KR20070032264A - Compounds having crth2 antagonist activity - Google Patents

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts, hydrates, lysates, complexes and prodrugs thereof are useful for the treatment of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.

I

Wherein R ¹ , R ² , R ³ and R ⁴ are independently hydrogen, halo, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl),-CON (R ⁹ ) ₂ ,- SOR ⁹ , -SO ₂ R ⁹ , -SO ₂ N (R ⁹ ) ₂ , -N (R ⁹ ) ₂ , -NR ⁹ COR ⁹ , -CO ₂ R ⁹ , -COR ⁹ , -SR ⁹ , -OH, -NO ₂ or -CN;

Each R ⁹ is independently hydrogen or C ₁ -C ₆ alkyl;

R ⁵ and R ⁶ are each independently hydrogen or C ₁ -C ₆ alkyl, the carbon atom combines with C ₃ -C ₇ cycloalkyl;

R ⁷ is hydrogen or C ₁ -C ₆ alkyl

n is 1 or 2;

X is a bond or n is 2 and X is also NR ⁹ ;

Wherein R ⁹ is as defined above;

If X is a bond, R ⁸ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, biphenyl or a 9-14 membered bicyclic or tricyclic heteroaryl group;

If X is NR ⁹ then R ⁸ is additionally phenyl, naphthyl, or a 5-7 membered heteroaromatic ring; And

R ⁸ is halo, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ ) alkyl, aryl, —O-aryl, heteroaryl, —O-heteroaryl, CON (R ⁹ ) ₂ , -SOR ⁹ , -SO ₂ R ⁹ , SO ₂ N (R ⁹ ) ₂ , -N (R ⁹ ) ₂ , -NR ⁹ COR ⁹ , -CO ₂ R ⁹ , -COR ⁹ , -SR ⁹ , -OH, -NO ₂ Also Optionally substituted with one or more substituents selected from the group consisting of -CN;

Wherein R ⁹ is as defined above.

CRTH2, prostaglandin D2 (prostaglandin D2, PGD2)

Description

Compound having an antagonistic effect on a pseudoreceptor inducer expressed in helper cell-2 {COMPOUNDS HAVING CRTH2 ANTAGONIST ACTIVITY}

The present invention provides a compound useful as a drug, a method for preparing the compound, a composition comprising the compound and an inducer of cellularity such as asthma, allergic rhinitis and atopic dermatitis and eosinophils, basophils and helper-2 (Th ₂ ) lymphocytes. It relates to the use for the prevention and treatment of other inflammatory diseases mediated by prostaglandin _{D 2 (prostaglandin D 2, PGD} 2) acting in a homogeneous molecular receptor.

PGD ₂ is an eicosanoid, a chemical mediator synthesized by cells in response to local tissue damage, conventional stimulation or hormonal stimulation, or through cell activation pathways. Eicosanoids bind specific cell surface receptors on a wide variety of tissues throughout the body and mediate various effects within these tissues. PGD ₂ is known to be produced by mast cells, macrophages and helper-2 (Th ₂ ) lymphocytes and is found at high concentrations in the airways of asthma patients that have been immunogenicly tested (Murray et al , (1986), N. Engl . J. Med . 315 : 800-804. Infusion of PGD ₂ into the airways was confirmed by airway contraction (Hardy et al , (1984) N. Engl . J. Med . 311 : 209-213; Sampson et al , (1997) Thorax 52 : 513-518) and emery accumulation. et al , (1989) J. Appl . Physiol . 67 : 959-962).

Translocation of exogenously applied PGD ₂ to elicit an immune response is a gene that overexpresses PGD ₂ synthase in humans with excessive eosinophilic lung inflammation and helper cell-2 (Th ₂ ) cytokine products for antigen This was confirmed by the use of transgenic mice. Fujitani et al , (2002) J. Immunol . 168 : 443-449)

The first receptor specific for PGD ₂ was the DP receptor associated with enhancement of intracellular levels of cAMP. However, PGD ₂ interacts with the G protein-coupled receptor called CRTH2 (a pseudoreceptor-inducing molecule expressed on helper cell-2 (Th ₂ )) expressed by helper-2 (Th ₂ ) lymphocytes, eosinophils and basophils. It is known to mediate many preinflammatory activities through action (Hirai et al , (2001) J. Exp . Med . 193 : 255-261, and EP0851030 and EP-A-1211513 and Bauer et al , EP-A- 1170594). It is clear that the effect of PGD ₂ on the activity of helper-2 (Th2) lymphocytes and eosinophils is mediated through CRTH2 because the selective CRTH2 agonist 13,14 dihydro-15-keto-PGD ₂ (dihydro-15 -keto-PGD ₂ ) (DK-PGD ₂ ) and 15R-methyl-PGD ₂ (15R-methyl-PGD ₂ ) can elicit this reaction and the effect on PGD ₂ is blocked by antiCRTH2 antibodies (Hirai et al , 2001; Monner et et al , (2003) J. Pharmacol . Exp . Ther . 304 : 349-355). Based on this evidence, PGD ₂ antagonizing at the CRTH2 receptor is an attractive approach for treating the inflammatory components of helper cell-2 (Th ₂ ) -dependent allergic diseases such as asthma, allergic rhinitis and atopic dermatitis. .

EP-A-1170594, a related compound that can be used to determine compounds useful for the treatment of allergic asthma, atopic dermatitis, allergic rhinitis, autoimmune diseases, reperfusion injury and many inflammatory diseases mediated by the activity of PGD ₂ at the CRTH2 receptor A method is disclosed.

 Compounds that bind CRTH2 are disclosed in WO-A-03066046 and WO-A-03066047. This compound is not new but is first described with similar compounds disclosed in GB 1356834, GB 1407658 and GB 1460348 as anti-inflammatory, analgesic and antipyretic agents. In WO-A-03066046 and WO-A-03066047, the compounds involved are mediators of CRTH2 receptor activity, so asthma, chronic obstructive pulmonary disease (COPD) and various bone and joint diseases, skin and eyes, gastrointestinal tract, central and peripheral nervous system And it is disclosed that it is useful for the treatment and prevention of obstructive airway diseases such as transplant organs as well as many other diseases including other tissue rejection. The compounds disclosed in this document are indoles having a carboxylic acid group at the 3 position of the indole ring and a quinoline, quinazoline or benzothiazole group at the 1 position.

The present invention relates to novel compounds that bind to CRTH2 and are useful for the treatment of diseases mediated by PGD ₂ activity at the CRTH2 receptor.

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, complex or prodrug thereof.

I

R in the above formula^One, R², R³ And R⁴ Is independently hydrogen, halo, C_One-C₆ Alkyl, -O (C_One-C₆ alkyl),-CON (R⁹)₂, -SOR⁹, -SO₂R⁹, -SO₂N (R⁹)₂, -N (R⁹)₂, -NR⁹COR⁹, -CO₂R⁹, -COR⁹, -SR⁹, -OH, -NO₂ Or -CN;

Each R ⁹ is independently hydrogen or C ₁ -C ₆ alkyl;

R ⁵ and R ⁶ are each independently hydrogen or a C ₃ -C ₇ cycloalkyl group bonded to a C ₁ -C ₆ alkyl or carbon atom;

R ⁷ is hydrogen or C ₁ -C ₆ alkyl

n is 1 or 2;

X is a bond or, if n is 2, X can also be NR ⁹ ;

R ⁹ is as defined above;

If X is a bond, R ⁸ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, biphenyl or a 9-14 membered bicyclic or tricyclic heteroaryl group;

If X is NR ⁹ then R ⁸ is additionally phenyl, naphthyl, or a 5-7 membered heteroaromatic ring; And

R ⁸ is halo, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ ) alkyl, aryl, —O-aryl, heteroaryl, —O-heteroaryl, CON (R ⁹ ) ₂ , -SOR ⁹ , -SO ₂ R ⁹ , SO ₂ N (R ⁹ ) ₂ , -N (R ⁹ ) ₂ , -NR ⁹ COR ⁹ , -CO ₂ R ⁹ , -COR ⁹ , -SR ⁹ , -OH, -NO ₂ or Optionally substituted with one or more substituents selected from the group consisting of -CN;

R ⁹ is as defined above.

Compounds of formula (I) are PGD ₂ antagonists at the CRTH2 receptor and are useful for the treatment of diseases mediated by PGD ₂ binding to CRTH2. The diseases are allergic, asthma and inflammatory diseases such as allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis), conjunctivitis, especially allergic conjunctivitis, eosinophilic bronchitis , Food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative proctitis and Crohn's disease, mastocytosis and other PGD ₂ -mediated diseases such as rheumatoid arthritis, psoriatic arthritis and osteoarthritis, as well as hyper IgE syndrome Autoimmune diseases such as systemic lupus erythematosus, psoriasis, acne, multiple sclerosis, organ rejection, reperfusion injury and chronic obstructive pulmonary disease.

Similar but not identical compounds are disclosed in WO-A-9950268. This compound is different from the compound of the present invention which does not contain a portion of sulfone / sulfonamide which is bound to the 3-position of the indole ring. Moreover, the compounds are not disclosed to be useful for the treatment of diseases such as asthma and allergic diseases mediated by PGD ₂ . Rather, the compounds have been described as useful for the treatment of complications that result from diabetes.

PL 65781 and JP 43-24418 are also for indole derivatives. However, the compounds described in both documents differ from the compounds of the present application in that they are indole N-sulfonamides rather than 3-sulfones or 3-sulfonamides such as the compounds of the present invention. The compounds described in PL 65781 and JP 43-24418 are similar in structure to indomethacin, and have inflammatory and antipyretic activities, like indomethacin. Therefore, although the above contents are not known at the time the document is published, the compounds described in the document are COX (cyclooxynase) inhibitors with activities different from those of the compounds of the present invention. Moreover, COX (cyclooxynase) inhibitors are sometimes contraindicated in the treatment of many diseases, such as asthma and inflammatory bowel disease, although sometimes used to treat joint diseases, in which the compounds of the present invention are useful.

Compounds that bind to the CRTH2 receptor are disclosed in WO-A-03 / 097042 and WO-A-03 / 097598. This compound is indole acetic acids but in WO-A-03 / 097042 the indole system is attached at the 2 to 3 position of the 5 to 7 membered carboxylic ring. In WO-A-03 / 097598 there is a pyrrolidine group in the indole 3-position.

WO-A-03 / 101981 and WO-A-03 / 101961 are both for CRTH2 agonists. The compounds described in WO-A-03 / 101961 are similar in structure to the compounds of the invention wherein X is a bond. The compound differs from general formula (I) because there is an —S— group bonded to the indole 3-position at the position of the SO or SO ₂ group of the compound of general formula (I). Moreover, the same group as the R ⁸ group in the compound of formula (I) is an aryl group or heteroaryl group. There is no aliphatic compound substituent at the same position as the compound of formula (I). Although the compound has a high intrinsic activity, it has been found to be less suitable for use as a medicament than the compound of the present invention. This is because certain compounds of WO-A-03 / 101961 are inhibitors of cytochrome P450s and this is closely related to the metabolism of any pharmaceutical agent administered with the compound. In contrast, the inventors of the present invention show that the compounds of the present invention do not inhibit cytochrome P450s. In addition, preliminary binding experiments indicate that the sulfide compounds described in WO-A-03 / 101961 bind human eosinophils at a slow rate, which may lead to an unexpected persistence of activity.

WO-A-03 / 10981 discloses that the substituents at the 3-position of the indole ring system have SO, SO ₂ or SO ₂ NR ⁹ as in the compounds of formula (I). Phenyl, naphthyl or heteroaryl groups without a linking agent. Clearly, inclusion of the linking group appears to have a substitutional effect on the activity of the compound. Moreover, the substituent at the indole 3-position cannot be an aliphatic compound as in the present invention.

