# US 7,612,086 B2 · JNK inhibitors

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 7,612,086 B2
- Document ID: US7612086B2
- Status: Granted
- Kind: B2
- Application number: 10/554,808
- Filed: 2004-05-14
- Published: 2007-06-21
- Granted: 2009-11-03
- Earliest claimed: 2003-05-16
- Assignees: Eisai R&D Management Co., Ltd.
- Inventors: Piotr Graczyk; Vanessa Palmer; Afzal Khan
- Web page: https://patentgrep.com/patent/US7612086B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 25/00: Drugs for disorders of the nervous system
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides novel compounds of formula (I) and their use in the inhibition of c-Jun N-terminal kinases. The present invention further provides the use of these compounds in medicine, in particular in the prevention and/or treatment of neurodegenerative disorders related to apoptosis and/or inflammation.

## Claims

### Claim 1

A compound of formula (I) or a pharmaceutically acceptable salt thereof
wherein R1 is an optionally substituted C3-12 carbocyclyl or C3-12 heterocyclyl group, Y is N or C and Z is lone electron pair, hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C3-12 carbocyclyl, C3-12 heterocyclyl, (CH2)nOR2, (CH2)nNR22, CO2R2, COR2, CONR22, wherein the C1-12 alkyl group optionally contains one or more insertions selected from —O—, —N(R2) —S—, —S(O)— and —S(O2)—; and each substitutable nitrogen atom in Z is optionally substituted by R3, COR3, SO2R3 or CO2R3;
wherein n is 1 to 6, preferably n is 1, 2 or 3;
wherein R2 is hydrogen, C1-12 alkyl, C3-12 carbocyclyl, C3-12 heterocyclyl, C1-12alkylC3-12carbocyclyl or C1-12alkylC3-12heterocyclyl optionally substituted by one or more of C1-6 alkyl, halogen, C1-6 haloalkyl, OR4, SR4, NO2, CN, NR4R4, NR4COR4, NR4CONR4R4, NR4COR4, NR4CO2R4, CO2R4, COR4, CONR42, S(O)2R4, SONR42, S(O)R4, SO2NR4R4, NR4S(O)2R4, wherein the C1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R4)—, —S(O)— and —S(O2)—, wherein each R4 may be the same or different and is as defined below;
wherein two R2 in NR22 may form a partially saturated, unsaturated or fully saturated five to seven membered ring containing one to three heteroatoms, optionally and independently substituted with one or more of halogen, C1-12 alkyl, C1-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C3-12 carbocyclyl, C3-12 heterocyclyl, OR5, SR5, NO2, CN, NR52, NR5COR5, NR5CONR52, NR5COR5, NR5CO2R5, CO2R5, COR5, CONR52, S(O)2R5, SONR52, S(O)R5, SO2NR52, or NR5S(O)2R5; and each saturated carbon in the optional ring is further optionally and independently substituted by ═O, ═S, NNR62, ═N—OR6, ═NNR6COR6, ═NNR6CO2R6, ═NNSO2R6, or ═NR6;
wherein R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C6-12 aryl;
wherein R4 is hydrogen, C1-6 alkyl, C1-6 haloalkyl or C6-12 aryl;
wherein R5 is hydrogen, C1-12 alkyl, C3-12 carbocyclyl or C3-12 heterocyclyl, optionally substituted by one or more of C1-6 alkyl, halogen, C1-6 haloalkyl, OR7, SR7, NO2, CN, NR7R7, NR7COR7, NR7CONR7R7, NR7COR7, NR7CO2R7, CO2R7, COR7, CONR72, S(O)2R7, SONR72, S(O)R7, SO2NR7R7, NR7S(O)2R7, wherein the C1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R7)—, —S(O)— and —S(O2)—, wherein each R7 may be the same or different and is as defined below;
wherein R6 is hydrogen, C1-12 alkyl, C3-12 carbocyclyl or C3-12 heterocyclyl, optionally substituted by one or more of C1-6 alkyl, halogen, C1-6 haloalkyl, OR7 SR7, NO2, CN, NR7R7, NR7COR7, NR7CONR7R7, NR7COR7, NR7CO2R7, CO2R7, COR7, CONR72, S(O)2R7, S(O)R7, SO2NR7R7, NR7S(O)2R7, wherein the C1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R7)—, —S(O)— and —S(O2)—, wherein each R7 may be the same or different and is as defined below;
wherein R7 is hydrogen, C1-6 alkyl, or C1-6 haloalkyl;
