyl group having from 3 to 7 carbon atoms; a cycloalkyl group having from 3 to 7 carbon atoms optionally substituted with an alkyl group having from 1 to 3 carbon atoms; a phenyl group optionally substituted with one or more substituents alpha; or a group Het1 optionally substituted with one or more substituents alpha;
Het1 represents a heterocyclic group having from 4 to 7 ring atoms which contains either from 1 to 4 nitrogen ring heteroatoms or from 0 to 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulfur ring heteroatom;
R2 and R3 independently represent a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; or R2 and R3 together form an alkylene chain having from 3 to 6 carbon atoms; and
said substituent alpha is selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, hydroxy groups, alkoxy groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, hydroxy alkyl groups having from 1 to 4 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms in alkoxy and alkyl groups, alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoyl groups having from 2 to 5 carbon atoms, alkenyl groups having from 2 to 4 carbon atoms, alkynyl groups having from 2 to 4 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, nitro groups, amino groups, mono- or di-alkylamino groups having from 1 to 4 carbon atoms, aminosulfonyl groups, alkoxycarbonyl groups having from 1 to 4 carbon atoms, alkylsulfonylamino groups having from 1 to 4 carbon atoms, cycloalkyl groups having from 3 to 7 carbon atoms and a mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms;
or a pharmaceutically acceptable ester of such compound;
or a pharmaceutically acceptable salt thereof.
In the compounds of Formula (III),
Y preferably represents NR4 or an oxygen atom; and R4 represents an alkyl group having from 1 to 3 carbon atoms. More preferably, Y represents NCH3 or an oxygen atom. Most preferably, Y represents an oxygen atom.
In the compounds of Formula (III),
Z preferably represents a halogen atom. More preferably, Z represents a chlorine atom or a fluorine atom.
In the compounds of Formula (III),
R1 preferably represents an alkyl group having from 1 to 6 carbon atoms; a cycloalkyl group having from 3 to 7 carbon atoms, a phenyl group optionally substituted with one or more substituents alpha; or a group Het1 optionally substituted with one or more substituents alpha;
Het1 represents a heterocyclic group having from 5 to 6 ring atoms which contains either from 1 to 2 nitrogen ring heteroatoms or from 0 to 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulfur ring heteroatom; said substituents alpha are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, hydroxy groups, alkoxy groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, hydroxy alkyl groups having from 1 to 4 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms in alkoxy and alkyl groups, alkylsulfonyl groups having from 1 to 4 carbon atoms and alkanoyl groups having from 2 to 5 carbon atoms.
More preferably, R1 represents an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 4 to 6 carbon atoms, a phenyl group, a pyridyl group, an oxazolyl group, a pyrazolyl group, a thiazolyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group; said phenyl group, pyridyl group, oxazolyl group, pyrazolyl group, thiazolyl group, tetrahydrofuranyl group and tetrahydropyranyl group referred to in the definitions of R1 are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents alpha; said substituents alpha are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 2 carbon atoms and cyano groups.
More preferably, R1 represents a butyl group, a pyridyl group, a phenyl group, an oxazolyl group, a pyrazolyl group or a thiazolyl group; said phenyl group, pyridyl group, oxazolyl group, pyrazolyl group, thiazolyl group referred to in the definitions of R1 are unsubstituted or are substituted by 1 to 2 substituent selected from the group consisting of substituents alpha; said substituents alpha are selected from the group consisting of halogen atoms and alkyl groups having from 1 to 2 carbon atoms.
Most preferably, R1 represents a phenyl group, optionally substituted by 1 to 2 groups independently selected from a fluorine atom, a chlorine atom and a methyl group.
In the compounds of Formula (III),
preferably, R2 and R3 independently represent a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms. More preferably, R2 represents a hydrogen atom; and R3 represents a methyl group.
Particularly preferred compounds of the invention include those in which each variable in Formula (III) is selected from the preferred groups for each variable. Even more preferable compounds of the invention include those where each variable in Formula (III) is selected from the more preferred groups for each variable.
A preferred individual compound of Formula (III) is selected from
In another preferred aspect, the EP4 receptor ligand (antagonist), which is disclosed in WO 2004/067524, is a compound of the following Formula (IV) or a pharmaceutically acceptable salt thereof.
A more preferred compound of Formula (IV) is sodium (4-((4-(5-methoxypyridin-2-yl)phenoxy)methyl)-5-methylfuran-2-carbonyl)(o-tolylsulfonyl)amide.
