# US 2008/0188473 A1 · Indoles Useful in the Treatment of Inflammation

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- Number: US 2008/0188473 A1
- Document ID: US20080188473A1
- Status: Published application
- Kind: A1
- Application number: 11/629,627
- Filed: 2005-06-17
- Published: 2008-08-07
- Earliest claimed: 2004-06-18
- Inventors: Kristofer Olofsson; Benjamin Pelcman; Wesley Schaal; Ivars Kalvins; Edgars Suna; Vita Ozola; Martins Katkevics
- Web page: https://patentgrep.com/patent/US20080188473A1

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/06: Antimigraine agents
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

There is provided a compound of formula: (I) wherein X, R1, R2, R3, R4, R5, R6, R7 and R8 have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of the activity of microsomal prostaglandin E synthase-1 is desired and/or required, and particularly in the treatment of inflammation.

## Claims

### Claim 1

A compound of formula I,
wherein
X represents a single bond, —C(O)— or —S(O)2—;
R1 represents an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from A;
one of the groups R2, R3, R4 and R5 represents an aryl group or a heteroaryl group (both of which are optionally substituted by one or more substituents selected from A) and:
a) the other groups are independently selected from hydrogen, G1, an aryl group, a heteroaryl group (which latter two groups are optionally substituted by one or more substituents selected from A), C1-8 alkyl and a heterocycloalkyl group (which latter two groups are optionally substituted by one or more substituents selected from G1 and/or Z1); and/or
b) any two other groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, a 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 4 1 to 3 double bonds, which ring is itself optionally substituted by one or more substituents selected from halo, —R8, —OR8 and ═O;
R6, R7 and R8 independently represent, on each occasion when used above:
I) hydrogen;
II) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B;
III) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1; or
R6 and R7 may be linked together to form along with the N atom and X group to which R6 and R7 are respectively attached, a 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from G1 and/or Z1;
A represents, on each occasion when mentioned above:
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B;
II) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally 20 substituted by one or more substituents selected from G1 and/or Z1;
III) a G1 group; or
IV) two A substituents may be linked together to form, along with at least two (e.g. adjacent) atoms of the aryl or heteroaryl group to which the two A substituents are attached, a further 3- to 5-membered ring, which ring optionally contains 1 to 3 hetereoatoms and/or 1 to 2 double bonds, and which is optionally substituted by halo or C1-8 alkyl, which latter group is optionally substituted by halo;
G1 represents, on each occasion when mentioned above, halo, cyano, —N3, —NO2, —ONO2 or -A1-R9;
wherein A1 represents a single bond or a spacer group selected from —C(O)A2-, —S(O)nA3-, —N(R10)A4- or —OA5-, in which:
A2 and A3 independently represent a single bond, —O—, —N(R10)— or —C(O)—;
A4 and A5 independently represent a single bond, —C(O)—, —C(O)N(R10)—, —C(O)O—, —S(O)n— or —S(O)nN(R10)—;
Z1 represents, on each occasion when mentioned above, ═O, ═S, ═NOR9, ═NS(O)nN(R10)(R9), ═NCN or ═C(H)NO2;
B represents, on each occasion when mentioned above:
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G2, methylenedioxy, difluoromethylenedioxy and/or dimethylmethylenedioxy;
II) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G2 and/or Z2;
III) a G2 group; or
IV) methylenedioxy, difluoromethylenedioxy or dimethylmethylenedioxy;
G2 represents, on each occasion when mentioned above, halo, cyano, —N3, —NO2, —ONO2 or -A6-R11;
wherein A6 represents a single bond or a spacer group selected from —C(O)A7-, —S(O)nA8-, —N(R12)A9- or —OA10-, in which:
A7 and A8 independently represent a single bond, —O—, —N(R12)— or —C(O)—;
A9 and A10 independently represent a single bond, —C(O)—, —C(O)N(R12)—, —C(O)O—, —S(O)n— or —S(O)nN(R12)—;
Z2 represents, on each occasion used above ═O, ═S, ═NOR11, when ═NS(O)nN(R12)(R11), ═NCN or —C(H)NO2;
R9, R10, R11 and R12 are independently selected from:
i) hydrogen;
ii) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G3, methylenedioxy, difluoromethylenedioxy and/or dimethylmethylenedioxy;
iii) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by G3 and/or Z3; or
any pair of R9 and R10, or R11 and R12, may, for example when present on the same or on adjacent atoms, be linked together to form with those, or other relevant, atoms a further 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from G3 and/or Z3;
G3 represents, on each occasion when mentioned above, halo, cyano, —N3, —NO2, —ONO2 or -A11-R13;
wherein A11 represents a single bond or a spacer group selected from —C(O)A12-, —S(O)nA13-, —N(R14)A14- or —OA15-, in which:
A12 and A13 independently represent a single bond, —O—, —N(R14)— or —C(O)—;
A14 and A15 independently represent a single bond, —C(O) . . . ; —C(O)N(R14)—, —C(O)O—, —S(O)n— or —S(O)nN(R14)—;
Z3 represents, on each occasion when mentioned above, ═O, ═S, ═NOR13, ═NS(O)nN(R14)(R13), ═NCN or ═C(H)N02;
n represents, on each occasion when mentioned above, 1 or 2;
R13 and R14 are independently selected from:
i) hydrogen;
ii) C1-6 alkyl or a heterocycloalkyl group, both of which groups are optionally substituted by one or more substituents selected from halo, C1-4 alkyl, —N(R15)(R16), —O(R15) and ═O; and
iii) an aryl or heteroaryl group, both of which are optionally substituted by one or more substituents selected from halo, C1-4 alkyl, —N(R15)(R16) and —O(R15); or
any pair R13 and R14 may, for example when present on the same or on adjacent atoms, be linked together to form with those, or other relevant, atoms a further 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from halo, C1-4 alkyl, —N(R15)(R16), —O(R15) and ═O;
R15 and R16 are independently selected from hydrogen and C1-4 alkyl, which latter group is optionally substituted by one or more halo groups;
or a pharmaceutically-acceptable salt thereof.