wherein the optionally substituted carbocyclyl or heterocyclyl group in R1 and Z is optionally and independently fused to a partially saturated, unsaturated or fully saturated five to seven membered ring containing zero to three heteroatoms, and each substitutable carbon atom in R1 or Z, including the optional fused ring, is optionally and independently substituted by one or more of halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C3-12 carbocyclyl, C3-12 heterocyclyl, (CH2)nOR12, (CH2)nNR122, OR12, SR12, NO2, CN, NR122, NR12COR12, NR12CONR122, NR12COR12, NR12CO2R12, CO2R12, COR12, CONR122, S(O)2R12, SONR122, S(O)R12, SO2NR122, or NR12S(O)2R12 wherein the C1-12 alkyl group optionally contains one or more insertions selected from —O—, —N(R12)— —S—, —S(O)— and —S(O2)—; and each saturated carbon in the optional fused ring is further optionally and independently substituted by ═O, ═S, NNR132, ═N—OR13, ═NNR13COR13, ═NNR13CO2R13, ═NNSO2R13, or ═NR13; and each substitutable nitrogen atom in R1 is optionally substituted by R14, COR14, SO2R14 or CO2R14;
wherein n is 1 to 6, preferably n is 1, 2 or 3;
wherein R12 is hydrogen , C1-12 alkyl, C3-12 carbocyclyl or C3-12 heterocyclyl, optionally substituted by one or more of C1-6 alkyl, halogen, C1-6 haloalkyl, OR15, SR15, NO2, CN, NR15R15, NR15COR15, NR15CONR15R15, NR15COR15, NR15CO2R15, CO2R15, COR15, CONR152, S(O)2R15, SONR152, S(O)R15, SO2NR15R15, NR15S(O)2R15, wherein the C1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R15)—, —S(O)— and —S(O2)—, wherein each R15 may be the same or different and is as defined below;
wherein two R12 in NR122 may form a partially saturated, unsaturated or fully saturated five to seven membered ring containing one to three heteroatoms, optionally and independently substituted with one or more of halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C3-12 carbocyclyl, C3-12 heterocyclyl, OR16, SR16, NO2, CN, NR162, NR16COR16, NR16CONR162, NR16COR16, NR16CO2R16, CO2R16, COR16, CONR162, S(O)2R16, SONR162, S(O)R16, SO2NR162, or NR16S(O)2R16; and each saturated carbon in the optional ring is further optionally and independently substituted by ═O, ═S, NNR172, ═N—OR17, ═NNR17COR17, ═NNR17CO2R17, ═NNSO2R17, or ═NR17;
wherein R13 is hydrogen, C1-12 alkyl, C3-12 carbocyclyl or C3-12 heterocyclyl, optionally substituted by one or more of C1-6 alkyl, halogen, C1-6 haloalkyl, OR15 SR15, NO2, CN, NR15R15, NR15COR15, NR15CONR15R15, NR15COR15, NR15CO2R15, CO2R15, COR15, CONR152,S(O)2R15, S(O)R15, SO2NR15R15, NR15S(O)2R15, wherein the C1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R15)—, —S (O)— and —S(O2)—,
wherein each R15 may be the same or different and is as defined below;
wherein R14 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C6-12 aryl;
wherein R15 is hydrogen, C1-6 alkyl, or C1-6 haloalkyl;
wherein R16 is hydrogen, C1-12 alkyl, C3-12 carbocyclyl or C3-12 heterocyclyl, optionally substituted by one or more of C1-6 alkyl, halogen, C1-6 haloalkyl, OR18, SR18, NO2, CN, NR18R18, NR18COR18, NR18CONR18R18, NR18COR18, NR18CO2R18, CO2R18, COR18, CONR182, S(O)2R18, SONR182, S(O)R18, SO2NR18R18, NR18S(O)2R18, wherein the C1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R18)—, —S(O)— and —S(O2)—, wherein each R18 may be the same or different and is as defined below;
wherein R17 is hydrogen, C1-12 alkyl, C3-12 carbocyclyl or C3-12 heterocyclyl, optionally substituted by one or more of C1-6 alkyl, halogen, C1-6 haloalkyl, OR18, SR18, NO2, CN, NR18R18, NR18COR18, NR18CONR18R18, NR18COR18, NR18CO2R18, CO2R18, COR18, CONR182, S(O)2R18, S(O)R18, SO2NR18R18, NR18S(O)2R18, wherein the C1-12 alkyl group optionally incorporates one or two insertions selected from the group consisting of —O—, —N(R18)—, —S(O)— and —S(O2)—,
wherein each R18 may be the same or different and is as defined below; and
wherein R18 is hydrogen, C1-6 alkyl, or C1-6 haloalkyl.