In another preferred aspect, the EP4 receptor ligand (antagonist), which is disclosed in Marc Blouim et al., J. Med. Chem. (DOI 10.1021/jm901771h) and WO2008/017164, is a compound of the following Formula (Va) or (Vb), or a pharmaceutically acceptable salt thereof:
wherein X and Y are independently selected from the group consisting of: N and C(R11), wherein each R11 is independently selected from the group consisting of: hydrogen, halo and C1-4alkyl;
B is selected from the group consisting of: —C(R5)(R6)—, —O—, —S—, —S(O)—, —SO2—, —C(R5)(R6)—C(R7)(R8)—, —O—C(R5)(R6)—, —S—C(R5)(R6)—, —S(O)—C(R5)(R6)— and —SO2—C(R5)(R6)—;
C is selected from the group consisting of aryl and heteroaryl, or a fused analog of aryl or heteroaryl, each optionally substituted with one to three substituents independently selected from R10;
E is selected from the group consisting of: —C(O)OH, —C(O)OC1-4alkyl, tetrazolyl and
wherein R is selected from the group consisting of: C1-4alkyl, aryl and heteroaryl, or a fused analog of aryl or heteroaryl, wherein aryl and heteroaryl or the fused analogs thereof are optionally substituted with one to three substituents independently selected from R10;
R1 to R8 are independently selected from the group consisting of: H, halo, —O—R12, C1-6 alkyl and C3-6cycloalkyl, and one or more pairs of R1 and R2, R5 and R6, and R7 and R8 may be joined together with the carbon atom to which they are attached to form a 3- to 5-membered monocyclic cycloalkyl ring, and R5 and R6 or R7 and R8 may be joined together to form carbonyl;
R9 is independently selected from the group consisting of: halo, hydroxyl and C1-4alkyl;
R10 is selected from the group consisting of: halo, cyano, C1-4alkyl, C1-4fluoroalkyl, C1-4 alkoxy, C1-4thioalkoxy and C1-4fluoroalkoxy; and
each R12 is selected from the group consisting of: H, C1-4alkyl, C3-6cycloalkyl and heterocyclyl.
A preferred individual compound of Formula (Va) or (Vb), is selected from
A preferred compound of this invention is selected from:
Those skilled in the art will fully understand the terms used herein in the description and the appendant claims to describe the present invention. Nonetheless, unless otherwise provided herein, the following terms are as described immediately below.
The term “cartilage disease”, as used herein, means diseases associated with destruction, damage or injury of articular cartilage. Examples of such cartilage disease include osteoarthritis, rheumatoid arthritis and arthritis/inflammation associated with cartilage degradation and the like.
By “EP4 receptor antagonist” is meant a chemical substance that reduces or attenuates the biological activity of an EP4 receptor. Such antagonists may include proteins such as anti-EP4 antibodies, nucleic acids, amino acids, peptides carbohydrates, small molecules (organic or inorganic), or any other compound or composition which decreases the activity of an EP4 receptor either by reducing the amount of EP4 receptor present in a cell, or by decreasing the binding or signaling activity of the EP4 receptor.
The term “alkyl”, as used herein, means a straight or branched saturated monovalent hydrocarbon radical including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, neopentyl and the like.
The term “alkenyl”, as used herein, means a hydrocarbon radical having at least one double bond including, but not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl and the like.
The term “alkynyl”, as used herein, means a hydrocarbon radical having at least one triple bond including, but not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl and the like.
The term “halo”, as used herein, refers to F, Cl, Br or I, preferably F or Cl.
The term “cycloalkyl”, as used herein, means a saturated carbocyclic radical including, but not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
The term “alkoxy”, as used herein, means an O-alkyl group wherein “alkyl” is defined above.
The term “monocyclic aromatic ring”, as used herein, means a monocyclic aromatic carbocyclic or heterocyclic ring (and containing 0-4 heteroatoms selected from O, N and S) including, but not limited to, phenyl, pyrazolyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, isooxazolyl, isothiazolyl, triazolyl, furazanyl and the like.
The term “bicyclic aromatic ring”, as used herein, means a monocyclic or bicyclic aromatic carbocyclic or heterocyclic ring (and containing 0-4 heteroatoms selected from O, N and S) including, but not limited to, naphthyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl and the like.
The term “alkylene”, as used herein, means a saturated hydrocarbon (straight chain or branched) wherein a hydrogen atom is removed from each of the terminal carbons such as methylene, ethylene, propylene, butylene, pentylene, hexylene and the like.
The term “cycloalkylene”, as used herein, means divalent cycloalkyl groups including, but not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and cycloheptylene and the like.
The term “alkenylene”, as used herein, means a straight or branched hydrocarbon chain spacer radical having at least one double bond including, but not limited to, —CH═CH—, —CH═CHCH2—, —CH═CHCH(CH3)—, and the like.