WO-A-2004 / 007451 relates to a compound of the present invention in that X is a bond, except that the same group as the R ⁸ group of the compound of formula (I) is a phenyl, naphthyl or 5-7 membered heteroaromatic group. For a similar CRTH2 inhibitor in structure. In fact, all illustrated compounds have a phenyl group substituted at this position. This is clearly different from the compounds of the present invention wherein the R ⁸ group is a bicyclic or tricyclic heteroaromatic ring or an alkyl, alkenyl or alkynyl group. Compounds containing alkyl, alkenyl and alkynyl groups have proved to be very active as they differ markedly in structure from the compounds of the prior art.

As used herein, "C ₁ -C ₆ alkyl" is a linear or branched saturated hydrocarbon having 1 to 6 carbon atoms and optionally substituted with one or more halo substituents or one or more C ₃ -C ₇ cycloalkyl groups. Say the chain. Examples are methyl, ethyl, n-propyl, isopropyl, t-butyl, n-hexyl, trifluoromethyl, 2-chloroethyl, methylenecyclopropyl, methylenecyclobutyl, and methylenecyclopentyl.

"C ₁ -C ₄ alkyl" and "C ₁ -C ₁₈ alkyl" have a similar meaning except that they have 1 to 4 and 1 to 18 carbon atoms.

C ₃ -C ₇ cycloalkyl refers to a saturated 3 to 7 membered carbocyclic ring. Examples of such functional groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The terms "C ₂ -C ₆ alkenyl" and "C ₂ -C ₆ alkynyl" have 2 to 6 carbon atoms and include at least one carbon-carbon double bond or at least one carbon-carbon triple bond It refers to a saturated hydrocarbon chain of linear or branched form. Like the alkyl groups, the compounds are optionally substituted with one or more halo substituents or one or more C ₃ -C ₇ cycloalkyl groups.

As used herein, "halo" refers to fluoro, chloro, bromo or iodo.

In the context of the present specification, "aromatic moiety" and "aryl" refer to an aromatic ring having 5 to 14 ring carbon atoms and containing up to three rings. Examples of aromatic moieties are benzene and naphthalene. The aryl group is substituted with one or more substituents selected from halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 5-7 membered heterocyclic ring or SO ₂ R ⁹ , wherein R ⁹ is defined above As it is.

The terms "heteroaromatic moiety" and "heteroaryl" refer to aromatic rings in which at least one ring carbon atom is replaced with a nitrogen, oxygen or sulfur atom. Examples include monocyclic systems such as pyridine, pyrimidine, pyrazole, thiophene, oxazole and isoxazole. Other examples include conjugated ring systems such as quinoline, isoquinoline, quinazoline, benzthiazol, benzozolazole, benzimidazole and indole groups.

Unless stated otherwise, heteroaromatic moieties have carbon atoms in the 5 to 14 ring positions but for example “5 to 7 membered heteroaromatic rings” contain atoms in the 5 to 7 ring positions. Bicyclic and tricyclic heteroaryl groups have two or three conjugated rings. For example, bicyclic heteroaryl groups are 6,6- or 6-5-ring systems as exemplified above.

Like aryl groups, heteroaryl groups are also substituted with one or more substituents selected from halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 5-7 membered heterocyclic ring or SO ₂ R ⁹ And R ⁹ is as defined above.

The term "5-7 membered heterocyclic ring" refers to a non-aromatic ring system having ring atoms in the 5-7 position and at least one ring carbon atom replaced with a nitrogen, oxygen or sulfur atom. Examples include piperidine, morpholine, imidazoline, pyperazine and terahydrofuran.

Salts of the compounds having formulas (I) and (II) which are pharmaceutically suitable and veterinarily acceptable are sodium, potassium, as well as crawlin, diethanolamine, ethanolamine, ethyl diamine and other well-known basic addition salts. There are basic addition salts, such as calcium, aluminum, zinc, magnesium and other metal salts.

The pharmaceutically suitable and veterinary acceptable salts include acetic acid, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, Benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropio , Picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorrate, undecanoate and succinate, organic sulfate-methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfo , Camphorsulfonate, 2-naphthalenesulfonate, benzenesulfonate, p-chlorobenzenesulfonate And p-toluenesulfonate; Inorganic acids-hydrochloric acid, hydrobromide, hydroiodide, sulfates, bisulfates, hemisulfates, in particular carboxylic acids.

Pharmaceutically or veterinary unacceptable salts are valuable as intermediates.

Prodrugs are covalent compounds which release the active parent drug in vivo by formula (I). Examples of prodrugs include alkyl esters of compounds of formula (I), for example esters of formula (II) below.

 If other forms of chiral centers or isomeric centers are present in the compounds of the invention, it is meant that all forms of isomers, including enantiomers and diastereomers, are included here. Compounds of the invention comprising chiral centers are used as racemic mixtures, mixtures rich in enantiomers, or racemic mixtures separated using well known techniques, and each enantiomer is used on its own.

In the compound of general formula (I), on its own or:

R ¹ is halo or hydrogen;

R ² is halo or hydrogen;

R ³ is halo or hydrogen;

R ⁴ is preferably in combination with either halo or hydrogen.

More preferably in the compound, R ¹ , R ³ and R ⁴ are hydrogen and R ² is halo, in particular fluoro.

In a preferred compound of formula (I), R ⁵ and R ⁶ are each independently hydrogen or C ₁ -C ₄ alkyl. However, the more active compound is at least one and preferably both hydrogen of R ⁵ and R ⁶ .

The compound of formula (I) preferably comprises a R ⁷ group selected from H or C ₁ -C ₆ alkyl; Most preferably R ⁷ is methyl.

Especially preferably, in the compound of general formula (I), n is 2.

When X is a bond, R ⁸ is C ₁ -C ₆ alkyl, biphenyl or bicyclic hetero, wherein one is substituted with halogen, phenyl, -CO ₂ R ⁹ CON (R ⁹ ) ₂ or -SO ₂ R ⁹ Is an aryl group and R ⁹ is as defined above.

More preferably, in a compound wherein X is a bond, R ⁸ is C ₁ -C ₄ alkyl, biphenyl, or bicy, which is substituted with phenyl, -CO ₂ R ⁹ CON (R ⁹ ) ₂ or -SO ₂ R ⁹ It is a click heteroaryl group and R ⁹ is as defined above.

When X is NR ⁹ , preferably R ⁹ is H or methyl and R ⁸ is:

One or more halo, phenyl partially substituted with C ₁ -C ₆ alkyl or —O (C ₁ -C ₆ alkyl) groups;

C ₁ -C ₆ alkyl, partially substituted with aryl; or

Heteroaryl.

More preferably, when X is NR ⁹ il R ⁸ is a group which is substituted by phenyl, benzyl or pyridyl, one or more halo, methyl or methoxy group and optionally.

Most preferred compounds are as follows.

1. [3- (Butane-1-sulfonyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (Butane-1-sulfonyl) -5-fluoro-2-methyl -indol-1-yl] -acetic acid)

2. [3- (Biphenyl-4-sulfonyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid (3- (Biphenyl-4-sulfonyl) -5-fluoro-2-methyl -indol-1-yl] -acetic acid)

3. [(3-carboxymethanesulfonyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid ((3-Carboxymethanesulfonyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid)

4. [(3-Carbamoylmethanesulfonyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid (3-Carbamoylmethanesulfonyl-5-fluoro-2-methyl-indol-1-yl)- acetic acid)

5. [5-Fluoro-3- (2-methanesulfonyl-ethanesulfonyl) -2-methyl-indol-1-yl] -acetic acid ([5-Fluoro-3- (2-methanesulfonyl-ethanesulfonyl)- 2-methyl-indol-1-yl] -acetic acid)

6. [3- (Benzothiazole-2-sulfonyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (Benzothiazole-2-sulfonyl) -5-fluoro-2 -methyl-indol-1-yl] -acetic acid)

7. [3- (bentothiazole-2-sulfinyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (Benzothiazole-2-sulfinyl) -5-fluoro-2 -methyl-indol-1-yl] -acetic acid)

8. [5-Fluoro-2-methyl] -3- (quinolin-2-sulfonyl) -indol-1-yl] -acetic acid ([5-Fluoro-2-methyl-3- (quinoline-2-sulfonyl ) -indol-1-yl] -acetic acid)

9. [5-Fluoro-2-methyl] -3- (quinolin-8-ylsulfonyl) -indol-1-yl] -acetic acid ([5-Fluoro-2-methyl-3- (quinolin-8-ylsulfonyl ) -indol-1-yl] -acetic acid)

10. (5-Fluoro-2-methyl-3-phenylmethanesulfonyl] -1H-indol-1-yl) -acetic acid ((5-Fluoro-2-methyl-3-phenylmethanesulfonyl-1H-indol-1- yl) -acetic acid)

11. [3- (4-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (4-Chloro-phenylsulfamoyl) -5-fluoro-2- methyl-indol-1-yl] -acetic acid)

12. [3- (3-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (3-Chloro-phenylsulfamoyl) -5-fluoro-2- methyl-indol-1-yl] -acetic acid)

13. [3- (4-Fluoro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (4-Fluoro-phenylsulfamoyl) -5-fluoro-2 -methyl-indol-1-yl] -acetic acid)

14. [3- (2-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (2-Chloro-phenylsulfamoyl) -5-fluoro-2- methyl-indol-1-yl] -acetic acid)

15. (3-Benzylsulfamoyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid ((3-Benzylsulfamoyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid)

16. [5-Fluoro-3- (2-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic acid ([5-Fluoro-3- (2-methoxy-phenylsulfamoyl) -2 -methyl-indol-1-yl] -acetic acid)

17. [5-Fluoro-3- (4-methoxy-phenylsulfamoyl) 2-methyl-indol-1-yl] -acetic acid ([5-Fluoro-3- (4-methoxy-phenylsulfamoyl) -2- methyl-indol-1-yl] -acetic acid)

18. (5-Fluoro-2-methyl-3-phenylsulfamoyl-indol-1-yl) -acetic acid ((5-Fluoro-2-methyl-3-phenylsulfamoyl-indol-1-yl) -acetic acid)

19. [3- (3,4-Dichloro-benzylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (3,4-Dichloro-benzylsulfamoyl) -5- fluoro-2-methyl-indol-1-yl] -aceticacid)

20. [5-Fluoro-3- (3-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic acid ([5-Fluoro-3- (3-methoxy-phenylsulfamoyl) -2 -methyl-indol-1-yl] -acetic acid)

21. (5-Fluoro-2-methyl-3-m-tolylsulfamoyl-indol-1-yl) -acetic acid ((5-Fluoro-2-methyl-3-m-tolylsulfamoyl-indol-1-yl) -acetic acid)

22. (5-Fluoro-2-methyl-3-p-tolylsulfamoyl-indol-1-yl) -acetic acid ((5-Fluoro-2-methyl-3-p-tolylsulfamoyl-indol-1-yl) -acetic acid)

23. [3- (4-Chloro-benzylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (4-Chloro-benzylsulfamoyl) -5-fluoro-2- methyl-indol-1-yl] -acetic acid)

24. [3- (Benzyl-methyl-sulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (Benzyl-methyl-sulfamoyl) -5-fluoro-2-methyl -indol-1-yl] -acetic acid)

25. [5-Fluoro-2-methyl-3- (pyridin-3-ylsulfamoyl) -indol-1-yl] -acetic acid ([5-Fluoro-2-methyl-3- (pyridin-3-ylsulfamoyl ) -indol-1-yl] -acetic acid);

Or C ₁ -C ₆ alkyl, aryl, (CH ₂ ) mOC (═O) C ₁ -C ₆ alkyl, (CH ₂ ) mN (R ¹¹ ) ₂ , CH ((CH ₂ ) mO (C═O) R ¹² ) any one of _two esters;

Wherein m is 1 or 2;

R ¹¹ is hydrogen or methyl;

R ¹² is C ₁ -C ₁₈ alkyl.