### Claim 2 (depends on 1)

A compound as claimed in claim 1 wherein R1 is preferably a five or six membered carbocyclyl or heterocyclyl group wherein the carbocyclyl or heterocyclyl group is optionally fused to one or more unsaturated rings and the carbocyclyl, heterocyclyl or fused rings can be optionally substituted.

### Claim 3 (depends on 1)

A compound as claimed in claim 1 wherein R1 is optionally substituted phenyl, cyclohexyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, furan, imidazole, indole, isoindole, isoquinoline, isoxazole, isothiazole, morpholine, napthaline, oxazole, phenazine, phenothiazine, phenoxazine, piperazine, piperidine, pyrazole, pyridazine, pyridine, pyrrole, quinoline, quinolizine, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, triazole, or trithiane.

### Claim 4 (depends on 1)

A compound as claimed in claim 1, wherein R1 is optionally substituted with one or more of OR12, NR122, SR12, (CH2)nOR12, (CH2)nNR12 2, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, haloalkyl, NO2, CN, CO2R12, COR12, CONR122, S(O)2R12, S(O)R12 or SO2NR122;
wherein R12 is hydrogen, C1-4 alkyl, heterocyclyl or aryl and n is 1, 2, 3, 4, 5 or 6, and each substitutable nitrogen atom in R1 is optionally substituted by R14, COR14, SO2R14 or CO2R14;
wherein R14 is C1-6 alkyl, C1-6 haloalkyl, or C6-12 aryl.

### Claim 5 (depends on 1)

A compound as claimed in claim 1 selected from

### Claim 6 (depends on 1)

A process for the production of a compound of formula (I) as claimed in claim 1,
comprising the conversion of a compound of formula (III) to a compound of formula (I) by the removal of the group R20;
wherein R1 is as defined in claim 1 and R20 is an amino protecting group.

### Claim 7 (depends on 6)

A process as claimed in claim 6 wherein R20 is R30SO2, R30C(O), (R30)3Si, R30OCH2, (R30)2NSO2, R30OC(O), R30(R30O)CH, PhC(O)CH2, CH2═CH, ClCH2CH2, Ph3C, Ph2(4-pyridyl)C, Me2N, HO—CH2, R30OCH2, (R30)SiOCH2, (R30O)2CH, t-BuOC(O)CH2, Me2NCH2 or tetrahydropyranylamine, wherein R30 is C1-6 alkyl or C6-12 aryl.

### Claim 8 (depends on 7)

A process as claimed in claim 7 wherein R20 is sulfonamide, and deprotection is carried out under basic conditions.