The term “alkynylene”, as used herein, means a straight or branched hydrocarbon chain spacer radical having at least one triple bond including, but not limited to,
—C═C—,—C—C═CCH2—,—C═CCH(CH3)—, [Chem.20]
and the like.
The term “two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms”, as used herein, means, but not limited to, —O—CH2—O—, —CH2—O—CH2—, —O—CH2CH2—, —CH2CH2—O—, —O—CH2CH2—O—, —CH2CH2CH2—O—, —O—CH2CH2CH2—, —CH2—O—CH2CH2—, —CH2CH2—O—CH2—, and the like.
The term “aryl”, as used herein, means aromatic radicals including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl and the like.
The term “protecting group”, as used herein, means a hydroxy or amino protecting group which is selected from typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1991).
The term “ester prodrug group” means a protecting group which can be cleaved in vivo by a biological method such as hydrolysis and forms a free acid or salt thereof. Whether a compound is such a derivative or not can be determined by administering it by intravenous injection to an experimental animal, such as a rat or mouse, and then studying the body fluids of the animal to determine whether or not the compound or a pharmaceutically acceptable salt thereof can be detected.
Preferred examples of groups for an ester of a carboxyl group or a hydroxy group include: (1) aliphatic alkanoyl groups, for example: alkanoyl groups such as the formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, icosanyl and henicosanoyl groups; halogenated alkylcarbonyl groups such as the chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl groups; alkoxyalkanoyl groups such as the methoxyacetyl group; and unsaturated alkanoyl groups such as the acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl and (E)-2-methyl-2-butenoyl groups; (2) aromatic alkanoyl groups, for example: arylcarbonyl groups such as the benzoyl, alpha-naphthoyl and beta-naphthoyl groups; halogenated arylcarbonyl groups such as the 2-bromobenzoyl and 4-chlorobenzoyl groups; alkylated arylcarbonyl groups such as the 2,4,6-trimethylbenzoyl and 4-toluoyl groups; alkoxylated arylcarbonyl groups such as the 4-anisoyl group; nitrated arylcarbonyl groups such as the 4-nitrobenzoyl and 2-nitrobenzoyl groups; alkoxycarbonylated arylcarbonyl groups such as the 2-(methoxycarbonyl)benzoyl group; and arylated arylcarbonyl groups such as the 4-phenylbenzoyl group; (3) alkoxycarbonyl groups, for example: alkoxycarbonyl groups such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl groups; and halogen- or tri(alkyl)silyl-substituted alkoxycarbonyl groups such as the 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl groups; (4) tetrahydropyranyl or tetrahydrothiopyranyl groups such as: tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, and 4-methoxytetrahydrothiopyran-4-yl groups; tetrahydrofuranyl or tetrahydrothiofuranyl groups such as: tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl groups; (5) silyl groups, for example: tri(alkyl)silyl groups such as the trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl and triisopropylsilyl groups; and silyl groups substituted by one or more aryl and alkyl groups such as the diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl groups; (6) alkoxymethyl groups, for example: alkoxymethyl groups such as the methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl groups; alkoxylated alkoxymethyl groups such as the 2-methoxyethoxymethyl group; and halo(alkoxy)methyl groups such as the 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl groups; (7) substituted ethyl groups, for example: alkoxylated ethyl groups such as the 1-ethoxyethyl and 1-(isopropoxy)ethyl groups; and halogenated ethyl groups such as the 2,2,2-trichloroethyl group; (8) aralkyl groups, for example: alkyl groups substituted by from 1 to 3 aryl groups such as the benzyl, alpha-naphthylmethyl, beta-naphthylmethyl, diphenylmethyl, triphenylmethyl, alpha-naphthyldiphenylmethyl and 9-anthrylmethyl groups; alkyl groups substituted by from 1 to 3 substituted aryl groups, where one or more of the aryl groups are substituted by one or more alkyl, alkoxy, nitro, halogen or cyano substituents such as the 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl groups; alkenyloxycarbonyl groups such as the vinyloxycarbonyl; aryloxycarbonyl groups such as phenoxycarbonyl; and aralkyloxycarbonyl groups in which the aryl ring may be substituted by 1 or 2 alkoxy or nitro groups, such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl groups.
The term “treating”, as used herein, refers to reversing, recovering, alleviating, inhibiting, or preventing the onset or the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment” as used herein refers to the act of treating, as “treating” is defined immediately above.