Another object of the present invention is to provide a compound of formula (II). :

Ⅱ

Ⅱ

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , n, X, R ⁷ and R ⁸ are as defined in general formula (I); R ¹⁰ Is C ₁ -C ₆ Alkyl, aryl, (CH ₂ ) _m OC (= 0) C ₁ -C ₆ Alkyl, (CH ₂ ) _m N (R ¹¹ ) ₂ , CH ((CH ₂ ) _m O (C═O) R ¹² ) ₂ ;

   m is 1 or 2;

R ¹¹ is hydrogen or methyl;

R ¹² is C ₁ -C ₁₈ alkyl.

Compounds of formula (II) are new and used as prodrugs for compounds of formula (I). When the compound of formula (II) acts as a prodrug, it is converted into a drug after the action of the esterase in the blood or in the patient's tissue.

Examples of suitable R ¹⁰ when the compound of formula (II) is used as prodrug are methyl, ethyl, propyl, phenyl, CH ₂ OC (═O) tBu, CH ₂ CH ₂ N (Me) ₂ CH ₂ CH ₂ NH ₂ Or CH (CH ₂ O (C = O) R ¹² ) ₂ , wherein R ¹² Is as defined above.

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , n, X, R ⁷ and R ⁸ are as defined in general formula (I), X is one bond of the compound of general formula (I), n is 0, X is one bond From a compound of formula (Ia), a compound of formula (I), to a suitable oxidizing agent such as potassium peroxymonosulfate, m-CPBA, hydrogen peroxide or other well-known oxidation reagents Combined by oxidation.

In addition, as well as prodrugs, compounds of formula (II) wherein R ¹⁰ is C ₁ -C ₆ alkyl will be used in the process for the combination of compounds of formula (I), which process is formula (II) Compound of the reaction with a base such as sodium hydroxide or lithium hydroxide (lithium hydroxide). This reaction takes place in an aqueous or organic solvent or a mixture of both. Representative solvents used in this reaction are mixtures of tetrahydrofuran and water. The same method is used to combine the compound of general formula (Ia) from the compound of general formula (IIa) as defined above. The compound of formula (IIa) is the same as the compound of formula (II) except that n is 0.

Compounds of formula (II) and (IIa), wherein X is a bond, are combined by reacting a compound of formula (III) with a compound of formula (IV).

                                       Ⅲ

Where R ¹ , R ² , R ³ , R ⁴ , R ⁷ and R ⁸ Is as defined in formula (I) and n is 0, 1 or 2.

X-CR ⁵ R ⁶ -CO ₂ R ¹⁰ (IV)

R ⁵ and R ⁶ are defined in formula (I), R ¹⁰ is defined in formula (II), and X is a halo group such as bromo among leaving groups. This reaction takes place in strong basic conditions such as, for example, excess sodium hydride and polar organic solvents such as dimethylformamide.

Compounds of formula (IV) are well known and readily available or may be combined by methods well known to those skilled in the art.

R ¹ , R ² , R ³ , R ⁴ , R ⁷ and R ⁸ Are as defined in formula (I), and compounds of formula (III) wherein n is 2 can be combined by reacting a compound of formula (V) with a compound of formula (VI).

Ⅴ

Where R ¹ , R ² , R ³ , R ⁴ , R ⁷ Is as defined in formula (I).

R ⁸ -SO ₂ Cl (VI)

Wherein R ⁸ is as defined in formula (I).

This reaction occurs when a Lewis acid such as indium (III) bromide is encountered. This reaction is treated in polar organic solvents, especially chlorinated solvents such as 1,2-dichloroethane.

Compounds of formulas (V) and (VI) are well known in the art and readily available or can be combined by known methods.

Compounds of formula (II) wherein X is NR ⁹ are combined from compounds of formula (VII).

Ⅶ

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined in formula (I) and R ¹⁰ is reacted with a compound of formula (VII) As defined in

HNR ⁸ R ⁹ (Ⅷ)

R ⁸ here And R ⁹ are already defined in formula (I).

This reaction solvent is a polar organic solvent such as dichloromethane.

Compounds of general formula are well known and readily available and may be combined by methods well known to those skilled in the art.

Compounds of formula IV are combined by reacting compounds of formula X with chlorosulfonic acid.

                              Ⅸ

Where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ Is defined in formula (I) and R ¹⁰ is as defined in formula (II).

This reaction is preferably carried out in a nonpolar organic solvent.

Compounds of general formula are well known and readily available or may be combined by methods well known to those skilled in the art.

R ¹ , R ² , R ³ , R ⁴ , R ⁷ And R ⁸ Are as defined for formula (I) and compounds of formula (III) wherein n is oxygen (O) are R ¹ , R ² , R ³ , R ⁴ , R ⁷ R ¹⁰ is combined by reacting a compound of formula (VII) with a compound of formula (VII) as defined in formula (I) and in formula (II).

R ⁸ -SH (X)

Wherein R ⁸ is defined in general formula (I).

This reaction occurs in the presence of iodine and potassium iodide. This reaction takes place in an aqueous solution, an organic solvent or a mixture of both. Representative solvents used for this reaction are mixtures of ethanol and water.

The compound of formula (I) is an antagonist of PGD ₂ at the CRTH2 receptor and formula (II) is a prodrug for the compound of formula (I). Therefore, the compounds of formulas (I) and (II) may be administered to patients in need of treatment for the treatment of diseases mediated by PGD ₂ in the CRTH2 receptor, in appropriate amounts of the compounds of formula (I) or (II). It is useful for the method.

A third object of the present invention is about a drug, in particular CRTH2 It provides compounds of formulas (I) and (II) for use as drugs for the prevention and treatment of PGD ₂ mediated diseases in the receptor.

Furthermore, the present invention provides the use of the compounds of the formulas (I) and (II) in the preparation of a medicament for use in the prevention or treatment of PGD ₂ mediated diseases in the CRTH2 receptor.

The diseases mentioned above are allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis), conjunctivitis, especially allergic conjunctivitis, eosinophilic bronchitis, food allergy, eosinophilic gastroenteritis, inflammatory bowel Diseases, ulcerative proctitis and Crohn's disease, mastocytosis and other PGD ₂ -mediated diseases such as rheumatoid arthritis, psoriatic arthritis and osteoarthritis, as well as autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematosus , Psoriasis, acne, multiple sclerosis, transplant rejection, reperfusion injury, and chronic obstructive pulmonary disease.

Compounds of formula (I) or (II) are formulated in appropriate ways depending on the diseases in need of treatment.

It is therefore another object of the present invention to provide a pharmaceutical composition comprising the compounds of formulas (I) and (II) together with pharmaceutical additives or carriers. Other active ingredients may be present that are considered suitable or desirable for the prevention or treatment of the disease.

The carrier, or, if present, at least one, must be acceptable in terms of compatibility with the other components of the formulation and must not be harmful to the recipient.

This preparation is oral, rectal, nasal, bronchial (inhaled), topical (including tears, mouth, under tongue), vaginal or parenteral (subcutaneous, intramuscular, intravenous, intradermal) And those suitable for administration, including those well known in the art of pharmacy.

The route of administration will depend on the disease to be treated but the preferred compositions are formulated for oral, nasal, bronchial or topical administration.

This composition is prepared by combining the active agent as defined above with a carrier. In general, the preparations are prepared by uniformly and intimately binding the active agent with a liquid carrier, a finely divided solid carrier, or both, and if so, it is necessary to shape the product. The present invention extends to methods of preparing pharmaceutical compositions consisting of novel compounds of general formula (I) or (II) together with or in combination with pharmaceutically or veterinary acceptable carriers or excipients.

Formulations for oral administration in the present invention are as follows:

Discrete units such as capsules, circuits or tablets each containing a precalculated amount of the active agent; Powdered medicines or granules; Liquid solutions or suspensions of active agents dissolved in water-soluble or insoluble liquids; Emulsions; Or large pills etc.

“Acceptable carriers” for compositions for oral administration (eg tablets, capsules) include excipients, such as binders such as syrups, gum arabic, gelatin, sorbitol, tragacanth rubber, polyvinylpyrroly Pig (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; Fillers and carriers such as corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, calcium phosphate, sodium chloride and alginic acid; And common additives such as lubricants such as magnesium stearate, sodium stearate, and other stearic acid metals, glycerol stearic acid stearic acid, silicone fluid, talc wax, oils and colloidal anhydrous silicic acid. Flavorings may also be used, such as peppermint, camellia oil, cherry flavor and the like. It is desirable to add a pigment so that the dosage form can be easily identified. Tablets are also coated by methods well known in the art.

Tablets are optionally made by compression or molding with one or more accessory ingredients. Compressed tablets are prepared by compressing in a suitable machine active agents in free flowing form, such as powders or granules, optionally mixed with fixatives, lubricants, inert diluents, preservatives, surfactants or dispersants. Molded tablets are made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets are optionally coated or golded and formulated to release slowly or inhibited active agent.

Other formulations suitable for oral administration include medicinal drops comprising an active agent in fragrant ingredients, usually sucrose and gum arabic or tragacanth gum; Candy comprising an active agent in gelatin and glycerin or sucrose and gum arabic; And mouthwashes comprising the active agent in a suitable liquid carrier.

As a topical external preparation to the skin, the compounds of formula (I) or (II) should be made into creams, ointments, jelly, solutions or suspensions, and the like. Cream or ointment preparations for use as medicines are traditional preparations well known in the art as described in standard textbooks of pharmacy, for example the British Pharmacopoeia.

Compounds of general formula (I) or (II) may be used in the Will be used for treatment. Pharmaceutical compositions with powder-dispersion properties generally comprise not only the active ingredient but also liquid compressive inert gases with boiling points below room temperature and adducts such as liquid or solid nonionic or anionic surfactants and / or diluents. Pharmaceutical compositions in which the pharmaceutically active ingredient is dissolved in solution, as well as contain a suitable (in spray) compressed inert gas and, if necessary, additional solvents and / or stabilizers. Compressed air can also be used instead of the compressed inert gas, which makes it possible to produce as required by suitable compression means and expansion devices.

Parenteral preparations will generally be sterilized.

In general, a single dose of the composite will be about 0.01 mg to 100 mg per Kg; This is to maintain the concentration of the drug in plasma (plasma) at an effective concentration to inhibit PGD ₂ in the CRTH2 receptor. The exact amount of a compound of general formula (I) or (II) that is effective for treatment and the route of best administration of this compound are conventional techniques in the art by comparing the blood levels of the drug with the concentrations required to have a therapeutic effect. Is easily determined by

Compounds of general formula (I) or (II) may comprise one or more active agents useful in the treatment of the diseases or disorders listed above, and although these active agents are not necessarily inhibitors of PGD ₂ at the CRTH ₂ receptor, Used together.

Therefore, the pharmaceutical compositions described above additionally comprise one or more active agents.

There is also provided the use of a compound of formula (I) or (II) in the preparation of a medicament for the treatment of diseases mediated by PGD ₂ at the CRTH2 receptor, the medicament also being a useful addition for the treatment of the same diseases. Contains active agents.

These additional active agents, in a completely different way of action, include the following existing therapies for allergies and other inflammatory diseases:

Β2 agonists such as salmeterol;

Corticosteroids such as fluticasone;

Antihistamines such as loratidine;

Leukotriene antagonists such as montelukast;

Anti-IgE antibody therapies such as omalizumab;

Antibacterial agents such as fusidic acid (particularly for treating atopic dermatitis);

Antifungal agents such as clotrimazole (particularly for the treatment of atopic dermatitis);

Immunosuppressants such as tacrolimus and pimecrolimus, especially for inflammatory skin diseases.

CRTH2 antagonists also combine with the following therapies that progress in inflammatory signs:

Other antagonists of PGD ₂ that act on other receptors, such as DP antagonists;

Inhibitors of phosphodiesterase type 4 such as cyronilast;

전환 효소(TACE) 억제제와 같은 사이토카인(cytokine) 생산을 조절하는 약제;TNF

Agents that regulate cytokine production, such as converting enzyme (TACE) inhibitors;

Th ₂ such as interfering monoantibodies and soluble receptors Agents that modulate the activity of cytokines IL-4 and IL-5;

항진제;PPAR- such as rosiglitazone

Antitussives;

5-lipoxygenase inhibitors such as zileuton.