### Claim 9 (depends on 1)

An intermediate of formula (III)
wherein R1, Y and Z are is as defined in claim 1 and R20 is R30SO2, R30C(O), (R30)3Si, R30OCH2, (R30)2NSO2, R30OC(O), R30(R30O)CH, PhC(O)CH2, CH2═CH, ClCH2CH2, Ph3C, Ph2(4-pyridyl)C, Me2N, HO—CH2, R30OCH2, (R30)SiOCH2, (R30O)2CH, t-BuOC(O)CH2, Me2NCH2 or tetrahydropyranylamine, wherein R30 is C1-6 alkyl or C6-12 aryl.

### Claim 10 (depends on 1)

A process for the production of an intermediate of formula (III)
by the palladium catalyzed introduction of the group C≡Y-Z into compound (II), wherein R1, Y and Z are as defined in claim 1, R20 is R30SO2, R30C(O), (R30)3Si, R30OCH2, (R30)2NSO2, R30OC(O), R30(R30O)CH, R30CH2CH2, R30CH2, PhC(O)CH2, CH2═CH, ClCH2CH2, Ph3C, Ph2(4-pyridyl)C, Me2N, HO—CH2, R30OCH2, R30)SiOCH2, (R30O)2CH, t-BuOC(O)CH2, Me2NCH2 or tetrahydropyranylamine, wherein R30 is C1-6 alkyl or C6-12 aryl and X1 is F, Cl, Br I or CF3SO3.

### Claim 11 (depends on 10)

A process as claimed in claim 10
wherein the compound of formula III, (Y═N) is produced from a compound of formula (II) by incubation with a CuCN, 1,1′-bis(diphenylphosphino)ferrocene (dppf) and a palladium catalyst wherein R1, R20 and X1 are as defined in claim 10.

### Claim 12 (depends on 10)

A process as claimed in claim 10
wherein the compound of formula III, (Y═C) is produced from a compound of formula (II) by incubation with an acetylene derivative H—C≡C-Z, a palladium catalyst and CuI,
wherein R1, R20, X1 and Z are as defined in claim 10.

### Claim 13 (depends on 1)

A process for the production of an intermediate of formula (III)
comprising a a) reaction of a compound of formula (IV) with stannane R1—Sn(R31)3 in the presence of a palladium catalyst or
b) reaction of a compound of formula (IV) with boronic acid or ester R1—B(OR32)2 in a presence of a suitable palladium catalyst or
c) reaction of a compound of formula (IV) with silane R1—Si(R33)3 in the presence of a palladium catalyst;
wherein R1, Y and Z are as defined in claim 1, X2 is a halide and R20 is R30SO2, R30C(O), (R30)3Si, R30OCH2, (R30)2NSO2, R30OC(O), R30(R30O)CH, PhC(O)CH2, CH2═CH, ClCH2CH2, Ph3C, Ph2(4-pyridyl)C, Me2N, HO—CH2, R30OCH2, (R30)SiOCH2, (R30O)2CH, t-BuOC(O)CH2, Me2NCH2 or tetrahydropyranylamine, wherein R30 is C1-6 alkyl or C6-12 aryl;
wherein each of R31 is independently C1-6 alkyl,
wherein each of R32 is independently hydrogen or C1-6 alkyl or wherein two R32 groups together form a five, six or seven membered optionally ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C1-6 alkyl group, and wherein R33 is independently C1-6 alkyl, F, OH.

### Claim 14 (depends on 13)

A process as claimed in claim 13 wherein R32 is hydrogen or both R32 groups form the group —C(CH3)2—C(CH3)2—.

### Claim 15 (depends on 13)

A process as claimed in claim 13 wherein the palladium catalyst is (PPh3)2PdCl2, (PPh3)4Pd, Pd(OAc)2, [PdCl(η3-C3H5]2, Pd2(dba)3(wherein dba=dibenzylidenacetone) or Pd/P(t-Bu)3.