### Claim 2 (depends on 1)

A compound as claimed in claim 1, wherein:
A2 and A3 independently represent a single bond, —O— or —N(R10)—;
Z1 represents, on each occasion when mentioned above, ═O, ═NOR9, ═NS(O)nN(R10)(R9), ═NCN or ═C(H)NO2;
A7 and A8 independently represent a single bond, —O— or —N(R12)—;
Z2 represents, on each occasion when mentioned above, ═O, ═NOR11, ═NS(O)nN(R12)(R11), ═NCN or ═C(H)NO2;
A12 and A13 independently represent a single bond, —O— or —N(R14)—; and/or
Z3 represents, on each occasion when mentioned above, ═O, ═NOR13, ═NS(O)nN(R14)(R13), ═NCN or ═C(H)NO2.

### Claim 3 (depends on 2)

A compound as claimed in claim 2, wherein n represents 2.

### Claim 4 (depends on 1)

A compound as claimed in claim 1, wherein 5× represents a single bond or —C(O)—.

### Claim 5 (depends on 1)

A compound as claimed in claim 1, wherein A represents G1.

### Claim 6 (depends on 1)

A compound as claimed in claim 1, wherein G1 represents halo or -A1-R9.

### Claim 7 (depends on 1)

A compound as claimed in claim 1, wherein A1 represents a single bond, —OA5- or —N(R10)A4-.

### Claim 8 (depends on 1)

A compound as claimed in claim 1, wherein A4 and A5 independently represent a single bond.

### Claim 9 (depends on 1)

A compound as claimed in claim 1, wherein B represents G2.

### Claim 10 (depends on 1)

A compound as claimed in claim 1, wherein G2 represents halo or —OR11.

### Claim 11 (depends on 1)

A compound as claimed in claim 1, wherein R9 represents C1-6 alkyl, which group is optionally substituted by one or more halo groups, or a phenyl, or pyridyl group.

### Claim 12 (depends on 1)

A compound as claimed in claim 1, wherein RIO represents C1-2 alkyl.

### Claim 13 (depends on 1)

A compound as claimed in claim 1, wherein R11 represents C1-2 alkyl optionally substituted by one or more halo groups.

### Claim 14 (depends on 1)

A compound as claimed in claim 1, wherein R1 represents an optionally substituted phenyl or pyridyl group.

### Claim 15 (depends on 1)

A compound as claimed in claim 1, wherein R3 and R4 independently represent G1, hydrogen or an optionally substituted phenyl or pyridyl group.

### Claim 16 (depends on 15)

A compound as claimed in claim 15, wherein R3 and R4 independently represent hydrogen or an optionally substituted phenyl or pyridyl group.

### Claim 17 (depends on 1)

A compound as claimed in claim 1, wherein at least one of R3 and R4 represents optionally substituted phenyl or pyridyl, and up to one other represents 01 or hydrogen;

### Claim 18 (depends on 1, 15)

A compound as claimed in claim 15, wherein, when R3 or R4 represents an optionally substituted phenyl or pyridyl group, then the other substituents on the essential benzene ring of the indole of formula I, as defined in claim 1, (i.e. R2, R5 and R3 or R4 (as appropriate)) represent hydrogen or G1.

### Claim 19 (depends on 1)

A compound as claimed in claim 1, wherein R6 represents H or an optionally substituted C1-4 alkyl group.

### Claim 20 (depends on 1)

A compound as claimed in claim 1, wherein R7 represents an optionally substituted C1-4 alkyl group or an optionally substituted phenyl or pyridyl group.

### Claim 21 (depends on 1)

A compound as claimed in claim 1, wherein R6 and R7 are linked to form, together with the nitrogen atom and X group to which they are respectively attached, a 5- to 6-membered ring, optionally containing 1 to 2 heteroatoms.

### Claim 22 (depends on 14)

A compound as claimed in claim 14, wherein the optional substituents are selected from cyano, halo, C1-6 alkyl, which alkyl group may be linear or branched, cyclic, part-cyclic, unsaturated and/or optionally substituted with one or more halo group, and —OR17, wherein R17 represents, H or C1-6 alkyl (which alkyl group is optionally substituted by one or more halo groups).