Moreover, in another aspect of this invention, one or more of the above-listed preparations combined as simultaneous, independent, or ordered doses in treating a disease or condition mediated by the action of PGD ₂ at the CRTH2 receptor Provided are products comprising drugs and new compounds of general formula (I) or (II).

The invention will now be described in more detail with reference to the following non-limiting examples and figures.

Figure 1 shows the effect of CRTH2 agonists on calcium migration in CHO / CRTH2 cells.

Example 1 Synthesis of 3-Sulfonyl Indole Derivative (Method A)

1.Synthesis of 3- (butane-1-sulfonyl) -5-fluoro-2-methyl-1H-indole (3- (Butane-1-sulfonyl) -5-fluoro-2-methyl-1H-indole)

5-fluoro-2-methylindole (50 mg, 0.34 mmol) and butanesulfonyl chloride in 1,2-dichloroethane (2 ml) at room temperature Indium bromide (III) (94.7 mg, 0.267 mmol) was added to the well mixed solution of butanesulfonyl chloride (418 mg, 2.67 mmol) at once. The mixture was placed in microwave conditions (85 ° C., 150 W) for 45 minutes, cooled at room temperature and concentrated in vacuo to a brown residue. Purified by flash column chromatography using silica gel using 10% ethyl acetate: hexane solution to 100% ethyl acetate solution as eluent to obtain sulfon (55 mg, 15%) as an off-white solid. Got it.

2. [3- (Butane-1-sulfonyl) -fluoro-2-methyl-indol-1-yl] -acetic acid) ([3- (Butane-1-sulfonyl) -5-fluoro-2-methyl- indol-1-yl] -acetic acid) (Compound 1)

3- (butane-1-sulfonyl) -5-fluoro-2-methyl-1H-indole (3- (Butane-1-sulfonyl) -5-fluoro-2-methyl-1H dissolved in DMF (1 ml) -indole) (55 mg, 0.204 mmol) in a well mixed suspension of sodium hydride (11 mg, 0.29 mmol; 60% in mineral oil) dissolved in DMF (1 ml) at 0 ° C. for at least 1 minute. Added. The solution was stirred at 0 ° C. for 45 minutes, then ethyl bromoacetate (0.032 ml, 0.29 mmol) was added dropwise, and the resulting mixture was stirred at room temperature for 18 hours. The mixture was adjusted to pH 4 with 10% citric acid and extracted with ethyl acetate (2 × 10 ml). The combined organic extracts were dried in vacuo and concentrated to leave a residue. The residue was taken up in THF (1 ml) and lithium hydroxide monohydrate (19 mg, 0.464 mmol) in water (1 ml) was added at one time at room temperature. The mixture was stirred at room temperature for 3 hours and then the solution was adjusted to pH 4 with 10% citric acid. The resultant was extracted with ethyl acetate and the combined organic extracts were dried and concentrated to leave a residue. The residue was triturated with diethylethr to give carboxylic acid (cafboxylic acid) as a pure off-white solid (5.4 mg, 8%).

δ _H (400 MHz, MeOD) 7.57 (1H, dd J 9.8, 2.3 Hz, Ar ), 7.43 (1H, dd J 9.1, 4.0 Hz, Ar ), 7.04 (1H, td J 9.1, 2.5 Hz, Ar ), 4.79 (2H, s, C H ₂ CO ₂ H), 3.23-3.19 (2H, m, SO ₂ C H ₂ ), 2.70 (3H, s, CC H ₃ ), 1.77-1.70 (2H, m, CH ₂ C H ₂ CH ₂ CH ₃ ), 1.47-1.41 (2H, m, CH ₂ CH ₂ C H ₂ CH ₃ ), 0.93 (3H, t J 7.6 Hz, CH ₂ CH ₂ CH ₂ C H ₃ ); Tr = 1.38 min, m / z (ES ⁺ ) (M + H) ⁺ 308.24. Tr = 1.82 min (98%), m / z (ES ⁺ ) (M + H) ⁺ 328.20.

Compound 2 was prepared using the same general method as Compound 1, but the starting materials were appropriately selected.

Compound 2-[3- (biphenyl-4-sulfonyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (Biphenyl-4-sulfonyl) -5-fluoro-2 -methyl-indol-1-yl] -acetic acid)

δ _H (400 MHz, MeOD) 8.03 (2H, d, J 8.6 Hz Ar ), 7.80 (2H, d, J 8.6 Hz, Ar ), 7.77-7.74 (1H, dd, J 9.6, 2.5 Hz, Ar ), 7.66-7.64 (2H, dd, J 8.0, 1.3 Hz, Ar ), 7.49-7.39 (4H, m, Ar ), 7.07 (1H, td, J 9.1, 2.5 Hz, Ar ), 5.07 (2H, s, C H ₂ ), 2.76 (3H, s, C H ₃ ); Tr = 1.52 min, m / z (ES ⁺ ) (M + H) ⁺ 424.1.

Example 2 Synthesis of 3-Sulfonyl Indole Derivative (Method B)

1.2-Methylsulfanyl-ethanethiol

Ethanol dithiol (11.24ml, 12.62g, 0.134mol) and potassium carbonate (37.04g, 0.268mol) were added to acetone (150ml) and methyl iodide was added to acetone (50ml). A solution in which (methyl iodide) (10 ml, 22.82 g, 0.161 mol) was added was added dropwise. The resulting mixture was stirred for 4 hours at room temperature. Water (150 ml) was added and the mixture was stirred for at least 15 minutes. The reaction mixture was extracted with dichloromethane (3 × 200 ml) and the combined organic washes were dried over sodium sulfate and evaporated to obtain 2-methylsulfanyl-ethanethiol. (Pressurized to 200 mbar or more to prevent the product from evaporating together). LC / MS shows a 2: 1 mixture of up to 5% of starting material and mono and bis methylated materials. This material was used in the next step without further purification.

2. [5-Fluoro-2-methyl-3- (2-methylsulfanyl-ethylsulfanyl) -indol-1-yl] -acetic acid ethyl ester ([5-Fluoro-2-methyl-3- (2 -methylsulfanyl-ethylsulfanyl) -indol-1-yl] -acetic acid ethyl ester)

(5-fluoro-2-methyl-indol-1-yl) -acetic acid ethyl ester ((5-fluoro-2-methyl-indol-1-yl)-in a 1: 1 solution of ethanol and water at room temperature (40 ml). acetic acid ethyl ester) (1.20g, 5.10mmol) and 2-methylsulfanyl-ethanethiol (1.04g, 6.12mmol), mix well and iodine (1.29g, 5.10mmol) Potassium iodine (0.847 g, 5.10 mmol) was added. The mixture was heated to 100 ° C. and stirred for 2 hours and then stirred at room temperature for 16 hours. The reaction mixture was precipitated by careful addition of saturated aqueous sodium hydrogen carbonate solution and then extracted with DCM (2 × 50 ml). The organic washings were combined and washed with saturated sodium thiosulfate (2 × 70 ml), dried over magnesium sulfate and evaporated to give an oil. This crude oil was purified by chromatography (column 3 × 12 cm; 4: 1 hexane: EtOAc as eluent) to give an ester (1.17 g, 67%). δ _H (400 MHz, CDCl ₃ ) 7.36 (1H, dd J 9.2, 2.5 Hz, Ar ), 7.11 (1H, dd J 8.8, 4.1 Hz, Ar ), 7.05 (1H, td J 9.2, 2.3 Hz, Ar), 4.79 (2H, s, C H ₂ CO ₂ Et), 4.21 (2H, q J 7.2 Hz, CO ₂ C H ₂ CH ₃ ), 2.86-2.79 (2H, m, C H ₂ CH ₂ ), 2.59-2.55 (2H, m, CH ₂ C H ₂ ), 2.50 (3H, s, SC H ₃ ), 2.04 (3H, s, CC H ₃ ), 1.25 (3H, t J 7.2 Hz, CO ₂ CH ₂ C H ₃ ).

3. [5-Fluoro-3- (2-methanesulfonyl-ethanesulfonyl) -2-methyl-indol-1-yl] -acetic acid ethyl ester ([5-Fluoro-3- (2-methanesulfonyl-ethanesulfonyl ) -2-methyl-indol-1-yl] -acetic acid ethyl ester)

[5-fluoro-2-methyl-3- (2-methylsulfanyl-ethylsulfanyl) -indol-1-yl] -acetic acid ethyl ester in a 4: 1 1,4-dioxane: water solution at room temperature Oxone (8.43 g) in a solution of ([5-fluoro-2-methyl-3- (2-methylsulfanyl-ethylsulfanyl) -indol-1-yl] -acetic acid ethyl ester) (1.17 g, 3.43 mmol) , 13.7 mmol) was added. After 30 minutes, a saturated sodium bicarbonate solution (50 ml; foam) was added carefully to precipitate the reaction mixture, which was then extracted with DCM (2 × 100 ml). The organic washings were combined and washed with brine (2 x 100 ml). The aqueous wash was then back extracted with DCM (100 ml). All organic layers were combined, dried over magnesium sulfate, and evaporated to give a solid green flies. This solid was suspended with DCM and filtered to give ester (1.06 g, 76%).

δ _H (400 MHz, CDCl ₃ ) 7.66 (1H, dd J 9.1, 2.5 Hz, Ar ), 7.22 (1H, dd J 9.0, 4.0 Hz, Ar ), 7.08 (1H, td J 8.9, 2.5 Hz, Ar) , 4.86 (2H, s, C H ₂ CO ₂ Et), 4.26 (2H, q J 7.1 Hz, CO ₂ C H ₂ CH ₃ ), 3.61-3.57 (2H, m, C H ₂ CH ₂ ), 3.48- 3.44 (2H, m, CH ₂ C H ₂ ), 2.99 (3H, s, SC H ₃ ), 2.71 (3H, s, C H ₃ ), 1.30 (3H, t J 7.1 Hz, CO ₂ CH ₂ C H ₃ ).

4. Compound 5-[[5-Fluoro-3- (2-methanesulfonyl-ethanesulfonyl) -2-methyl-indol-1-yl] -acetic acid ([[5-Fluoro-3- (2- methanesulfonyl-ethanesulfonyl) -2-methyl-indol-1-yl] -acetic acid)

THF: [5-Fluoro-3- (2-methanesulfonyl-ethanesulfonyl) -2-methyl-indol-1-yl] -acetic acid ethyl ester in water (5: 1; 15 ml) solution Lithium hydroxide monohydrate (Lithium hydroside) in a solution containing fluoro-3- (2-methanesulfonyl-ethanesulfonyl) -2-methyl-indol-1-yl] -acetic acid ethyl ester (1.06 g, 2.61 mmol) monohydrate) (132 mg, 3.14 mmol) was added in one portion and the resulting mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo to leave a residue, which was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and the aqueous solution was extracted with ethyl acetate (3 × 100 ml). The combined organic extracts were dried and concentrated in vacuo to leave an off-white solid. The solid was precipitated with dichloromethane to give carboxylic acid as an off-white solid (438 mg, 44%). δ _H (400 MHz, d6 -Acetone) 7.58-7.63 (2H, m, Ar ) 7.09 (1H, td J 9.2, 2.6 Hz, Ar ), 5.22 (2H, s, C H ₂ CO ₂ H), 3.60- 3.66 (2H, m, SO ₂ C H ₂ CH ₂ ), 3.45 (2H, m, SO ₂ CH ₂ C H ₂ ), 3.02 (3H, s, SO ₂ C H ₃ ), 2.75 (3H, s, C H ₃ ); Tr = 1.08 min (98%), m / z (ES ⁺ ) (M + H) ⁺ 378.16.

Compounds 3 and 4 were prepared by similar routes using the appropriate starting materials.