It has been known that a compound of formula (I), (II), (III), (IV), (Va) or (Vb) exhibits an excellent EP4 antagonistic activities, and that it shows various effects based on the activities. However, it has never been known that a compound of formula (I), (II), (III), (IV), (Va) or (Vb) normalizes the condition of the cartilage lesion by excellent chondroprotective effect, cartilage destruction suppressing effect and anti-catabolic effect on cartilage.
In this point the present invention is quite different from the above mentioned prior art. Therefore the pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (Va) or (Vb) of the present invention is useful for preventing or treating the cartilage disease, that it is especially effective for preventing or treating such disease before sickness reaches bone itself. Therefore the composition can be used not only for treating early stage of a cartilage defect, chronic rheumatoid arthritis and osteoarthritis, but also for preventing these diseases.
Since a compound of formula (I), (II), (III), (IV), (Va) or (Vb) has potent cartilage destruction suppressing effect, chondroprotective effect, anti-catabolic effect on cartilage, inhibition of matrix metalloprotease(MMP)-mediated type II collagen degradation and MMP-mediated aggrecan degradation, and is more excellent in terms of clinically useful characteristics such as stability, absorption, bioavailability, it can be used for prevention and treatment of a cartilage destruction in a joint in any of various cartilage diseases such as cartilage defect, chronic rheumatoid arthritis involving a cartilage, osteoarthritis involving a cartilage as well as disorders related thereto, in animals (e.g., human, rat, mouse, cat, dog, rabbit, cattle, pig, horse etc.).
Other features and advantages of the invention will be apparent from the following detailed description and from the claims. While the invention is described in connection with specific embodiments, it will be understood that other changes and modifications that may be practiced are also part of this invention and are also within the scope of the appendant claims. This application is intended to cover any equivalents, variations, uses, or adaptations of the invention that follow, in general, the principles of the invention, including departures from the present disclosure that come within known or customary practice within the art. All publications mentioned herein are incorporated by reference in their entireties.
The present invention is directed to the use of an EP4 receptor antagonist in the manufacture of a medicament for the treatment of cartilage diseases.
Therapeutic Methods
Agents identified as EP4 receptor antagonist are administered in a dose effective to treat cartilage diseases. Such therapeutically effective amounts will be determined using routine optimization techniques that are dependent on the particular condition to be treated, the condition of the patient, the route of administration, the formulation, the judgment of the practitioner, and other factors evident to those skilled in the art in light of this disclosure.
An agent that inhibits EP4 activity can be incorporated into a therapeutic composition. Such EP4 receptor antagonists can include small molecules, nucleic acids, e.g., EP4 antisense nucleic acids, amino acids, peptides, carbohydrates, and anti-EP4 antibodies. Preferably, such agents are combined with a pharmaceutically acceptable delivery vehicle or carrier. Examples of EP4 antibodies include, for example, polyclonal, monoclonal, humanized, anti-idiotypic, chimeric or single chain antibodies, Fab, F(ab′)2, and Fab expression library fragments, scFV molecules, and epitope-binding fragments thereof. An antisense oligonucleotide directed to the EP4 gene or mRNA to inhibit its expression is made according to standard techniques (see, e.g., Agrawal et al., Methods in Molecular Biology: Protocols for Oligonucleotides and Analogs, Vol. 20 (1993)).
As used herein, a pharmaceutically acceptable delivery vehicle includes solvents, dispersion media, coatings, antibacterial and antifungal agents, and isotonic and absorption delaying agents that are compatible with pharmaceutical administration. The vehicle may also include other active or inert components, and/or may be targeted to joint tissue by virtue of its composition.
A therapeutic composition is formulated to be compatible with its intended route of administration. Non-limiting examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., by ingestion or inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions can be made as described in Remington's Pharmaceutical Sciences, (18th ed., Gennaro, ed., Mack Publishing Co., Easton, Pa., (1990)).
Therapeutic efficacy of such EP4 antagonists can be determined in light of this disclosure by standard therapeutic procedures in cell cultures or experimental animals, e.g., for determining the ED50 (the dose therapeutically effective in 50% of the population).
The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage may vary depending upon the formulation and the route of administration. For any EP4 antagonist used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.
The compound with EP4 antagonistic activity, or a pharmaceutically acceptable salt thereof can be used in combination with one or more additional compounds known to be useful in the treatment or prevention of cartilage disease or the symptoms thereof. Such example includes, but not limited to, NSAIDs, COX-2 inhibitors, steroids, matrix metalloproteinase inhibitors and hyaluronic acid.
The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a mammal including, but not limited to, the severity of the disease or disorder, previous treatments, the general health and/or age of the mammal, and other diseases present. Moreover, treatment of a mammal with a therapeutically effective amount of an EP4 antagonist can include a single treatment or, preferably, can include a series of treatments.