### Claim 16 (depends on 1)

A process for the production of a compound of formula (I) as defined in claim 1,
comprising a a) reaction of a compound of formula (V) with stannane R1—Sn(R31)3 in the presence of a palladium catalyst; or
b) reaction of a compound of formula (V) with boronic acid or ester R1—B(OR32)2 in a presence of a suitable palladium catalysts; or
c) reaction of a compound of formula (V) with silane R1—Si(R33)3 in the presence of a palladium catalyst,
wherein,
X2 is a halide,
wherein each of R31 is independently C1-6 alkyl,
wherein each of R32 is independently hydrogen or C1-6 alkyl or wherein two R32 groups together form a five, six or seven membered optionally ring with the boron and oxygen atoms, wherein the ring is optionally substituted with one or more C1-6 alkyl group,
and wherein R33 is independently C1-6 alkyl, F, OH; and
wherein R1, Y and Z are as defined in claim 1.

### Claim 17 (depends on 16)

A process as claimed in claim 16 wherein the palladium catalyst is (PPh3)2PdCl2, (PPh3)4Pd, Pd(OAc)2, [PdCl(η3-C3H5]2, Pd2(dba)3 (wherein dba=dibenzylidenacetone), or Pd/P(t-Bu)3.

### Claim 18 (depends on 1)

An intermediate of formula (V)
wherein Y and Z are as defined in claim 1, and
wherein X2 is a halide.

### Claim 19 (depends on 18)

An intermediate of formula (V) as claimed in claim 18 wherein said compound is

### Claim 20 (depends on 1)

A process for the production of an intermediate of formula (V)
comprising the conversion of a compound of formula (IV) into a compound of formula (V) by removal of the group R20,
wherein Y and Z are as defined in claim 1,
X2 is a halide and
R20 is R30SO2, R30C(O), (R30)3Si, R30OCH2, (R30)2NSO2, R30OC(O), R30(R30)CH, PhC(O)CH2, CH2═CH, ClCH2CH2, Ph3C, Ph2(4-pyridyl)C, Me2N, HO—CH2, R30OCH2, (R30SiOCH2, (R30O)2CH, t-BuOC(O)CH2, Me2NCH2 or tetrahydropyranylamine, wherein R30 is C1-6 alkyl or C6-12 aryl.

### Claim 21 (depends on 1)

An intermediate of formula (IV)
wherein Y and Z are as defined in claim 1,
wherein X2 is a halide and
wherein R20 is R30SO2, R30C(O), (R30)3Si, R30OCH2, (R30)2NSO2, R30OC(O), R30(R30O)CH, PhC(O)CH2, CH2═CH, ClCH2CH2, Ph3C, Ph2(4-pyridyl)C, Me2N, HO—CH2, R30OCH2, (R30SiOCH2, (R30O)2CH, t-BuOC(O)CH2, Me2NCH2 or tetrahydropyranylamine, wherein R30 is C1-6 alkyl or C6-12 aryl.

### Claim 22 (depends on 1)

A process for the production of an intermediate of formula (VII)
comprising the reaction of aldoxime (VI) with selenium dioxide,
wherein R11 is X2 or R1;
wherein X2 is a halide and R1 is defined in claim 1;
and wherein R20 is R30 SO2, R30C(O), (R30)3Si, R30OCH2, (R30)2NSO2, R30OC(O), R30(R30O)CH, PhC(O)CH2, CH2═CH, ClCH2CH2, Ph3C, Ph2(4-pyridyl)C, Me2N, HO—CH2, R30OCH2, (R30SiOCH2, (R30O)2CH, t-BuOC(O)CH2, Me2NCH2 or tetrahydropyranylamine, wherein R30 is C1-6 alkyl or C6-12 aryl.