Compound 3-(3-carboxymethanesulfonyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid ((3-Carboxymethanesulfonyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid)

Tr = 1.16 min, m / z (ES ⁺ ) (M + H) ⁺ 330.10.

Compound 4-(3-Carbamoylmethanesulfonyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid (3-Carbamoylmethanesulfonyl-5-fluoro-2-methyl-indol-1-yl)- acetic acid

Tr = 1.50 min, m / z (ES ⁺ ) (M + H) ⁺ 329.17.

Example 3 Synthesis of 3-sulfonyl Indole Derivative (Method B2)

A similar method as described in step 2 of Example 2 was used for the synthesis of the following intermediates. However, the acid was hydrolyzed prior to oxidation to give sulfone or sulfoxide derivatives.

[5-Fluoro-2-methyl-3- (quinolin-8-ylsulfanyl) -indol-1-yl] -acetic acid ([5-Fluoro-2-methyl-3- (quinolin-8-ylsulfanyl) -indol -1-yl] -acetic acid)

δ _H (400 MHz, MeOD) 8.85-8.94 (1H, m, Ar ), 8.36 (1H, dd J 8.3, 1.7 Hz, Ar ), 7.64-7.60 (2H, m, Ar), 7.45 (1H, dd J 8.8, 4.2 Hz, Ar ), 7.29 (1H, t J 7.8 Hz, Ar ), 7.09 (1H, dd J 9.2, 2.6 Hz, Ar ), 7.00 (1H, td J 9.2, 2.6 Hz, Ar ), 6.85 (1H, app d J 7.3 Hz, Ar ), 5.14 (2H, s, C H ₂ CO ₂ H), 2.52 (3H, s, CC H ₃ ); Tr = 1.30 min, m / z (ES ⁺ ) (M + H) ⁺ 367.39.

[5-Fluoro-2-methyl-3- (quinolin-2-ylsulfanyl) -indol-1-yl] -acetic acid ([5-Fluoro-2-methyl-3- (quinolin-2-ylsulfanyl) -indol -1-yl] -acetic acid

δ _H (400 MHz, MeOD) 8.01 (1H, d J 8.6 Hz, Ar ), 7.83 (1H, d J 7.8 Hz, Ar ), 7.82 (1H, d J 8.1 Hz, Ar ), 7.76 (1H, app td J 7.1, 1.4 Hz, Ar ), 7.53 (1H, app td J 7.0, 1.1 Hz, Ar ), 7.47 (1H, dd J 9.1, 4.2 Hz, Ar ), 7.16 (1H, dd J 9.0, 2.4 Hz, Ar ), 7.03 (1H, td J 9.2, 2.6 Hz, Ar ), 6.87 (1H, d J 8.8 Hz, Ar ), 5.14 (2H, s, C H ₂ CO ₂ H), 2.55 (3H, s, CC H ₃ ); Tr = 1.37 min, m / z (ES ⁺ ) (M + H) ⁺ 367.24.

[3- (benzothiazol-2-ylsulfanyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (Benzothiazol-2-ylsulfanyl) -5-fluoro-2-methyl -indol-1-yl] -acetic acid)

δ _H (400 MHz, MeOD) 7.81 (1H d J 8.3 Hz, Ar ), 7.71 (1H, d J 7.8 Hz, Ar ), 7.50-7.43 (2H, m, Ar ), 7.31-7.24 (2H, m, Ar ), 7.06 (1H td J 9.0, 2.4 Hz, Ar ), 5.15 (2H, s, C H ₂ CO ₂ H), 2.60 (3H, s, CC H ₃ ); Tr = 1.49 min, m / z (ES ⁺ ) (M + H) ⁺ 373.34.

(3-benzylsulfanyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid (3-Benzylsulfanyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid

δ _H (250 MHz, d ₆ -DMSO) 7.46 (1H, dd J 8.8, 4.3 Hz, Ar ), 7.21-7.18 (3H, m, Ar ), 7.14 (1H, dd J 9.5, 2.5 Hz, Ar ), 7.01-6.92 (3H, m, Ar ), 4.99 (2H, s, C H ₂ CO ₂ H), 3.75 (2H, s, ArC H ₂ ), 2.01 (3H, s, C H ₃ ); Tr = 1.56 min (100%) m / z (ES ⁺ ) (M + H) ⁺ 330.16.

The intermediate product can be oxidized to obtain a compound of formula (I) wherein n is 1 or 2 by the following method.

1.Compound 6- [3-benzothiazole-2-sulfonyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3-Benzothiazole-2-sulfonyl) -5-fluoro- 2-methyl-indol-1-yl] -acetic acid) and compound 7-[3- (benzothiazole-2-sulfinyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ( [3-Benzothiazole-2-sulfinyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid)

1,4-dioxane (1,4-dioxane): [3- (benzothiazol-2-ylsulfanyl) -5-fluoro-2-methyl-indole- in a solution of water (0.3 ml; 4: 1) 1-yl] -acetic acid ([3- (benzothiazol-2-ylsulfanyl) -50fluoro-2-methyl-indol-1-yl] -acetic acid) (20.0 mg, 53.6 mmol) was added to potassium peroxymono Potassium peroxymonosulfate (131.0 mg, 214 mmol) was added in one portion at room temperature. The mixture was stirred at room temperature for 18 hours and then saturated solution of sodium bicarbonate (5 ml) was added. The product was extracted with ethyl acetate (3 × 2 ml) and the combined organic extracts were washed with brine, dried in vacuo to remain solid and concentrated. This solid was purified by preparative HPLC to give an off-white solid, δ _H (400 MHz, MeOD) 8.11 (2H, obs dd J 7.9, 2.8 Hz, Ar ), 7.79 (1H, dd J 9.6, 2.5 Hz, Ar ), 7.65-7.57 (2H, m, Ar ), 7.43 (1H, dd J 8.8, 4.3 Hz, Ar ), 7.06 (1H, td J 9.1, 2.5 Hz, Ar ), 4.76 (2H, s, C H ₂ CO ₂ H), 2.85 (3H, s, CC H ₃ ); Tr = 1.44 min (100%), sulfone with m / z (ES ⁺ ) (M + H) ⁺ 405.21, compound 6 (10.0 mg, 46%) with off-white solid, δ _H (400 MHz, MeOD) 8.16 (1 H , app d J 9.1 Hz, Ar ), 8.01 (1H, d J 8.1 Hz, Ar ), 7.62-7.54 (2H, m, Ar ), 7.47 (1H, dd J 9.1, 4.0 Hz, Ar ), 7.23 (1H, dd J 9.6, 2.5 Hz, Ar ), 7.02 (1H, t d J 9.1, 2.0 Hz, Ar ), 5.10 (2H, s, C H ₂ CO ₂ H), 2.78 (3H, s, CC H ₃ ); A sulfoxide, compound 7 (3.2 mg, 15%) with Tr = 1.34 min (100%), m / z (ES ⁺ ) (M + H) ⁺ 389.09 was obtained.

Compounds 8 to 10 used the same general method as for compounds 6 and 7, but starting materials were selected and combined appropriately.

Compound 8-[5-Fluoro-2-methyl-3- (quinolin-2-sulfonyl) -indol-1-yl] -acetic acid ([5-Fluoro-2-methyl-3- (quinolin-2-sulfonyl ) -indol-1-yl] -acetic acid)

δ _H (400 MHz, MeOD) 8.57 (1H, d J 8.6 Hz, Ar ), 8.20 (1H, d J 8.6 Hz, Ar ), 8.13 (1H, d J 8.6 Hz, Ar ), 8.02 (1H, d J 8.1 Hz, Ar ), 7.89-7.82 (2H, m, Ar ), 7.73 (1H, app t J 8.1 Hz, Ar ), 7.42 (1H, dd J 8.8, 4.3 Hz, Ar ), 7.05 (1H, td J 9.1, 2.5 Hz, Ar ), 5.08 (2H, s, C H ₂ CO ₂ H), 2.86 (3H, s, CC H ₃ ); Tr = 1.39 min (92%), m / z (ES ⁺ ) (M + H) ⁺ 399.26.

Compound 9-[5-Fluoro-2-methyl-3- (quinolin-8-ylsulfonyl) -indol-1-yl] -acetic acid ([5-Fluoro-2-methyl-3- (quinolin-8-ylsulfonyl ) -indol-1-yl] -acetic acid)

δ _H (400 MHz, MeOD) 8.89 (1H, app d J 4.3 Hz, Ar ), 8.71 (1H, dd J 7.3 Hz, Ar ), 8.34 (1H, app d J 8.3 Hz, Ar ), 8.20 (1H, app d J 8.3 Hz, Ar ), 7.80 (1H, t J 8.1 Hz, Ar ), 7.58 (1H, dd J 10.1, 2.5 Hz, Ar ), 7.53 (1H, dd J 8.3, 4.3 Hz, Ar ), 7.34 (1H, dd J 8.8, 4.3 Hz, Ar ), 6.95 (1H, td J 9.1, 2.5 Hz, Ar ), 5.02 (2H, s, C H ₂ CO ₂ H), 2.97 (3H, s, CC H ₃ ); Tr = 1.78 min (100%), m / z (ES ⁺ ) (M + H) ⁺ 399.29.

Compound 10-(5-Fluoro-2-methyl-3-phenylmethanesulfonyl-1H-indol-1-yl) -acetic acid ((5-Fluoro-2-methyl-3-phenylmethanesulfonyl-1H-indol-1- yl) -acetic acid)

δ _H (250 MHz, d ₆ -DMSO) 7.61 (1H, dd J 9.0, 4.5 Hz, Ar ), 7.35 (1H, dd J 9.8, 2.5 Hz, Ar ), 7.30-7.19 (3H, m, Ar ), 7.10 (1H, t d J 9.1, 2.6 Hz, Ar ), 7.02 (2H, m, Ar ), 5.10 (2H, s, C H ₂ CO ₂ H), 4.51 (2H, s, ArC H ₂ ), 2.06 ( 3H, s, C H ₃ ); Tr = 1.30 min (100%) m / z (ES ⁺ ) (M + H) ⁺ 362.13.

Example 4 Synthesis of 3-Sulfamoyl Indole Derivative (Method C)

Was used as the method that is described later is X in the compounds of the general formula NR ⁹ (Ⅰ).

1. [3- (4-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ethyl ester ([3- (4-Chloro-phenylsulfamoyl) -5-fluoro- 2-methyl-indol-1-yl] -acetic acid ethyl ester)

(5-fluoro-2-methyl-indol-1-yl) -acetic acid ethyl ester ((5-fluoro-2-methyl-indol-1-yl) -acetic acid at ether (1 ml) at 0 ° C. Ethyl ester) (100 ml, 0.43 mmol) was added to the stirred solution, and chlorosulfonic acid (Chlorosulfonic acid) (0.042 ml, 0.63 mmol) was added dropwise for at least 1 minute. The solution was stirred at 0 ° C. for 10 minutes and concentrated in vacuo to leave a residue. The residue was azeotropically mixed with dichloromethane (2 × 2 ml). The residue was recovered from dichloromethane, followed by N, N-diisopropyl ethylamine (0.075ml, 0.43mmol) and 4-chloroaniline (53.4mg). , 0.42 mmol) was added. The resulting mixture was stirred for 40 minutes at room temperature and then concentrated in vacuo to leave a residue that was partitioned between ethyl acetate (5 ml) and water (5 ml). The organic layer was separated and washed with a saturated solution of sodium hydroxide (20 ml), dried and evaporated in vacuo to leave a residue. The residue was purified by flash column chromatography ( Flashmaster ) using silica gel in 15% ethyl acetate: heptane solution as eluent, and sulfonamide as an off-white solid (6 mg, 3%). Got.