Compounds list:
A compound which has EP4 receptor antagonistic activity can be confirmed by known method (For example, Eur J Pharmacol. 1997: 340: 227-241).
The in vitro assays for assessing EP4 receptor antagonistic activity are typically membrane binding assay and cell-based functional assay. The binding activity of compounds for EP4 receptor was determined with using membrane prepared from HEK293 cells expressing EP4 receptor and radiolabeled ligands PGE2. The antagonistic activity of compounds on the EP4 receptor was determined by using HEK293 cells expressing EP4 receptor and PGE2. The inhibition of the PGE2-evoked cAMP level by compounds was analyzed.
The method of this assay is described in the following literature (Rheumatol Int. 2013 February; 33(2):401-11).
Full-depth cartilage explants were harvested from the knee of either back legs of a cow less than 24 month old. All the FDC explants are divided into different treatment group according to the explants weight and metabolic activity (viability) measured by Alamar Blue. Compounds were freshly added to the explants at each media change. The explants were cultured in serum-free conditions. Supernatants retrieved from the culture were analyzed by biomarkers (P2NP, C2M, AGN×1, AGN×2) at day 7, 14 and 21.
These results are shown in
From results of
The similar inhibition of cartilage destruction in ex vivo bovine cartilage explant model is shown in Compound C
The compounds describe in the compounds list are similarly conducted in this cartilage destruction assay. The dose-dependent inhibition of cartilage destruction in ex vivo bovine cartilage explant model is observed in all cases.
#### p<0.0001 versus disease control by ANOVA test.
The compounds described in the compounds list are conducted in the rat mono-iodoacetate and/or meniscal transection induced osteoarthritis model. These compounds exhibit potent inhibitory activities on cartilage destruction and serum biochemical markers associated with cartilage degradation and tissue inflammation in the rat mono-iodoacetate and/or meniscal transection model.
The study was performed in female Sprague-Dawley rats, age 6 months at MNX surgery.
7 days after MNX surgery monoiodoacetate 2 mg/0.2 ml was injected intra-articularly in the right knee joint. The test compounds or vehicle is injected to the animals after the MNX. In the MNX or sham group, the test compounds or vehicle was administered until termination.
Weekly fasting blood sampling are taken for the analysis of biomarker (P2NP, C2M, AGN×1, AGN×2). Knee joints is isolated at termination. Cartilage damage is scored by experienced histo-pathologist according to Colombo score.
The compounds described in the compounds list are similarly conducted in rat mono-iodoacetate and/or meniscal transection model. The potent activities are observed in all cases.
The compounds describe in the compounds list are conducted in the rat meniscal (MNX) transection and/or ovariectomised (OVA) induced osteoarthritis model. These compounds exhibit excellent inhibitory activities on cartilage destruction and serum biochemical markers associated with cartilage degradation and tissue inflammation in the rat meniscal transection and/or ovariectomised model.
The study is performed in female Sprague-Dawley rats with MNX and OVX surgery.
The test compounds or vehicle is injected to the animals after the surgery. In the MNX/OVX or sham group, the test compounds or vehicle was administered until termination.
Weekly fasting blood sampling are taken for the analysis of biomarker (P2NP, C2M, AGN×1, AGN×2). Knee joints is isolated at termination. Cartilage damage is scored by experienced histo-pathologist according to Colombo score.
The compounds describe in the compounds list are similarly conducted in rat mono-iodoacetate and/or meniscal transection model. The potent activities are observed in all cases.
According to the present invention, a compound of formula (I), (II), (III), (IV), (Va) or (Vb), or a pharmaceutically acceptable salt thereof is useful for the treatment and/or prevention of cartilage disease.
All publications, including but not limited to, issued patents, patent applications, and journal articles, cited in this application are each herein incorporated by reference in their entirety. Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2013-057180 | Mar 2013 | JP | national |
| Number | Name | Date | Kind |
|---|---|---|---|
| 5843959 | Bergeron, Jr. | Dec 1998 | A |
| Number | Date | Country |
|---|---|---|
| 0232422 | Apr 2002 | WO |
| 0232900 | Apr 2002 | WO |
| 2004067524 | Aug 2004 | WO |
| 2005021508 | Mar 2005 | WO |
| 2005102389 | Nov 2005 | WO |
| 2005105732 | Nov 2005 | WO |
| 2006095268 | Sep 2006 | WO |
| 2008017164 | Feb 2008 | WO |
| 2011124524 | Oct 2011 | WO |
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| Number | Date | Country | |
|---|---|---|---|
| 20170360764 A1 | Dec 2017 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14777610 | US | |
| Child | 15669031 | US |