### Claim 23 (depends on 22)

An intermediate of formula (VI)
wherein R11 is as defined in claim 22, and R20 is R30SO2, R30C(O), (R30)3Si, R30OCH2, (R30)2NSO2, R30OC(O), R30(R30O)CH, PhC(O)CH2, CH2═CH, ClCH2CH2, Ph3C, Ph2(4-pyridyl)C, Me2N, HO—CH2, R30OCH2, (R30SiOCH2, (R30O)2CH, t-BuOC(O)CH2, Me2NCH2 or tetrahydropyranylamine, wherein R30 is C1-6 alkyl or C6-12 aryl.

### Claim 24 (depends on 22)

A process for the production of an intermediate of formula (VI)
comprising the reaction of aldehyde (VIII) with hydroxylamine,
wherein R11 and R20 are as defined in claim 22.

### Claim 25 (depends on 22)

An intermediate of formula (VIII)
wherein R11 and R20 are as defined in claim 22.

### Claim 26 (depends on 22)

A process for the production of an intermediate formula (VIII)
comprising the addition of the R20 group to a compound of general formula (IX) wherein R11 and R20 are as defined in claim 22.

### Claim 27 (depends on 22)

An intermediate of formula (IX)
wherein R11 is as defined in claim 22.

### Claim 28 (depends on 22)

A process for the production of an intermediate of formula (IX)
comprising the reaction of a compound of a formula (X) with hexamethylenetetramine in aqueous propionic acid
wherein R11 is as defined in claim 22, and R31 is each independently C1-6 alkyl.

### Claim 29

A process for the production of an intermediate of formula (IV)
by the palladium catalyzed introduction of the group C≡Y-Z into compound (XII), wherein Y is N or C and Z is lone electron pair, hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C1-12 haloalkyl, C3-12 carbocyclyl, C3-12 heterocyclyl, (CH2)nOR2, (CH2)nNR22, CO2R2, COR2, CONR22, wherein the C1-12 alkyl group optionally contains one or more insertions selected from —O—, —N(R2)— —S—, —S(O)— and —S(O2)—; and each substitutable nitrogen atom in Z is optionally substituted by R3, COR3, SO2R3 or CO2R3, R20 is R30SO2, R30C(O), (R30)3Si, R30OCH2, (R30)2NSO2, R30OC(O), R30(R30O)CH, PhC(O)CH2, CH2═CH, ClCH2CH2, Ph3C, Ph2(4-pyridyl)C, Me2N, HO—CH2, R30OCH2, (R30)SiOCH2, (R30O)2CH, t-BuOC(O)CH2, Me2NCH2 or tetrahydropyranylamine, wherein R30 is C1-6 alkyl or C6-12 aryl, X1 is F, Cl, Br I or CF3SO3 and X2 is a halide.

### Claim 30 (depends on 29)

A process as claimed in claim 29
wherein the compound of formula (IV, Y═C) is produced from a compound of formula (XII) by incubation with an acetylene derivative H—C≡C-Z, a palladium catalyst and CuI;
wherein Y is C and Z, R20, X1 and X2 are as defined in claim 29.

### Claim 31

An intermediate selected from

### Claim 32 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier, diluent or excipient.

### Claim 33 (depends on 32)

A composition as claimed in claim 32 further comprising one or more other active agent.

### Claim 34 (depends on 33)

A composition as claimed in claim 33 wherein the composition further comprises an anti-inflammatory agent and/or an AMPA receptor antagonist.

### Claim 35 (depends on 1)

A method of treating a JNK-mediated disorder in an individual, which method comprises administering to said individual a compound as claimed in claim 1.

### Claim 36 (depends on 35)

A method as claimed in claim 35, wherein the disorder is an inflammatory disease and/or autoimmune disease such as Rheumatoid arthritis.

### Claim 37 (depends on 35)

A method as claimed in claim 35, wherein the disorder is inflammatory bowel disorder or rheumatoid arthritis.

### Claim 38 (depends on 35)

A method as claimed in claim 35, wherein one or more other active agent is administered to the individual simultaneously, subsequently or sequentially to administering the compound.

### Claim 39 (depends on 38)

A method as claimed in claim 38, wherein the other active agent is an anti-inflammatory agent.