δ _H (400 MHz, CDCl ₃ ) 7.63 (1H, dd J 9.5, 2.4 Hz, Ar ), 7.18-7.12 (3H, m, Ar ), 7.05-6.99 (1H, m, Ar ), 6.96-6.90 (2H, m, Ar ), 6.55 (1H, s, N H ), 4.73 (2H, s, NC H ₂ ), 4.20 (2H, q J 7.3 Hz, OC H ₂ CH ₃ ), 2.33 (3H, s, CC H ₃ ), 1.22 (3H, t J 7.3 Hz, OCH ₂ C H ₃ ); Tr = 1.57 min (100%), m / z (ES ⁺ ) (M + H) ⁺ 425.

2. Compound 11-[3- (4-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (4-Chloro-phenylsulfamoyl) -5-fluoro -2-methyl-indol-1-yl] -acetic acid)

In tetrahydrofuran (2 ml) [3- (4-chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ethyl ester ([3- (4-chloro Lithium hydroxide monohydrate (7.0) dissolved in water (2 ml) in a solution containing -phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ethyl ester mg, 0.17 mmol) was added in one portion. The resulting mixture was stirred for 3 hours at room temperature and then the pH of the mixture was adjusted to pH 1 with 1M hydrochloric acid. The product was extracted with ethyl acetate (2 × 10 ml), and the combined organic extracts were dried and evaporated in vacuo to give carboxylic acid (4.3 mg, 77%) as an off-white solid.

δ _H (400 MHz, CDCl ₃ ) 8.74 (1H, s, N H ), 7.70 (1H, dd J 9.5, 2.6 Hz, Ar ), 7.13-7.06 (3H, m, Ar ), 6.99-6.92 (3H, m, Ar ), 4.67 (2H, s, NC H ₂ ), 2.41 (3H, s, C H ₃ ); Tr = 1.84 min (91%), m / z (ES ⁺ ) (M + H) ⁺ 397.

Compounds 12 to 25 used the same general method but were prepared with the appropriate selection of starting materials.

Compound 12-[3- (3-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (3-Chloro-phenylsulfamoyl) -5-fluoro-2 -methyl-indol-1-yl] -acetic acid)

δ _H (400 MHz, CDCl ₃ ) 7.63 (1H, dd J 9.3, 2.6 Hz, Ar ), 7.17-7.14 (1H, m, Ar ), 7.10-6.98 (5H, m, Ar , N H ), 6.86- 6.84 (1 H, m, Ar ), 4.73 (2H, s, NC H ₂ ), 2.46 (3H, s, C H ₃ ); Tr = 1.84 min (100%), m / z (ES ⁺ ) (M + H) ⁺ 397.

Compound 13-[3- (4-Fluoro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (4-Fluoro-phenylsulfamoyl) -5-fluoro- 2-methyl-indol-1-yl] -acetic acid)

δ _H (400 MHz, CDCl ₃ ) 8.45 (1H, s, N H ), 7.66 (1H, dd J 9.7, 2.3 Hz, Ar ), 7.11 (1H, dd J 9, 4.2 Hz, Ar ), 6.97-6.90 (3H, m, Ar ), 6.81-6.77 (2H, m, Ar ), 4.64 (2H, s, NC H ₂ ), 2.29 (3H, s, C H ₃ ); Tr = 1.79 min (99%), m / z (ES ⁺ ) (M + H) ⁺ 381.

Compound 14-[3- (2-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (2-Chloro-phenylsulfamoyl) -5-fluoro-2 -methyl-indol-1-yl] -acetic acid)

δ _H (400 MHz, CDCl ₃ ) 7.69 (1H, s, N H ), 7.58-7.49 (2H, m, Ar ), 7.23-7.13 (3H, m, Ar ), 7.03-6.93 (2H, m, Ar ), 4.70 (2H, s, NC H ₂ ), 2.44 (3H, s, C H ₃ ); Tr = 1.83 (100%), m / z (ES ⁺ ) (M + H) ⁺ 397.

Compound 15-(3-benzylsulfamoyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid ((3-Benzylsulfamoyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid )

δ _H (400 MHz, d ₆ -DMSO) 7.99 (1H, t J 6.3 Hz, Ar ), 7.58 (2H, m, Ar ), 7.21 (4H, m, Ar ), 7.09 (1H, td J 9.23, 2.65 Hz, Ar ), 5.11 (2H, s, C H ₂ CO ₂ H), 3.92 (2H, d J 6.31 Hz, NC H ₂ ) 2.56 (3H, s, C H ₃ ), Tr = 1.31 min (100%), m / z (ES ⁺ ) (M + H) ⁺ 377.25.

Compound 16-[5-Fluoro-3- (2-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic acid ([5-Fluoro-3- (2-methoxy-phenylsulfamoyl)- 2-methyl-indol-1-yl] -acetic acid)

δ _H (400 MHz, d ₆ -DMSO) 9.18 (1H, s, SO ₂ N H ), 7.52 (1H, dd J 9.00, 4.4 Hz, Ar ), 7.47 (1H, dd J 10.2, 2.6 Hz, Ar ) , 7.23 (1H, dd J 7.9, 1.6 Hz, Ar ), 7.09-7.01 (2H, m, Ar ), 6.84 (1H, t J 7.7 Hz, Ar ), 6.77 (1H, d J 7.2 Hz, Ar ), 5.05 (2H, s, C H ₂ CO ₂ H), 3.24 (3H, OC H ₃ ), 2.30 (3H, s, C H ₃ ); Tr = 1.31 min (100%), m / z (ES ⁺ ) (M + H) ⁺ 393.25.

Compound 17-[5-Fluoro-3- (4-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic acid ([5-Fluoro-3- (4-methoxy-phenylsulfamoyl)- 2-methyl-indol-1-yl] -acetic acid)

δ _H (400 MHz, d ₆ -DMSO) 9.62 (1H, s, SO ₂ N H ), 7.49 (1H, dd J 10.3, 2.6 Hz, Ar ), 7.36 (1H, dd J 9.0, 4.6 Hz, Ar ) , 6.98 (1H, dd J 9.2, 2.8 Hz, Ar ), 6.93 (2H, d J 9.1 Hz, Ar ), 6.74 (2H, d J 9.1 Hz, Ar ), 4.45 (2H, s, C H ₂ CO ₂ H), 3.64 (3H, s, OC H ₃ ), 2.36 (3H, s, C H ₃ ); Tr = 1.27 min (100%), m / z (ES ⁺ ) (M + H) ⁺ 393.26.

Compound 18-(5-Fluoro-2-methyl-3-phenylsulfamoyl-indol-1-yl) -acetic acid ((5-Fluoro-2-methyl-3-phenylsulfamoyl-indol-1-yl) -acetic acid )

δ _H (400 MHz, d ₆ -DMSO) 10.15 (1H, s, SO ₂ N H ), 7.60 (1H, dd J 10.1, 2.6 Hz, Ar ), 7.53 (1H, dd J 9.1, 4.5 Hz, Ar ) , 7.17 (2H, m, Ar ), 7.07 (1H, dd J 9.1, 2.6 Hz, Ar ), 7.03 (2H, m, Ar ), 6.96 (1H, t J 7.3 Hz, Ar ), 5.03 (2H, s , C H ₂ CO ₂ H), 2.48 (3H, s, C H ₃ ); Tr = 1.28 min (96%), m / z (ES ⁺ ) (M + H) ⁺ 363.25.

Compound 19-[3- (3,4-Dichloro-benzylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (3,4-Dichloro-benzylsulfamoyl) -5 -fluoro-2-methyl-indol-1-yl] -acetic acid)

δ _H (400 MHz, d ₆ -DMSO) 7.92 (1H, bs, SO ₂ N H ), 7.47 (1H, dd J 10.3, 2.6 Hz, Ar ), 7.40 (1H, d J 8.3 Hz, Ar ), 7.37 (1H, d J 1.7 Hz, Ar ), 7.31 (1H, dd J 9.0, 4.6 Hz, Ar ), 7.13 (1H, dd J 8.2, 2.0 Hz, Ar ), 6.96 (1H, td J 9.3, 2.7 Hz, Ar ), 4.32 (2H, s, C H ₂ CO ₂ H), 3.93 (2H, s, NC H ₂ ), 2.49 (3H, s, C H ₃ ); Tr = 1.43 min (97%), m / z (ES ⁺ ) (M + H) ⁺ 445.15.

Compound 20-[5-Fluoro-3- (3-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic acid ([5-Fluoro-3- (3-methoxy-phenylsulfamoyl)- 2-methyl-indol-1-yl] -acetic acid)

δ _H (400 MHz, d ₆ -DMSO) 10.22 (1H, s, SO ₂ N H ), 7.60 (1H, dd J 9.9, 2.5 Hz, Ar ), 7.50 (1H, dd J 9.1, 4.1 Hz, Ar ) , 7.05 (2H, m, Ar ), 6.61 (2H, m, Ar ), 6.50 (1H, d 8.7 Hz, Ar ), 4.88 (2H, s, C H ₂ CO ₂ H), 3.60 (3H, s, OC H ₃ ), 2.54 (3H, s, C H ₃ ); Tr = 1.28 min (100%), m / z (ES ⁺ ) (M + H) ⁺ 393.28.

Compound 21 - (5-fluoro-2-methyl -3- m-tolyl-sulfamoyl-indol-1-yl) acetate ((5-Fluoro-2- methyl-3- m -tolylsulfamoyl-indol-1-yl ) -acetic acid)

δ _H (400 MHz, d ₆ -DMSO) 10.11 (1H, s, SO ₂ N H ), 7.61 (1H, dd J 10.1, 2.6 Hz, Ar ), 7.55 (1H, dd J 9.1, 4.5 Hz, Ar ) , 7.08 (1H, dd J 9.2, 2.6 Hz, Ar ), 7.03 (1H, d J 7.8, Ar ), 6.85-6.81 (2H, m, Ar ), 6.76 (1H, d J 7.6 Hz, Ar ), 5.08 (2H, s, C H ₂ CO ₂ H), 2.50 (3H, s, C H ₃ ), 2.15 (3H, s, ArC H ₃ ), Tr = 1.33 min (100%), m / z (ES ⁺ ) (M + H) ⁺ 377.24.

Compound 22 - (5-fluoro-2-methyl -3- p-tolyl-sulfamoyl-indol-1-yl) acetate ((5-Fluoro-2- methyl-3- p -tolylsulfamoyl-indol-1-yl ) -acetic acid)

δ _H (400 MHz, d ₆ -DMSO) 9.90 (1H, bs, SO ₂ N H ), 7.55 (1H, dd J 10.2, 2.6 Hz, Ar ), 7.32 (1H, dd J 9.1, 4.6, Ar ), 6.94 (5H, m, Ar ), 4.31 (2H, s, C H ₂ CO ₂ H), 2.45 (3H, s, C H ₃ ), 2.15 (3H, s, C H ₃ ), Tr = 1.33 min ( 100%), m / z (ES ⁺ ) (M + H) ⁺ 377.25.

Compound 23-[3- (4-Chloro-benzylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (4-Chloro-benzylsulfamoyl) -5-fluoro -2-methyl-indol-1-yl] -acetic acid)

δ _H (400 MHz, d ₆ -DMSO) 8.04 (1H, t J 5.9 Hz, N H ), 7.58-7.51 (2H, m, Ar ), 7.25 (2H, d J 8.6 Hz, Ar ), 7.18 (2H , d J 8.6 Hz, Ar ), 7.07 (1H, td J 9.5, 2.7 Hz, Ar ), 5.07 (2H, s, C H ₂ CO ₂ H), 3.93 (2H, d J 6.3 Hz, NC H ₂ ) 2.56 (3H, s, C H ₃ ); Tr = 1.38 min (91%), m / z (ES ⁺ ) (M + H) ⁺ 411.07.