### Claim 23 (depends on 22)

A compound as claimed in claim 22, wherein the optional substituents are selected from halo, C1•6 alkyl, which alkyl group may be linear or branched, cyclic, part-cyclic, unsaturated and/or optionally 20 substituted with one or more halo group, and _OR17, wherein R17 represents, H or C1-6 alkyl (which alkyl group is optionally substituted by one or more halo groups).

### Claim 24 (depends on 1)

A compound as claimed in claim 1, wherein R8 represents hydrogen.

### Claim 25 (depends on 1)

A compound as defined in claim 1, or a pharmaceutically-acceptable salt thereof, for use as a pharmaceutical.

### Claim 26 (depends on 1)

A pharmaceutical formulation including a compound as defined in claim 1 or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

### Claim 27 (depends on 1)

The use of a compound as defined in claim 1, or a pharmaceutically-acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease in which inhibition of the activity of microsomal prostaglandin E synthase-1, leukotriene C4 and/or 5-lipoxygenase-activating protein is desired and/or required.

### Claim 28 (depends on 27)

A use as claimed in claim 27, wherein inhibition of the activity of microsomal prostaglandin E synthase-1 is desired and/or required.

### Claim 29 (depends on 27)

A use as claimed in claim 27, wherein the disease is inflammation.

### Claim 30 (depends on 29)

A use as claimed in claim 29 wherein the disease is inflammatory bowel disease, irritable bowel syndrome, migraine, headache, low back pain, fibromyalgia, a myofascial disorder, a viral infection, a bacterial infection, a fungal infection, dysmenorrhea, a burn, a surgical or dental procedure, a malignancy, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, fever, ankylosing spondylitis, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, a neurodegenerative disorder, an autoimmune disease, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, an allergic disorder, rhinitis, an ulcer, coronary heart disease, sarcoidosis, inflammatory pain, hyperprostaglandin E syndrome, classic Bartter syndrome, Hodgkin's disease, persistent ductus, any other disease with an inflammatory component, Paget's disease or a periodontal disease.

### Claim 31 (depends on 1)

A method of treatment of a disease in which inhibition of the activity of mPGES-1, LTC4 and/or FLAP is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound as defined in claim 1, or a pharmaceutically-acceptable salt thereof, to a patient suffering from, or susceptible to, such a condition.

### Claim 32 (depends on 31)

A method as claimed in claim 31, wherein inhibition of the activity of mPGES-1 is desired and/or required.

### Claim 33 (depends on 1)

A combination product comprising:
(A) a compound as defined in claim 1, or a pharmaceutically-acceptable salt thereof; and
(B) another therapeutic agent that is useful in the treatment of inflammation, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

### Claim 34 (depends on 1, 33)

A combination product as claimed in claim 33 which comprises a pharmaceutical formulation including a compound as defined in claim 1, or a pharmaceutically-acceptable salt thereof, another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier.

### Claim 35 (depends on 1, 33)

A combination product as claimed in claim 33 which comprises a kit of parts comprising components:
(a) a pharmaceutical formulation including a compound as defined in claim 1, or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and
(b) a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of inflammation in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier,
which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

### Claim 36 (depends on 1)

A process for the preparation of a compound as defined in claim 1, which comprises:
(i) reaction of a compound of formula II,
wherein X, —R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 1, with a compound of formula II,
R1L1 III
wherein L1 represents a suitable leaving group and R1 is as defined in claim 1;
(ii) reaction of a compound of formula IV,
wherein L1 is as defined above and R1, R2, R3, R4, R5 and R8 are as defined in claim 1, with a compound of formula V,
HN(R6)XR7 V
wherein X, R6 and R7 are as defined in claim 1;
(iii) reaction of a compound of formula VI,
wherein L3 represents L1 or L2, in which L2 represents a suitable leaving group and is attached to one or more of the carbon atoms of the benzenoid ring of the indole, and wherein the remaining positions of the benzenoid ring are substituted with 1 to 3 (depending on the number of L3 substituents) R2-R5 substituents, R2-R5 represents anyone of the substituents, i.e. R2, R3, R4 and R5, that are already present in that ring (as appropriate), L1 is as defined above and X, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in claim 1, with a compound of formula VII,
R18L4 VII
wherein R18 represents R2, R3, R4 or R5 (as appropriate) and L4 represents L1 (when L3 is L2) or L2 (when L3 is L1) as defined above;
(iv) reaction of a compound of formula VIII,
wherein R1, R2, R3, R4, R5, R6 and R8 are as defined in claim 1, with a compound of formula IX,
R7XL1 IX
wherein L1 is as defined above and X and R7 are as defined in claim 1; or
(v) for compounds of formula I wherein X represents a single bond and R7 is a C1-8 alkyl group, reduction of a compound of formula I, wherein X represents —C(O)— and R7 represents H or a C1-7 alkyl group.