Compound 24-[3- (benzyl-methyl-sulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (Benzyl-methyl-sulfamoyl) -5-fluoro-2- methyl-indol-1-yl] -acetic acid)

δ _H (400 MHz, d ₆ -DMSO) 7.52 (1H, dd J 10.0, 2.6 Hz, Ar ), 7.46 (1H, dd J 8.9, 4.4 Hz, Ar ), 7.39-7.28 (5H, m, Ar ), 7.03 (1H, t d J 9.4, 2.8 Hz, Ar ), 4.46 (2H, s, C H ₂ CO ₂ H), 4.10 (2H, s, NC H ₂ ), 2.60 (3H, s, NC H ₃ ), 2.48 (3H, s, C H ₃ ); Tr = 1.43 min (100%), m / z (ES ⁺ ) (M + H) ⁺ 391.15.

Compound 25- [5-fluoro-2-methyl-3- (pyridin-3-ylsulfamoyl) -indol-1-yl] -acetic acid ([5-Fluoro-2-methyl-3- (pyridin-3- ylsulfamoyl) -indol-1-yl] -acetic acid)

δ _H (400 MHz, d ₆ -DMSO) 10.42 (1H, s, SO ₂ N H ), 8.25 (1H, d J 2.6 Hz, Ar ), 8.19 (1H, d, 3.3 Hz, Ar ), 7.59-7.55 (2H, m, Ar ), 7.40 (1H, d J 8.3 Hz, Ar ), 7.24-7.21 (2H, m, Ar ), 5.10 (2H, s, C H ₂ CO ₂ H), 2.49 (3H, s , C H ₃ ); Tr = 0.96 min (100%), m / z (ES ⁺ ) (M + H) ⁺ 364.1.

Example 5 Measurement of CRTH2 Antagonist Activity

Materials and methods

material

Calcium-3 dye was purchased from Molecular Devices (Wokingham, UK). Mono-poly dissolution media was purchased from Dainippon Phamaceuticals (Osaka, Japan). Max anti-CD16 microbeads were obtained from Miltenyi biotec (Bisley, Surrey). ChemoTx plates were purchased from Neuroprorobe (Gaithesburg, MD). 96-well plates coated with Poly-D-lysine were obtained from Grainstershire, UK. [ ³ H] PGD ₂ was purchased from Amesham Biosciences (Buckinghamshire, UK) and [ ³ H] SQ29548 was purchased from Perkin Elmer Life Sciences (Buckinghamshire, UK) It was. All other reagents were obtained from Sigma-Aldrich (Dorset, UK) and were otherwise officially represented.

Way

Cell culture

Minimal essential supplementation of Chinese hamster ovary cells (CHO cells) with CRTH2 or DP receptors (CHO / CRTH2 and CHO / DP) and supplemented with 10% bovine embryo serum, 2mM glutamine, and 1mg ml- ¹ active G418 The medium (MEM) was preserved by culturing in humid air at 37 ° C. (5% CO ₂ ). These cells were changed every 2-3 days. Cells were prepared in three layer flasks or 175 cm ² square flasks (for membrane specimens) for radioligand binding assays. Cells were grown for 24 hours in 96 well plates for calcium mobilization assqy and then assayed at 80,000 cell densities per well.

Preparation of Cell Membrane

Membranes were prepared from CHO / CRTH2 and CHO / DP cells, or from platelets (as a source of TP receptors). CHO cells grown in clumps were washed with PBS and isolated using Versene solution (15 ml per flask). These cells are 175 cm ² When mature in square flasks, each was collected in pieces with PBS. The cell suspension was centrifuged (1,700 rpm, 10 minutes, 4 ° C.) and resuspended in 15 ml of buffer (supplemented with 1 × HBSS, pH 7.3, 10 mM HEPES). The cell suspension was then homogenized using Ultra Turrax set at 4-6 in 20 seconds. The homogeneous suspension was centrifuged at 1,700 rpm for 10 minutes, and the surface floating was collected and centrifuged at 20,000 rpm for 1 hour at 4 ° C. The resulting small mass was resuspended in a buffer and then stored at exactly 80 [deg.] C. between 200 [mu] l and 500 [mu] l. The concentration of this protein was measured by the Bradford method (Bradford, 1976) using bovine serum albumin as a control. The platelets were resuspended in analytical buffer (10 mM Tris-HCl, pH 7.4, 5 mM glucose, 120 mM sodium chloride, 10 μM indomethacin), washed by centrifugation at 600 × g for 10 minutes and cooled on ice. Centrifuged at 20,000 rpm for 30 minutes at < RTI ID = 0.0 > The resulting small mass was treated as described above.

Radioligand binding assays

[ ³ H] PGD ₂ (160 Ci / mmol) binding experiments were performed with membranes prepared as described above. The final volume of 100 μl buffer (1 × HBSS / HEPES 10 mM, pH 7.3) was analyzed. Cell membrane (15 μg). 15 mg of cell membranes were preincubated with various concentrations of competing ligands for 15 minutes at room temperature. Then [ ³ H] PGD ₂ (mol, final concentration) was added to incubate another hour at room temperature. 200 μl of ice-cold assay buffer was added to each well to terminate the reaction and Whatman GF / B glass using a Unifilter Cell harvester (PerkinElmer Life Sciences). Fast filtration with a fiber filter was followed by six washes with 300 μl of ice-cooled buffer. Dry this Unifilter plate for at least one hour at room temperature, add 40 μl of Optiphase Hi-Safe 3 (Wallac) liquid scintillation, and then release the remaining radioactivity from the filter It was measured with a Beta Trilux counter (PerkinElmer Life Sciences). 10 μM of unlabeled PGD ₂ was added to reveal unspecific binding. The analysis was duplicated.

The results of radiolabeling experiments on CRTH2 and DP receptors are shown in Table 1.

The results shown in Table 1 demonstrate that the compound of formula (I) has a high affinity for the CRTH2 receptor. In comparison, compounds of formula (I) have a much higher affinity for the CRTH 2 receptor than the DP receptor.

Table 1-Radiolabel Binding Data (Ki in CRTH2 Receptor and DP Receptor)

compound CRTH2 binding Ki nM DP binding Ki μM One 192 > 10 2 75 > 10 3 2000 ND 4 2300 ND 5 89 > 10 6 209 ND 7 54 ND 8 249 ND 9 254 > 10 10 6 ND 11 51 > 10 12 45 > 10 13 182 ND 14 225 ND 15 278 > 10 16 771 > 10 17 1450 > 10 18 236 > 10 19 181 > 10 20 531 > 10 21 176 > 10 22 1240 > 10 23 164 > 10 24 119 > 10 25 4250 > 10

The TP receptor was bound to the radiolabel in the membrane prepared from platelets. 15-40 μg of protein was prepared in assay buffer (10 mM Tris-HCl, pH 7.4, 5 mM glucose, 120 mM sodium chloride, 10 μM indomethacin) with varying concentrations of competing ligands for 15 minutes at room temperature. Incubated. And [ ³ H] SQ29548 (38 Ci / mmol, 10 nM final concentration) was added and further incubated for 30 minutes at room temperature. Each well was terminated by adding 200 μl of ice-cold assay buffer to the Whatman GF / C glass fiber filter using a Unifilter Cell Counter (PerkinElmer Life Sciences). After rapid filtration by filtration, the cells were washed six times with 300 µl of ice-cold buffer.

Radioactivity was measured as described above.

All compounds studied in this assay bound the TP receptor with low affinity (Ki> 10 μM).

Compounds of formula (I) bind to CRTH2 receptors expressed in CHO cells with a wide range of affinity from very high to moderate levels. In fact, the Ki values were measured competitively for various [ ³ H] PGD ₂ from 500 pM to 1 μM. Compounds of general formula (I) did not (or very weakly) function at the DP and TP receptors. The binding selectivity of the compound of formula (I) to the CRTH2 receptor is 200 times higher compared to the DP receptor and TP receptor.

Calcium mobilization Assay

Cells were applied at a concentration of 80,000 cells per well in 96-well plates coated with poly-D-lysine and incubated overnight at 37 ° C. to allow the cells to adhere. Cells were washed twice with HBSS and incubated at 37 ° C. for one hour in 100 μl HBSS and 100 μl calcium-3-dye (Molecular Devices) solution supplemented with 4 mM probeneside. Agonists were added at 17 s using Flexstation (Molicular Devices) and fluorescence changes over time of 50 s were observed.

Effect of CRTH2 Agonists on CHO-CRTH2 Cells with Calcium mobilisation

PGD ₂ is according to the dosage increases the Ca ^{2 +} movement in CHO / CRTH2 _{cells. (EC 50 = 2.4 ± 0.5nM} (n = 3)) ( figure 1)

Effect of Compounds of Formula (I) on Calcium Migration Induced by PGD ₂

Ca ^{2 +} go by PGD ₂ has IC ₅₀ values for each compound in a fully inhibited by the compounds of formula (Ⅰ), calcium assay is comparable to the Ki value of the radioactive labeling substance bond. IC ₅₀ values of compounds of general formula (I) range from 5 nM to 1 μM. Table 2 shows the results for some compounds of formula (I). Increasing the dose of the compound of formula (I) resulted in a dose dependent and corresponding change in the PGD ₂ dose response curve in CHO / CRTH2 cells, whereby the compound was a competitive CRTH2 antagonist. It can be seen that.

The antagonistic effect of the compound represented by the general formula (Ⅰ) does not appear with the inhibitory effect of ATP-stimulated Ca ^{2 +} by to move in CHO / CRTH2 cells, it appears to be CRTH2 selective in.

Table 2-Inhibition of PGD ₂ causing calcium migration

compound CRTH2 Ca flux IC ₅₀ (nM) One 280 2 163 5 268 6 345 7 163 8 330 10 79 11 197 12 82 13 1650 14 390 21 1060

Compounds of formula (I) are PGD ₂ antagonists at the CRTH2 receptor and are useful for the treatment of diseases mediated by PGD ₂ binding to CRTH2. The diseases are allergic, asthma and inflammatory diseases such as allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis), conjunctivitis, especially allergic conjunctivitis, eosinophilic bronchitis , Food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative proctitis and Crohn's disease, mastocytosis and other PGD ₂ -mediated diseases such as rheumatoid arthritis, psoriatic arthritis and osteoarthritis, as well as hyper IgE syndrome Autoimmune diseases such as systemic lupus erythematosus, psoriasis, acne, multiple sclerosis, organ rejection, reperfusion injury and chronic obstructive pulmonary disease.

Claims (30)

A compound of formula (I) or a pharmaceutically acceptable salt, hydrate, lysate, complex or prodrug thereof.

 I Wherein R ¹ , R ² , R ³ and R ⁴ are independently hydrogen, halo, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ alkyl),-CON (R ⁹ ) ₂ ,- SOR ⁹ , -SO ₂ R ⁹ , -SO ₂ N (R ⁹ ) ₂ , -N (R ⁹ ) ₂ , -NR ⁹ COR ⁹ , -CO ₂ R ⁹ , -COR ⁹ , -SR ⁹ , -OH, -NO ₂ or -CN; Each R ⁹ is independently hydrogen or C ₁ -C ₆ alkyl; R ⁵ and R ⁶ are each independently hydrogen or C ₁ -C ₆ alkyl, the carbon atom combines with C ₃ -C ₇ cycloalkyl; R ⁷ is hydrogen or C ₁ -C ₆ alkyl n is 1 or 2; X is a bond or n is 2 and X is also NR ⁹ ; Wherein R ⁹ is as defined above; If X is a bond, R ⁸ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, biphenyl or a 9-14 membered bicyclic or tricyclic heteroaryl group; If X is NR ⁹ then R ⁸ is additionally phenyl, naphthyl, or a 5-7 membered heteroaromatic ring; and R ⁸ is halo, C ₁ -C ₆ alkyl, —O (C ₁ -C ₆ ) alkyl, aryl, —O-aryl, heteroaryl, —O-heteroaryl, CON (R ⁹ ) ₂ , -SOR ⁹ , -SO ₂ R ⁹ , SO ₂ N (R ⁹ ) ₂ , -N (R ⁹ ) ₂ , -NR ⁹ COR ⁹ , -CO ₂ R ⁹ , -COR ⁹ , -SR ⁹ , -OH, -NO ₂ Also Optionally substituted with one or more substituents selected from the group consisting of -CN; Wherein R ⁹ is as defined above. A compound of formula (II) below.

Ⅱ Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , n, X, R ⁷ and R ⁸ are as defined in formula (I); R ¹⁰ is C ₁ -C ₆ alkyl, aryl, (CH ₂ ) mOC (═O) C ₁ -C ₆ alkyl, (CH ₂ ) mN (R ¹¹ ) ₂ , CH ((CH ₂ ) mO (C═O ) R ¹² ) ₂ ; m is 1 or 2; R ¹¹ is hydrogen or methyl; R ¹² is C ₁ -C ₁₈ alkyl. A compound according to claim 1 or 2, characterized in that it is independent or a combination of: R ¹ is halo or hydrogen; R ² is halo or hydrogen; R ³ is halo or hydrogen; R ⁴ is halo or hydrogen. A compound according to any one of claims 1 to 3, wherein R ¹ , R ³ and R ⁴ are hydrogen and R ² is halo. The compound of claim 4, wherein R ² is fluorine. The compound of any one of claims 1-5, wherein R ⁵ and R ⁶ are each independently hydrogen or C ₁ -C ₄ alkyl. The compound of claim 6, wherein at least one of R ⁵ and R ⁶ is hydrogen. The compound of claim 7, wherein R ⁵ And R ⁶ All are hydrogen. The compound of any one of claims 1-8, wherein R ⁷ is hydrogen or C ₁ -C ₆ alkyl. The compound of claim 9, wherein R ⁷ is methyl. The compound of any one of claims 1 to 10, wherein n is 2. 11. The compound of any one of claims 1-11, wherein X is a bond, R ⁸ is C ₁ -C ₆ alkyl, biphenyl or bicyclic heteroaryl, halogen, phenyl, —CO ₂ R ⁹ CON (R ⁹ ) ₂ or —SO ₂ R ⁹ may be substituted, wherein R ⁹ is as defined above. 13. The compound of claim 12, wherein R ⁸ is C ₁ -C ₄ alkyl, biphenyl or bicyclic heteroaryl, or a 5-7 membered heterocyclic group, phenyl, -CO ₂ R ⁹ CON (R ⁹ ) ₂ or- SO ₂ R ⁹ may be substituted, wherein R ⁹ is as defined above. The compound of any one of claims 1-18, wherein X is NR ⁹ and R ⁹ is hydrogen or methyl, and R ⁸ is: One or more halo, phenyl optionally substituted with C ₁ -C ₆ alkyl or —O (C ₁ -C ₆ alkyl); C ₁ -C ₆ alkyl optionally substituted with aryl; or A compound characterized in that it is heteroaryl. The compound of claim 14, wherein R ⁸ is pyridyl optionally substituted with phenyl, benzyl or one or more halo, methyl or methoxy. [3- (Butane-1-sulfonyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (Butane-1- sulfonyl) -5-fluoro-2-methyl-indol- 1-yl] -acetic acid) 3- (biphenyl-4-sulfonyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid (3- (Biphenyl-4-sulfonyl) -5-fluoro-2-methyl-indol-1 -yl] -acetic acid) (3-carboxymethanesulfonyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid ((3-Carboxymethanesulfonyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid) (3-Carbamoylmethanesulfonyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid ((3-Carbamoylmethanesulfonyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid) [5-Fluoro-3- (2-methanesulfonyl-ethanesulfonyl) -2-methyl-indol-1-yl] -acetic acid ([5-Fluoro-3- (2-methanesulfonyl-ethanesulfonyl) -2-methyl -indol-1-yl] -acetic acid) [5-Fluoro-3- (2-methanesulfonyl-ethanesulfonyl) -2-methyl-indol-1-yl] -acetic acid () [3- (benzothiazole-2-sulfonyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (Benzothiazole-2-sulfonyl) -5-fluoro-2-methyl- indol-1-yl] -acetic acid) [3- (benzothiazole-2-sulfinyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (Benzothiazole-2-sulfinyl) -5-fluoro-2-methyl- indol-1-yl] -acetic acid) [5-Fluoro-2-methyl-3- (quinolin-2-sulfonyl) -indol-1-yl] -acetic acid ([5-Fluoro-2-methyl-3- (quinoline-2-sulfonyl) -indol- 1-yl] -acetic acid) [5-Fluoro-2-methyl-3- (quinolin-2-ylsulfonyl) -indol-1-yl] -acetic acid ([5-Fluoro-2-methyl-3- (quinolin-8-ylsulfonyl) -indol- 1-yl] -acetic acid) (5-Fluoro-2-methyl-3-phenylmethanesulfonyl-1H-indol-1-yl) -acetic acid ((5-Fluoro-2-methyl-3-phenylmethanesulfonyl-1H-indol-1-yl) -acetic acid) [3- (4-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (4-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol -1-yl] -acetic acid) [3- (3-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (3-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol -1-yl] -acetic acid) [3- (4-Fluoro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (4-Fluoro-phenylsulfamoyl) -5-fluoro-2-methyl-indol -1-yl] -acetic acid) [3- (2-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (2-Chloro-phenylsulfamoyl) -5-fluoro-2-methyl-indol -1-yl] -acetic acid) (3-benzylsulfamoyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid ((3-Benzylsulfamoyl-5-fluoro-2-methyl-indol-1-yl) -acetic acid) [5-Fluoro-3- (2-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic acid ([5-Fluoro-3- (2-methoxy-phenylsulfamoyl) -2-methyl- indol-1-yl] -acetic acid) [5-Fluoro-3- (4-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic acid ([5-Fluoro-3- (4-methoxy-phenylsulfamoyl) -2-methyl- indol-1-yl] -acetic acid) (5-Fluoro-2-methyl-3-phenylsulfamoyl-indol-1-yl) -acetic acid ((5-Fluoro-2-methyl-3-phenylsulfamoyl-indol-1-yl) -acetic acid) [3- (3,4-Dichloro-benzylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (3,4-Dichloro-benzylsulfamoyl) -5-fluoro-2 -methyl-indol-1-yl] -aceticacid) [5-Fluoro-3- (3-methoxy-phenylsulfamoyl) -2-methyl-indol-1-yl] -acetic acid ([5-Fluoro-3- (3-methoxy-phenylsulfamoyl) -2-methyl- indol-1-yl] -acetic acid) (5-fluoro-2-methyl -3- m-tolyl-sulfamoyl-indol-1-yl) acetate ((5-Fluoro-2- methyl-3-m-tolylsulfamoyl-indol-1-yl) -acetic acid ) (5-fluoro-2-methyl -3- p-tolyl-sulfamoyl-indol-1-yl) acetate ((5-Fluoro-2- methyl-3-p-tolylsulfamoyl-indol-1-yl) -acetic acid ) [3- (4-Chloro-benzylsulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (4-Chloro-benzylsulfamoyl) -5-fluoro-2-methyl-indol -1-yl] -acetic acid) [3- (Benzyl-methyl-sulfamoyl) -5-fluoro-2-methyl-indol-1-yl] -acetic acid ([3- (Benzyl-methyl-sulfamoyl) -5-fluoro-2-methyl-indol- 1-yl] -acetic acid) [5-Fluoro-2-methyl-3- (pyridin-3-ylsulfamoyl) -indol-1-yl] -acetic acid ([5-Fluoro-2-methyl-3- (pyridin-3-ylsulfamoyl) -indol -1-yl] -acetic acid); Or C ₁ -C ₆ alkyl, aryl, (CH ₂ ) mOC (═O) C ₁ -C ₆ alkyl, (CH ₂ ) mN (R ¹¹ ) ₂ , CH ((CH ₂ ) mO (C═O) R ¹² ) any one of _two esters; Wherein m is 1 or 2; R ¹¹ is hydrogen or methyl; R ¹² is C ₁ -C ₁₈ alkyl. In the compound of the general formula (I) according to any one of claims 1 to 13 or 16, in the method for producing a compound represented by the general formula (I) wherein n is 1 or 2, X is a bond, A process comprising treating a compound of formula (Ia) oxidized with a suitable oxidant, wherein n is 0 and X is a bond in the compound of formula (I). The method according to any one of claims 1 to 16, wherein the method for producing a compound of formula (I) comprises reacting a compound of formula (II) of claim 2, wherein R ¹⁰ is a base. A process for producing a C ₁ -C ₆ alkyl group. The compound according to any one of claims 1 to 16, which is used for medical purposes. 17. The compound of any one of claims 1 to 16, wherein the allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity reactions (including contact dermatitis), conjunctivitis, in particular allergic conjunctivitis, eosinophilic bronchitis Food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative proctitis, Crohn's disease, mastocytosis, and other PGD2-mediated diseases, such as autoimmune diseases such as hyper IgE syndrome and systemic lupus erythematosus, Psoriasis, acne, multiple sclerosis, organ rejection, reperfusion injury and chronic obstructive pulmonary disease; Compounds for the treatment of rheumatoid arthritis, psoriatic arthritis or osteoarthritis. 17. The use of the compound of any one of claims 1 to 16, in which allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity (including contact dermatitis), conjunctivitis, in particular allergic conjunctivitis, eosinophilia Constituent bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative proctitis, Crohn's disease, mastocytosis, another PGD2-mediated disease, for example autoimmunity such as hyper IgE syndrome and systemic lupus erythematosus Diseases, psoriasis, acne, multiple sclerosis, transplant rejection, reperfusion injury and chronic obstructive pulmonary disease; Use of a compound for the manufacture of a medicament for the treatment or prevention of rheumatoid arthritis, psoriatic arthritis or osteoarthritis. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 16 together with a pharmaceutical excipient or carrier. 23. The composition of claim 22 for oral, rectal, nasal, bronchial (inhaling), topical (eye, buccal and sublingual), vaginal or parenteral (including subcutaneous, muscle, vein and skin) administration. Formulated composition. The composition of claim 23 prepared for oral, nasal, bronchial or topical administration. The composition of any one of claims 22-24, wherein the composition comprises one or more additional active ingredients useful for the treatment of diseases and conditions regulated by PGD ₂ in the CRTH2 receptor. The composition of claim 25, wherein said additional active ingredient is selected from the group below: Β2 agonist such as salmeterol; Inflammatory agents such as fluticasone; Antihistamines such as loratidine; Leukotriene agonists such as montelukast; Anti-IgE antibodies, such as omalizumab; Anti-inflammatory agents such as fusidic acid (particularly for treating atopic dermatitis); Antifungal agents such as clotrimazole (particularly for treating atopic dermatitis); Immunosuppressive agents such as tacrolimus and pimecrolimus, particularly in the case of inflammatory skin diseases; Other agonists of PGD ₂ that act on other receptors, such as DP agonists; Inhibitors such as cyronilast; Type 4 phosphodiesterase inhibitors such as cyronilast; TNF

Drugs that regulate cytokine production, such as converting enzyme (TACE) inhibitors; Blocking Drugs that regulate the activity of Th2 cytokines IL-4 and IL-5, such as monoclonal antibodies and water soluble receptors. PPAR- [gamma] agonists such as rosiglitazone; 5-lipoxygenase inhibitors such as zileuton; 27. A method of preparing a pharmaceutical composition of any one of claims 22-26 comprising binding or linking a compound of any one of claims 1-16 with a pharmaceutically or veterinary acceptable carrier. Pharmaceutical composition manufacturing method. 17. A combination formulation for simultaneous, separate or collective therapeutic uses for a disease or condition mediated by the action of PGD ₂ at the compound of any one of claims 1 to 16 and a pseudoreceptor inducer (CRTH2) receptor. A product comprising at least one active agent as listed in claim 26. The use of claim 21, wherein the medicament comprises an additional effective drug useful for the treatment of a disease or condition mediated by the action of PGD _{2 at} the pseudoreceptor inducer (CRTH2) and / or DP receptor. 30. The use of claim 29, wherein said additional effective drug is one of the agents listed in claim 26.

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